Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[N:5]=1)=O.[OH-].[K+:18]>C(O)C>[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[O:16])[C:11]([O-:13])=[O:12])[N:5]=1.[K+:18]
Reactant: CCOC(=O)C(=O)c1nccc(NC=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccnc(C(=O)C(=O)[O-])n1
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate obtained in Preparation 6-(1) was dissolved in ethanol (30 ml.) and thereto was added dropwise 1 N ethanol solution of potassium hydroxide (11 ml.) under ice-cooling with stirring, and then stirring was continued for 2 hours at ambient temperature. The reaction mixture was filtered and the filtered precipitates were washed successively with a small amount of ethanol and diethyl ether and then dried to give a brown powder of potassium 2-(4-aminoprimidin-2-yl)-glyoxylate (0.4 g.). The filtrate and washings were combined together and concentrated to the volume of about 15 ml, and to the residue was added diethyl ether (20 ml.). The precipitates were collected by filtration and washed successively with a small amount of ethanol and diethyl ether to give further a pale brown powder of a mixture of potassium 2-(4-aminopyrimidin-2-yl)-glyoxylate and its monohydrate (0.8 g.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10]1(N)CC[CH2:11]1.C(N)C>>[CH:1]1([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH2:11][CH2:10][CH2:2]1
Reactant: CCNC(=NC#N)SC
Reactant: NC1CCC1
Agent: CCN
Product: CSC(=NC#N)NC1CCC1

Procedure:
1-Cyclobutyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except that cyclobutylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 1.62-1.79 (m, 2H), 1.92-2.08 (m, 2H), 2.29-2.45 (m, 5H), 4.11 (br s, 1H), 6.74 (br s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[C:15](O)=O.O.[OH-].[Na+]>C1COCC1>[N:7]1[CH:8]=[CH:9][CH:10]=[C:15]([CH:8]2[CH2:9][CH:10]3[CH2:13][CH2:14][N:7]2[CH2:12][CH2:11]3)[CH:12]=1
Reactant: O=C(O)C1CC2CCN1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cncc(C2CC3CCN2CC3)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 180.6 %

Procedure:
Lithium aluminum hydride (0.1 mol, 3.9 g) was suspended in THF (200 mL) in a 50 mL flask at 0° C. (VI) (0.03 mol, 5.76 g) was added in small portions. After the addition, the reagents were refluxed under a nitrogen atmosphere for 12 hours, cooled to 0° C. followed by dropwise addition of water (3.8 mL) and NaOH (3.9 mL of a 15% aqueous solution). After stirring for 30 minutes, water (12 mL) was added to the reaction mixture followed by additional stirring for 30 minutes. The reaction mixture was filtered, and hot THF was used for additional washings of the precipitate. The filtrate obtained was dried over anhydrous potassium carbonate and filtered again. Removal of THF on a rotary evaporator yielded (VII) as a colorless oil (5.1 g). Distillation at 0.3 mm Hg yielded (VII) (2.75 g) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2F)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (600 mg, 1.7 mmol) and 3-chloroindole-6-carboxylic acid (367 mg, 1.9 mmol) afforded, after purification (SiO2: 10 DCM: 2 EtOAc: 2 Hexane: 0 to 0.125 isopropyl amine), 800 mg (90%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[CH:7]=1)[CH3:2].Cl[CH2:15][C:16](=[O:18])[CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:15][C:16](=[O:18])[CH3:17])[CH:7]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)Cc1cccc(S)c1
Product: CCOC(=O)Cc1cccc(SCC(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 1, using the following starting materials: (3-mercapto-phenyl)-acetic acid ethyl ester and chloroacetone.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N.[C:22]1([C:28]2([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:36]([N:43]1[CH2:47][C@H:46]2[CH:48]([NH2:51])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@H:48]([NH:51][C:33]([C:28]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:35])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Hydroxybenzotriazole (33 mg, 0.24 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (43 μL, 0.24 mmol) were added to a solution of 1-phenylcyclopentanecarboxylic acid (46 mg, 0.24 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature for 10 minutes, then (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (52 mg, 0.24 mmol) was added and the reaction stirred at room temperature overnight. The reaction was quenched with water, and extracted with dichloromethane, then purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/chloroform as eluent to give the title compounds.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[I:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH3:22])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1nc(Nc2ccc(I)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(I)cc2)sc2ncccc2c1=O
Yield: 62.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.36 mmol) of 2-(4-iodoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 23 mg of lithium hydride and 402 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 580 mg of 2-[(4-iodophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (62%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:14][CH:13]=1.CCCCCCC.C(OCC)(=O)C.C(O)C#C>ClCCl>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C#CCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: C#CCO
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C#CC=O)cc1
Yield: 57.1 %

Procedure:
Pyridinium chlorochromate (22.1 g; 102.6 mmol; 2 eq) was added to a stirred solution of 3-p-tolylprop-2-yn-1-ol (7.5 g; 51.3 mmol) in dichloromethane (200 mL) at room temperature under nitrogen. The mixture was stirred for 4 h until TLC (2:1 heptane/ethyl acetate) indicated the disappearance of the starting propargyl alcohol. The mixture was then filtered through a bed of celite, and the filter cake was rinsed with dichloromethane (100 mL). The dichloromethane was concentrated using a rotary evaporator to give the desired product (4.22 g; 29.3 mmol; 57%) which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 3 H) 7.20 (d, 2H) 7.50 (d, 2H) 9.41 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C@H:15]([CH3:29])[CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C@H:15]([CH3:29])[CH2:16][CH2:17][O:18][Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:27])[CH3:28])[CH:10]=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCC[C@@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: -75 °C
Reaction time: 0.75 h

Procedure:
A solution of 3.35 g methyl 2(S)-tert-butoxycarbonylamino-4(S)-methyl-6-triisopropylsilyloxyhexanoate in 44 ml of toluene is cooled to -75° C. under argon, and 12.9 ml of a 20% solution of diisobutylaluminium hydride in toluene are then added dropwise in the course of 30 min. The mixture is stirred at -75° C. for a further 45 min. The reaction is then quenched by rapid addition of 2.8 ml of methanol and the mixture is poured onto 50 ml of a half-saturated aqueous potassium sodium tartrate solution. The mixture is extracted with diethyl ether and the combined organic phases are dried over sodium sulfate and concentrated. The title compound (Rf (E)=0.34) is further reacted directly as the crude product.
Reaction SMILES: [Cl-].P1CCCCCCCC1.P(OC)(OC)OC.[C:18]1([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21](C=O)=[CH:20][CH:19]=1>>[C:18]1([CH:26]=[CH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Agent: C1CCCCPCCC1
Agent: COP(OC)OC
Agent: [Cl-]
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
To improve the performance it was decided to synthesise distyrylbenzene (8). (Scheme 2) which should give emission at a longer wavelength, be a solid and have the required lack of symmetry and the necessary polymer compatibility. The first step in the synthesis of (8) was the reduction of (5) with lithium aluminium hydride under standard conditions to give the alcohol (9) in 82% yield. The alcohol (9), dissolved in 1,4-dioxane, was treated with concentrated hydrochloric acid to yield (10) in 89% yield. The chloride (10) was converted into the phosphonane (11) in 55% yield by treatment with trimethyl phosphite at reflux. The phosphonate (11) was coupled with 4-stilbenecarbaldehyde (12) under the same conditions used to form (4) and the distyrylbenzene (8) was isolated in 73% yield. ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=O)[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:38][CH:37]=3)=[O:15])[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)c[nH]c1-c1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a suspension of 5-[4-chloro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylic acid (0.36 g, 1.2 mmol) in dichloromethane (5.0 ml) was added oxalyl chloride (0.3 ml, 3.5 mmol). The mixture was stirred at room temperature for 1.0 h, after which time the solvent was removed on a rotary evaporator. To this brown residue was added THF (5.0 ml), 4-(methanesulfonyl)aniline hydrochloride (0.3 g, 1.4 mmol), and DIEA (0.81 ml, 4.8 mmol). The solution was stirred at room temperature for 3.0 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. To the residue was added IPE and triturated. The solid was filtered to give the title compound (0.24 g, 44%).
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=1N.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=1[Cl:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To anhydrous copper(II)chloride (6.3 g, 47 mmol) in acetonitrile (100 mL) was added tert-butyl nitrite (6.85 mL, 58 mmol), followed dropwise by a solution of 2-bromo-4-(trifluoromethoxy)aniline (10 g, 39 mmol) in acetonitrile (15 mL). The solution was stirred at ambient temperature for 1 hour then poured into hydrochloric acid (250 mL, 2M). The suspension formed was extracted with diethyl ether (2×250 mL) and the extracts were dried (MgSO4). Concentration yielded the title compound as an oil (7.82 g, 28 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:14][C:12]1[CH:13]=[C:8]([Cl:7])[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:11]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
Morpholine (5.0 g) was added to a suspension of 2,4,6-trichloropyridine (10.0 g) and sodium carbonate (5.9 g) in acetonitrile (100 mL). The reaction mixture was then stirred at 70° C. for 16 hours, cooled to ambient temperature, filtered through celite and concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 4:1) to furnish 3.90 g (30% yield) of the title compound as an off-white solid. LC-MS (m/z) 323.8 (M+); tR=3.10, (UV, ELSD) 98.5%, 98.9%. 1H NMR (500 MHz, CDCl3): 3.50 (m, 4H), 3.80 (m, 4H), 6.45 (s, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CCOC(=O)CCc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc2ccccc2c1

Procedure:
Following a procedure similar to that described in the first part of Preparation 4, the whole of this ethyl 3-(2-naphthyl)propionate was reacted with 668 mg of lithium aluminum hydride in tetrahydrofuran at room temperature for 1.5 hours. At the end of this time, the reaction mixture was worked up and purified as described in the first part of Preparation 4, to give 3.29 g of 3-(2-naphthyl)propanol as a colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.C(N(CC)CC)C.C(Cl)(Cl)=S.[Cl-:54].[Na+].CN(C)C=[O:59]>O>[CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.[CH2:36]1[C:37](=[O:38])[N:39]([Cl:54])[C:40](=[O:59])[CH2:41]1
Reactant: [Cl-]
Reactant: CN(C)C=O
Agent: NCCNC(=O)Cc1cccc(NC(=O)Cc2ccc(Nc3ncnc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1Cl

Procedure:
ADAC, 25 mg, 43 micromol, and 6 microliters triethylamine were dissolved in 1 ml dimethylformamide with warming. After cooling in an ice bath, 3.9 microl, 51 micromol of distilled thiophosgene was added with stirring. Water and saturated sodium chloride were added to obtain a white precipitate, which was dried in vacuo over sodium hydroxide. The yield was 13 mg, or 48%, of product. IR peaks appeared at 3460, 2120, 1640, 1600, 1515, 1480, 1420, 1100, 1060, and 1030 cm-1. Thin layer chromatography and the Cf plasma desorption spectrum was consistent with the assigned structure and showed no evidence of residual ADAC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[N:10][C:11]=1Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[K].O.Cl>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:11]2[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:7]([Cl:14])[N:8]=[C:9]([Cl:13])[N:10]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
5-(2-Methoxyphenoxy)-2,4,6-trichloropyrimidine (4) (4.8 g; 15.6 mmol) was dissolved in dimethyl sulfoxide (45 ml). Potassium 4-t-butylbenzenesulfonamide (8.0 g; 32 mmol) was added to the mixture while being cooled on ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from ether, to thereby obtain 4.9 g (yield: 65%) of the title compound as colorless needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCC1=O.F[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>O>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:27][CH:28]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
1 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester, 10 ml of N-methylpyrrolidinone, 0.57 g of 4-fluorobenzonitrile and 0.96 g of potassium tert-butoxide are introduced into a 20 ml glass tube. The reaction medium is stirred for 5 min, water is added and extraction is carried out 3 times with diethyl ether. The organic phases are combined, washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of ethyl acetate from 3.5% to 35% in heptane. 0.9 g of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Mg+2].[Cl-].[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:10]([N:17]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C@H:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Temperature: 50 °C

Procedure:
Lithium aluminium hydride in THF (7.24 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.698 g), in THF (32 ml) with stirring under nitrogen keeping the temperature below 20° C. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (2.15 g, preparable as described in WO96/36636) in THF (3.92 ml) and toluene (2.32 ml) was added dropwise over approximately 30 minutes. The reaction mixture was stirred and boiled under reflux for 4.0 hours. The mixture was cooled to 0-5° C. in an ice/water bath whilst sodium hydroxide solution (2.48 g, 5%w/w) was added. The suspension was filtered. The residue was washed with THF (8 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil. This oil was analysed by GLC, Chiral HPLC and 1H nmr. The title compound contained 0.24% of the desfluoro compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)O)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 9.9 %

Procedure:
Using {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.74 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.57 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 10%) was obtained as an amorphous pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:13]=[C:12]([C:22]([O:24]C)=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[NH3:26]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[CH:13]=[C:12]([C:22]([NH2:26])=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: N
Reactant: COC(=O)c1cc(N2CCCCC2)nc2c1[nH]c1cc(OC)ccc12
Solvent: CO
Product: COc1ccc2c(c1)[nH]c1c(C(N)=O)cc(N3CCCCC3)nc12
Temperature: 75 °C
Yield: 87 %

Procedure:
A mixture of methyl 7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (15 mg, 0.044 mmol) and 7 N NH3 in MeOH (1.5 mL) in a sealed microwave tube was heated at 75° C. for 40 h. Removal of solvent to afford 7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (14 mg, 0.038 mmol, 87% yield) as a solid. MS (ESI) m/z 325.1 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.04 (1H, d, J=8.85 Hz), 7.21 (1H, s), 7.06 (1H, d, J=2.14 Hz), 6.82 (1H, dd, J=8.70, 2.29 Hz), 3.91 (3H, s), 3.49-3.62 (4H, m), 1.74-1.82 (4H, m), 1.66-1.73 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][N:24]4[C:28](=[O:29])[C:27]5=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]5[C:25]4=[O:34])[CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1
Reactant: Clc1ccc2c(c1)Cc1ccccc1[C@@H]1CNCCN21
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(Cl)cc3Cc3ccccc3[C@@H]2C1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-8-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 47%.