Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[I:11](Cl)Cl)([O-:3])=[O:2].[OH-:14].[Na+]>>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[I:11]=[O:14])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1I(Cl)Cl
Agent: [Na+]
Product: O=Ic1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Nitro-4-chloro(dichloroiodo)benzene (2.0 g) was added to 100 mL of cold (about 5° C.) 20 percent aqueous solution of sodium hydroxide. The mixture was stirred for 0.5 hr, and the desired orange product was subsequently isolated by filtration and air dried; yield, 1.13 g; m.p. 118° C. (decomposed (dec.)).
Reaction SMILES: [N:1]([CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17].C(Cl)Cl>C(O)(=O)C>[CH3:15][N:16]([CH3:18])[NH:17][C:2]([NH:1][CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])=[O:3]
Reactant: CCOC(=O)C(N=C=O)c1cccs1
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)NC(=O)NC(C(=O)O)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.02 mole) of DL-α-isocyanato-2-thiopheneacetic acid, ethyl ester and 1.2 g. (0.02 mole) of N,N-dimethylhydrazine in 80 ml. of methylene chloride is stirred overnight. The solution is concentrated and to the syrupy residue are added 10 ml. of 2N sodium hydroxide solution. After stirring for 30 minutes, a clear yellow solution results. By the addition of acetic acid, 3.9 g. of α-dimethylhydrazinocarbonylamino-2-thiopheneacetic acid are obtained, m.p. 208°-210°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:45][C:42]3[CH:43]=[CH:44][C:39]([N:36]4[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]4)=[CH:40][N:41]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A solution of 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (110 mg, 0.30 mmol) and 4-(6-amino-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg, 1.1 mmol) in toluene was heated at 100° C. for 10 hours and then cooled to room temperature. Diethyl ether was added to the reaction mixture and the product precipitated. This precipitate was collected by filtration and dried to provide 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 29%). M++1: Calc'd. 578.3, Found 578.4.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9]
Reactant: OCCO
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of n-butyllithium in hexanes (13.0 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (30 ml) at 10° C. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1-(2-methylphenyl)-1-phenyl-1-propene (9.3 g, 32 mmol) was added and the reaction mixture was stirred at room temperature for 100 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts was dried (Na2SO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and THF (4:1) as eluent provided 3.9 g (45%) of 2-(3-(2-methyl-phenyl)-3-phenyl-2-propen-1-yloxy)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CCC(C)=O>[CH3:19][C@@H:13]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccccc1F
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@@H](C)Oc1ccccc1F
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A reaction vessel was charged with 10 g of 2-fluorophenol, 25 g of (S)-1-methylhexyl tosylate, 20 g of potassium carbonate and 160 ml of MEK, and the mixture was refluxed with stirring for 14 hours (the disappearance of the starting materials was confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt, and the solvents were distilled off. The residue was distilled under reduced pressure to obtain 14 g (74.5%) of (R)-2-(1-methylhexyl)oxyfluorobenzene.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl.[NH2:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].Br[C:22]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>C(#N)C>[CH3:20][O:19][C:17](=[O:18])[C@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH:10][C:33]1[C:34]2[CH:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@H](Nc1cccc2c1C(c1ccccc1)c1ccccc1-2)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a stirred suspension of anhydrous Pb(NO3)2 (45.0 g, 138.7 mmol) and anhydrous K3PO4 (75.0 g, 353.3 mmol) in dry acetonitrile (300.0 mL) was added sequentially L-aspartic acid dimethyl ester hydrochloride of Example 1 (32.0 , 161.9 mmol) and 9-bromo-9-phenylfluorene (62.0 g, 193.2 mmol). The mixture which resulted was stirred for 20 h at room temperature and then filtered through celite. The filter cake was washed with chloroform (3×300.0 mL). The combined organic solvents were removed under reduced pressure and the residue oil was partitioned between ether (800.0 mL) and the solution of citric acid (5%, 200.0 mL). The ether layer was removed and the aqueous phase extracted with ether (3×200.0 mL). The combined organic layers were washed with brine (2×150.0 mL), dried (MgSO4) and then removed under reduced pressure. The residue was purified by a flash chromatograph (600.0 g silica gel, EtOAc/hexane, 1/10 to 1/4 ) to provide the product as a pale yellow oil (64.0 g).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].CN(C)C=O>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3ccccc23)CC1
Yield: 85.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-l H-indazole (4.0 g, 20 mmol), K2CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-ethanone, m.p.=155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][C:7]=1[CH3:8].C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][CH2:8][C:7]1[N:6]=[C:5]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c(CBr)n1
Yield: 116.1 %

Procedure:
Following the procedure of Example 2, the product from Example 25 (6.07 g, 22 mmol) was reacted with NBS (3.96 g, 22 mmol) in CH2Cl2 (150 mL). The crude title product (8.98 g, >100%) was obtained and used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:7]2
Reactant: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from 2-({1-bromo-6-[3-(3-methylbutanoyl)-1-benzofuran-2-yl]-2-naphthyl}oxy) acetonitrile (0.207 g, 0.448 mmol), sodium azide (0.147 g, 2.26 mmol) and ammonium chloride (0.125 g, 2.34 mmol) in DMF (10 mL). The compound was purified by HPLC using 75% acetonitrile/0.1% TFA in water. Drying for 14 hours at 90° C. yielded a cream-colored solid (0.0966 g), mp 176-177° C. Mass spectrum (−ESI, [M−H]−) m/z 503. 1HNMR (500 MHz, DMSO-d6): δ16.8-17.1 (br s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.25 (q, 2H, J=8.2 Hz), 8.0-8.05 (m, 2H), 7.75 (q, 2H, J=8.3 Hz), 7.4-7.5 (m, 3H), 5.8 (s, 2H), 2.7 (d, 2H, J=6.9 Hz), 2.05-2.15 (m, 1H), and 0.75 ppm (d, 6H, J=6.6 Hz). Elemental Analysis for C25H21BrN4O3.0.10 H2O: Calculated: C, 59.20; H, 4.21; N, 11.05. Found: C, 58.84; H, 3.80; N, 10.83.
Reaction SMILES: C([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18])C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:12]([O:13][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:13])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)=[O:18])[C:11]1[CH:15]=[CH:16][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: C1CCNCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and piperidine as the raw materials, the same operation as the example 84(3) gave the title compound.
Reaction SMILES: [C:1]([C:9](O)=[O:10])(=[O:8])C1C=CC=CC=1.[CH2:12]([OH:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([O:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:10])[CH:1]=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C=O
Yield: 162.8 %

Procedure:
A solution of 5 g of benzoylformic acid (glyoxalic acid), 11.3 g of octadecanol and 0.19 g of p-toluenesulfonic acid in 60 ml of toluene is heated at reflux for 22 hours. The mixture is poured into saturated NaHCO3 solution and the phases are separated. The organic phases are washed with water and dried over sodium sulfate. Filtration and evaporation of the solvent give octadecyl glyoxalate (17.7 g) as a yellow solid. The product is recrystallized from methanol to give slightly yellowish crystals (11.29 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:6]2[CH3:21].O.O.[Sn](Cl)Cl.O.N>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:21])[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4]3)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc([N+](=O)[O-])cc3)c2n1C
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc(N)cc3)c2n1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of 4.10 g (10.9 mmol) of ethyl 4-chloro-1-methyl-7-(4-nitrophenoxy)-2-indolecarboxylate, 12.34 g (54.7 mmol) of tin (II) chloride dihydrate and 150 ml of ethanol was stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature, 28% ammonia water was added to render alkaline and the mixture was extracted with ethyl acetate. Insoluble matters were filtered off. The filtrate was washed with 5% sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.70 g of ethyl 7-(4-aminophenoxy)-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:30]=2)=[O:28])[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>ClCCl>[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:30]=2)(=[O:9])=[O:28])[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1cccc(CS(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(CS(=O)(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (<86%, 62 mg, 0.31 mmol) is added to a solution of isobutyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-phenylsulfanylmethyl]-benzoate (73 mg, 0.16 mmol, example 85) in dichloromethane (1 mL) and the reaction is stirred overnight. The reaction is partitioned between ethyl acetate and sodium bicarbonate and the organic phase is washed with additional bicarbonate solution, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 30% ethyl acetate in hexanes) to provide the title compound. MS (ESI) 504 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:13][CH2:14][CH3:15])[C:22]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[C:25]([OH:24])=[O:26])=[O:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCNc1ccc(-n2ccnc2)cc1
Reactant: O=C1OC(=O)C2CCCCC12
Product: CCCN(C(=O)C1CCCCC1C(=O)O)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 6, react 4-(1H-imidazol-1-yl)-N-propylbenzenamine with 1,2-cyclohexanedicarboxylic acid anhydride to obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=4[NH:38][C:39]([C@@H:41]4[CH2:44][CH2:43][NH:42]4)=[O:40])[CH:23]=3)[C:15]=2[N:16]=1)(=[O:10])[CH3:9].[CH:45](=O)[CH:46]([CH3:48])[CH3:47]>>[C:8]([NH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:29]=4[NH:38][C:39]([C@@H:41]4[CH2:44][CH2:43][N:42]4[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:40])[CH:23]=3)[C:15]=2[N:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCN4)ncn3)cccc2s1
Reactant: CC(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCN4CC(C)C)ncn3)cccc2s1

Procedure:
The title compound was prepared by reacting (2S)-N-(2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)azetidine-2-carboxamide trifluoroacetic acid salt [Example 37(c)] with isobutyraldehyde (Aldrich) under the conditions of Example 3(d). MS (ESI, pos. ion.) m/z: 585 (M+1). Mp: 174.4-174.9° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-(1H-indol-5-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (90 mg, 0.23 mmol) in MeOH (20 mL) was added sodium hydroxide (40 mg, 0.93 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(1H-indol-5-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a brown solid (65.8 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=O)[C:14]([NH2:16])=O)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.C1COCC1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C(=O)C(N)=O)c2c1
Agent: B
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cccc(CCN)c2c1
Yield: 80 %

Procedure:
480 mg of the compound obtained in Step B dissolved in THF (20 ml) are introduced into a reactor, followed by 2 eq. of AlCl3 and finally, slowly, 6 eq. of BH3.THF solution, and the reaction mixture is stirred for 2.5 hours. Water (12 ml) is then added, followed by 25 ml of 1N sodium hydroxide solution together with 800 mg of solid sodium hydroxide, and three extractions with methyl tert-butyl ether (20 ml) are carried out. The solvents are then dried over Na2SO4 and then evaporated off to yield the title product in the form of a yellow oil in a yield of 80% and with a chemical purity of 95%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C(=O)O)c1Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nc(OCc2ccccc2)c(CO)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid (4.6 g) was dissolved in tetrahydrofuran (30 mL) and to the stirred solution was added dropwise 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (21 mL) under ice cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with ice bath and to the reaction mixture was dropwise added 50 mL of water. Then 1 mol/L hydrochloric acid (20 mL) was added dropwise to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 3.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([NH:9][NH2:10])=O)=[CH:5][N:6]=1.Cl.[CH3:12][NH:13][C:14](=NC)[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH3:12][N:13]1[C:14]([CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[N:10][N:9]=[C:7]1[C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1
Reactant: Cc1ncc(C(=O)NN)s1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2cnc(C)s2)n1C
Yield: 43 %

Procedure:
The title compound was prepared in analogy to the method described in Preparation 11 starting from 2-methyl-1,3-thiazole-5-carbohydrazide and N,N′-dimethyl-5-hexenimidamide hydrochloride in 43% yield by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: C1CCNC1
Reactant: O=Cc1cccc(Cl)c1F
Product: O=Cc1cccc(Cl)c1N1CCCC1

Procedure:
The title compound was synthesized from 3-chloro-2-fluorobenzaldehyde and pyrrolidine as described in Example 67, Step 1 (800 mg, 30%). 1H NMR 300 MHz (CDCl3) δ 10.36 (s, 1H), 7.71-7.73 (m, 1H), 7.59-7.61 (m, 1H), 7.18-7.26 (m, 1H), 3.33-3.42 (m, 4H), 2.01-2.10 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])[O:10][CH2:11][CH2:12][CH3:13])#[N:2].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:6]1[S:5][C:4]([N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])[O:10][CH2:11][CH2:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCOC(=Nc1sccc1C#N)OCCC
Solvent: c1ccncc1
Product: CCCOC(=Nc1sc(Cl)cc1C#N)OCCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a sulfonation flask, 3.02 g (0.012 mol) 3-cyano-2-(1,1-dipropoxymethylenamino)thiophene, are added, with stirring to 15 ml of absolute pyridine. The internal temperature is then raised to 60° C. and 1.9 g (0.0144 mol) N-chlorosuccinimide are added in three portions. After stirring for 3 hours at 60° C., the pyridine is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and after drying, the solvent is removed in a water jet vacuum. The crude product is purified by column chromatography over silica gel (eluant: tert.butylmethylether/hexane 1:6). Yield: 3.5 g of 5-chloro-3-cyano-2-(1,1-dipropoxymethyleneamino)thiophene in the form of brownish crystals, m.p. 55-57° C.