Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1 H), 8.57 (s, 1 H), 7.67 (s, 1 H), 7.21 (dd, J=8.6, 5.5 Hz, 2 H), 7.01 (t, J=8.7 Hz, 2 H), 4.39 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.65 (m, 2 H), 3.59 (m, 2 H), 3.41 (s, 3 H), 3.14 (t, J=7.0 Hz, 2 H), 2.95 (s, 3 H), 2.21 (m, 2 H); HRMS C23H26FN3O6S (M+H)+ calcd 492.1526, found 492.1603.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[N:9]=[C:10]([C:15]#[C:16][Si](CC)(CC)CC)[C:11]([NH2:14])=[N:12][CH:13]=1>CN1CCCC1=O.[Cl-].[Na+].O>[Cl:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC[Si](C#Cc1nc(Cl)cnc1N)(CC)CC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc2[nH]ccc2n1
Temperature: 80 °C

Procedure:
A solution of potassium tert-butoxide (1 g, 4.5 mM) in N-methylpyrrolidone (3 ml) was heated to 80° C. under nitrogen. A solution of 5-chloro-3-(triethyl-silanylethynyl)-pyrazin-2-ylamine (3) (1.2 g, 4.5 mmol) in N-methylpyrrolidone (10 ml) was added dropwise. The reaction mixture was stirred at 80° C. for a further fifty minutes and then the reaction mixture was allowed to cool to room temperature. Brine (10 ml) was added to the reaction mixture and extracted with ethyl acetate (5×20 ml). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solution in N-methylpyrrolidone. MS (ES+): 154
Reaction SMILES: ClC1C(C)=C(C(=O)C)C(O)=C(OCCCC2C=CC(F)=CC=2)C=1OC.Cl[C:27]1[C:28]([CH3:58])=[C:29]([C:55](=[O:57])[CH3:56])[C:30]([O:46][CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[C:31]([O:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42](F)=[CH:41][CH:40]=2)[C:32]=1[O:33][CH3:34]>>[CH3:34][O:33][C:32]1[CH:27]=[C:28]([CH3:58])[C:29]([C:55](=[O:57])[CH3:56])=[C:30]([O:46][CH2:47][CH2:48][N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)[C:31]=1[O:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCCc1ccc(F)cc1
Agent: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCCc1ccc(F)cc1
Product: COc1cc(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCCc1ccccc1

Procedure:
Example 33b was prepared in a using a similar method as used in the conversion from 1d to 1f. 1H NMR (300 MHz, CDCl3) δ 7.30-7.15 (m, 5H), 6.47 (s, 1H), 4.12 (t, J=5.7 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 3.69-3.66 (m, 4H), 2.81 (t, J=7.3 Hz, 2H), 2.62 (t, J=5.7 Hz, 2H), 2.52 (s, 3H), 2.47-2.44 (m, 4H), 2.20 (s, 3H), 2.09-2.00 (m, 2H). MS (ES+) m/z 428.0 (M+H+).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([CH:24]2[N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[CH2:27]1[C:26]2([CH2:29][CH2:30][NH:31][CH:24]([C:22]([NH:21][C@H:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][CH:15]=3)[CH3:20])=[O:23])[CH2:25]2)[CH2:28]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2C(=O)OC(C)(C)C)CC3)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2)CC3)cc1
Yield: 97.2 %

Procedure:
The title compound (D91) (96 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 5-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (D56) (130 mg).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12]/[C:13](/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:14]\[CH2:15][CH2:16][OH:17].O>N1C=CC=CC=1>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:17][CH2:16][CH2:15]/[CH:14]=[C:13](\[CH3:12])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])(=[O:3])=[O:2]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
Tosylchloride (3.51 g, 9 mmol) was added to a stirred solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienol (1.66 g, 7 mmol) in pyridine (30 mL) at 0° C. The resulting mixture was placed in a refrigerator overnight, then poured into cold water and extracted with ether. The ethereal extract was washed with diluted hydrochloric acid to remove pyridine. After drying and filtration, the filtrate was evaporated to afford the title compound as an oil which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Nc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: COc1ccc(Nc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
21.4 g of 3-amino-4-phenylaminoanisole was dissolved in 210 ml of pyridine. The solution was then ice-cooled. Thereto was dropwise added 12 g of methanesulfonyl chloride in 30 minutes. Stirring was conducted for 2 hours at 5°-10° C. The mixture was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 500 ml of water and 300 ml of ethyl acetate. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The organic layer was then subjected to distillation under reduced pressure to remove the solvent. Toluene was added to the residue, and the resulting crystal was filtered to obtain 23.9 g (yield: 81.8%) of 3-methylsulfonylamino-4-phenylaminoanisole having a melting point of 109°-111° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:20])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[ClH:21]>O1CCOCC1>[ClH:21].[F:20][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:10][NH:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(C2(F)CNC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate (compound 43.3, 1.00 g, 3.62 mmol) in dioxane (10 mL) and HCl in dioxane (4 M in dioxane, 10 mL, 40 mmol). The resulting mixture was stirred for 1 h at 60° C., then cooled and concentrated under reduced pressure. The residue was washed with EtOAc (20 mL) and the product solids were collected by filtration to yield 522 mg (68%) of the title compound as a white solid. m/z (ES+) 177 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.91 (d, J=7.8 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 4.85-4.52 (m, 4H).
Reaction SMILES: Cl.[Cl-].[CH3:3][N:4]([CH3:7])[CH2:5][CH3:6].[C:8]([NH2:13])([CH2:11][CH3:12])([CH3:10])[CH3:9]>>[C:8]([NH:13][CH2:6][CH2:5][N:4]([CH3:7])[CH3:3])([CH2:11][CH3:12])([CH3:10])[CH3:9]
Reactant: CCC(C)(C)N
Reactant: CCN(C)C
Agent: Cl
Agent: [Cl-]
Product: CCC(C)(C)NCCN(C)C
Yield: 59.6 %

Procedure:
Into a 300 mL-volume flask equipped with a stirrer and a thermometer were placed 20.6 g (143 mmol) of 2-(dimethylamino)ethane chloride hydrochloride and 74.0 g (859 mmol) of t-pentylamine. And then, the mixture was heated to reflux for 8 hours. After the completion of the reaction, the reaction mixture was filtrated and washed with 100 ml of hexane twice, and the hexane layer was concentrated under reduced pressure. The resultant concentrate was distilled under reduced pressure (120° C., 11.0 kPa), to provide 13.5 g of 1-t-pentylamino-2-dimethylaminoethane. (Isolation yield: 60%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17](N(OC)C)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[S:11][C:10]=1[C:17]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1sc(C(C)C)cc1OCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2sc(C(C)C)cc2OCc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
860 mg of 3-benzyloxy-5-isopropyl-N-methoxy-N-methylthiophene-2-carboxamide were dissolved in 50 ml of tetrahydrofuran (THF) and cooled to 0> C. in an ice bath, and 31.3 ml of 0.5 molar 4-methoxyphenymagnesium bromide solution in tetrahydrofuran were added. After 30 min, the ice bath was removed and the reaction mixture was warmed to 22° C. After one hour, 70 ml of saturated sodium bicarbonate solution were added to the reaction mixture, and it was extracted twice with 100 ml of methyl acetate each time. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[ClH:14].Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N.Cl>C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:14].[ClH:14].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][C:20]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:27][CH2:26]1)=[O:13]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)c3ccc4ccccc4n3)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a mixture of 2-quinolinecarboxylic acid (0.55 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (1.2 g) and N,N-dimethylformamide (20 ml) is added dropwise at room temperature diethyl cyanophosphonate (1.2 ml), followed by stirring for one hour. After addition of water (100 ml) and ethyl acetate (100 ml), the reaction mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:acetone=2:1-1:1) to give an oily product, which is led to its hydrochloride, followed by crystallizing from a mixture of methanol, ethyl acetate and ethyl ether to give 1-(2-quinolylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.4 g) as colorless crystals, m.p. 151°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]([CH3:21])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C>C1CCCCC1>[C:28]1([O:27][C:25]([N:8]2[C:7]([CH3:21])=[CH:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)=[N:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Yield: 57.9 %

Procedure:
15 g (45.7 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-5H-2,3-benzodiazepine are boiled in a mixture of 28.85 ml (228.5 mmoles) of phenyl chloroformate and 6.34 ml (45.7 mmoles) of triethylamine for 3.5 hours. The reaction mixture is diluted with 150 ml of cyclohexane, the solvent is decanted off the separated oily product, the residue is dissolved in dichloromethane, washed first with saturated sodium hydrogen carbonate solution, then with water and dried over anhydrous sodium sulfate. After evaporation the crude product is recrystallized from ethanol. Thus 11.86 g (58%) of the desired compound (yellow) melting at 188-190° C. are obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)O)=[CH:16][C:15]=1[F:29].FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[CH:16][C:15]=1[F:29]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)c(F)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.08 g (4.23 mmol) of the compound from Example 176A in analogy to the synthesis of the compound from Example 278. 460 mg (26% of theory) of the target compound were obtained.
Reaction SMILES: [NH:1]([C:8]1([C:21](OCC)=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1C=CC=CC=1>[NH:1]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing solution of 101.4 parts of ethyl 4-anilino-1-benzyl-4-piperidinecarboxylate in 640 parts of dry benzene is added dropwise a solution of 172 parts of sodium dihydro-bis(2-methoxyethoxy)aluminate 70% solution in benzene, in 160 parts of dry benzene. Upon completion, stirring is continued for 2h. 30 at 80° C. The reaction mixture is cooled, poured onto ice-water, alkalized with sodium hydroxide solution and the product is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol and ether. The salt is filtered off, boiled in 2-propanol and after cooling, the product is filtered off. It is boiled once more in acetonitrile and the salt is filtered off again after cooling. The free base is liberated in the conventional manner. After extraction with ether, the latter is washed with water, dried and evaporated, yielding 4-anilino-1-benzyl-4-piperidinemethanol as an oily residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23](OCC)=[O:24].O.[NH2:29][NH2:30]>C(O)C>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[C:13]([NH:12][C:7]1[C:6]2[N:5]=[CH:4][C:3]3[C:23](=[O:24])[NH:29][NH:30][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:22]
Reactant: NN
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Solvent: O
Solvent: CCO
Product: O=C(Nc1cccc2c1ncc1c(=O)[nH][nH]c12)c1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (297 mg) and hydrazine monohydrate (175 mg) in ethanol (3 ml) was refluxed for 1 hour. To the mixture was added ice-water, and the resulting precipitate was collected by filtration and washed with water to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1H-pyrazolo[4,3-c]-quinolin-3-one (250 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5]>C(O)C>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: CCO
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 65 °C

Procedure:
A 500 ml laboratory reactor is charged with 123.8 g of ethanol. Then 41.2 g of carnitine is added. The reactor is closed and heated up to 65° C. until all solids have been dissolved. The stirrer is set to 500 RPM.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[C:11]([CH3:12])[N:10]=1
Reactant: CSC(=S)NN=Cc1nc(C)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(C)n2c(=S)[nH]ncc12

Procedure:
A mixture of 30.26 gm. of 3-[(2,5-dimethyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 125 ml. of diphenyl ether is reacted as described in Example 58 giving a solid which is the desired product, m.p. 287.5°-290° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:4]([CH3:18])[N:3]=1.Cl.Cl[C:21]([NH2:23])=[NH:22]>COCCOCCOC>[NH2:23][C:21]1[N:22]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][C:4]([CH3:18])=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[N:6]=2)[N:1]=1
Reactant: N=C(N)Cl
Reactant: Cc1nc(N)c(C#N)nc1C(=O)c1ccccc1
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1nc2nc(N)nc(N)c2nc1C(=O)c1ccccc1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 7, using 2.1 grams (0.009 mole) of 2-amino-3-cyano-6-methyl-5-phenylcarbonylpyrazine and 0.9 gram (0.009 mole) chloroformamidine hydrochloride in 20 mL of diglyme, yielding 2,4-diamino-7-methyl-6-phenylcarbonylpteridine.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=[O:17].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[N:31]O)[CH2:26][CH2:25]2>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:17])[NH:31][CH2:26][CH2:25]2
Reactant: CS(=O)(=O)O
Reactant: COc1ccc2c(c1)CCC2=NO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorous pentoxide (1.0 g, 7.1 mmol) is added all at once to methanesulfonic acid (10 g, 104.1 mmol) and stirred for 3 hours at room temperature. 5-Methoxy-1-indanone oxime (100 mg, 0.53 mmol) is added in portions, with each portion allowed to dissolve completely before the next is added. The stirred reaction mixture is heated at 100° for 1.5 hours. The reaction is quenched by the addition of saturated sodium bicarbonate (10 ml) and extracted with 3×5 ml dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to yield the 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with boron tribromide (see example 1) yields 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[CH2:21]([O:20][C:18]([C@@H:17]1[CH2:2][C@H:16]1[C:13]1[CH:14]=[N:15][C:10]([Br:9])=[CH:11][CH:12]=1)=[O:19])[CH3:22]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(Br)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in small portions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO (400 mL) at rt., stirred for 1 h until clear solution was obtained. A solution of (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate (Intermediate F, 20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h. After completion, the reaction mixture was poured into ice water (700 mL), extracted with EtOAc (2×350 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4, filtered and evaporated to give (trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10 g, 47° A)) as brown liquid.
Reaction SMILES: CO[C:3](=[O:34])[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:10][CH:9]=1)=[CH:5]OC.S(O)(O)(=O)=O.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[NH2:45].C[O-].[Na+]>C(O)C>[C:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[C:3](=[O:34])[N:45]=[C:41]3[NH:42][CH:43]=[CH:44][N:40]3[CH:5]=2)=[CH:9][CH:10]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: Nc1ncc[nH]1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3cc[nH]c3nc2=O)cc1)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 48.2 %

Procedure:
To a mixture of 2-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-3-methoxy-acrylic acid methyl ester (97 mg, 0.2 mmol), 1H-imidazol-2-ylamine sulfate (29 mg, 0.223 mmol) and ethanol (10 mL) was added a solution of sodium methoxide (0.5 mL, 0.5 M in methanol, 0.25 mmol). The resulted mixture was refluxed for 18 h, additional 0.5 mL of sodium methoxide (0.5 M in methanol, 0.5 mmol) was added and continued to reflex for 20 h. The reaction was concentrated and diluted with EtOAc (30 mL) and washed with water (20 mL), brine (20 mL). The EtOAc solution was concentrated. The crude product was purified by flash chromatography (10% methanol in dichloromethane) to give desired product (48 mg, 48%) as white solid. 1NMR (300 MHz, CD3OD): δ 8.40 (s, 1H), 7.59 (br.s, 2H), 7.29 (m, 4H), 4.46 (s, 2H), 3.23 (m, 2H), 3.02 (m, 2H), 1.68 (m, 2H), 1.52 (br.d, 9H), 1. 42 (s, 9H). LCMS (EI) m/z: 498.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:23])=[N:4][C:5]2[CH:6]=[C:7]([N+:20]([O-])=O)[C:8]3[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.Cl>CN(C)C=O.[Ni]>[NH2:20][C:7]1[C:8]2[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:23])=[N:4][C:5]=2[CH:6]=1
Reactant: NS(=O)(=O)c1cccc2c1c([N+](=O)[O-])cc1nc(O)c(O)nc12
Agent: [Ni]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cc2nc(O)c(O)nc2c2cccc(S(N)(=O)=O)c12
Yield: 43.8 %

Procedure:
A solution of 0,5 g (1,49 mmol) 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline in 75 ml dimethylformamide was hydrogenated at atm. pressure by using ca. 1 g Ra-Ni as a catalyst. The filtered reaction mixture was added 5 ml 1N hydrochloric acid, and then evaporated in vacuo. The crude product was recrystallized (dimethylformamide-water) to give 0,2 g (40%) 6-amino-2,3-dihydroxy-7-sulphamoyl-benzo[f]quinoxaline as a hydrochloride salt.
Reaction SMILES: C[O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(-c3nnc(C(F)(F)F)o3)oc12
Agent: BrB(Br)Br
Product: Oc1cccc2cc(-c3nnc(C(F)(F)F)o3)oc12
Yield: 96.4 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(7-methoxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole (2.4 g) and boron tribromide (5.0 ml), the title compound (2.2 g) was obtained as yellow crystals.