Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:12]>CS(C)=O>[NH2:12][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: N
Solvent: CS(C)=O
Product: Nc1cnc2ccccc2n1
Reaction time: 8 h

Procedure:
Three g. of 2-chloroquinoxaline (commercially available) was dissolved in 50 ml. of dimethylsulfoxide and heated on the steam bath while anhydrous ammonia was bubbled into the mixture. The mixture was heated and stirred overnight on the steam bath. It was poured into 150 ml. of a mixture of ice and water, and the solid which precipitated was collected by filtration. This solid was recovered starting material and was discarded. The filtrate was cooled in an ice bath and the solid which precipitated was filtered off. This solid was identified by infrared spectrum as the desired compound, 2-aminoquinoxaline. It was used as is without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].O.C[N+]1([O-])CC[O:25]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[O:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-5-vinyl-benzyl)-carbamic acid tert-butyl ester (2.7 g, 9.5 mmol) in acetone (20 mL) was added N-methylmorpholine-N-oxide monohydrate (1.5 g, 11 mmol) and a solution of 4% aq. osmiumtetraoxide (3.7 mL, 0.5 mmol). The reaction was stirred for 1 h, saturated aqueous Na2S2O3-solution was added and stirring was continued for one hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone/water (3:1, 40 mL) and NalO4 (4.0 g, 19 mmol) was added. After stirring for 2 h at ambient temperature, the reaction mixture was filtered, washed with EtOAc, extracted with EtOAc, dried (Na2SO4) and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 5.22 min.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][CH2:13][C:14]([O-])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([NH:9][NH:10][C:14](=[O:15])[CH2:13][CH2:12][C:11]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
The mixture of benzhydrazide (1.5 g, 11.0 mmol), butanedioic acid, monomethyl ester (2.0 g, 15 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.4 g, 12 mmol), N,N-diisopropylethylamine (3.8 mL, 22 mmol) and 4-dimethylaminopyridine (0.87 g, 7.2 mmol) in DMF (30 mL) was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed by brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (900 mg, 32.6%). LCMS calculated for C12H15N2O4 (M+H): 251.1. Found: 251.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8]2.[OH-:16].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[CH2:8][C@@H:7]([CH3:15])[C@H:6]([OH:16])[CH2:5]2
Reactant: [OH-]
Reactant: COc1ccc(OC)c2c1CC=C(C)C2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@H](C)[C@H](O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 (5.00 g, 24.5 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and treated with 1 M borane-tetrahydrofuran complex (24.5 mL, 24.5 mmol) and the resulting solution was stirred at room temperature for 4 h. Then, 12 mL of 3 N NaOH solution was added slowly to the stirring reaction solution followed by the addition of 6 mL of 30% aqueous hydrogen peroxide. After stirring for 30 min, the resultant mixture was diluted with 500 mL of ethyl acetate and washed by brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified on silica gel (30% ethyl acetate/hexane) to give 5 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@H:11]1[CH2:16][O:15][C@@H:14]([CH3:17])[O:13][C@H:12]1[CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O)=[O:4].O.NN>C(O)C>[NH2:19][CH2:18][C@H:12]1[C@@H:11]([CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:16][O:15][C@@H:14]([CH3:17])[O:13]1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-phthalimidomethyl-1,3-dioxane (54 mg) in ethanol (2 ml) was added hydrazine monohydrate (0.007 ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (chloroform:methanol:conc.aqueous ammonia=85:15:0.1) to give (2R,4R,5S)-4-aminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (13 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[CH:4]=[C:3]1[C:14]([OH:16])=O.CCN(CC)CC.[NH2:24][C:25]1[C:26]([O:40][CH3:41])=[C:27]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=1>>[C:31]([C:29]1[CH:28]=[C:27]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:26]([O:40][CH3:41])=[C:25]([NH:24][C:14]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])=[O:16])[CH:30]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1c(C(=O)O)cc2cccc([N+](=O)[O-])c21
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)c2cc3cccc([N+](=O)[O-])c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 86.4 %

Procedure:
A suspension of 1-methyl-7-nitroindole-2-carboxylic acid (220 mg, 1 mmol) in 5 mL of SO2Cl was heated at reflux for 3 h to give a yellow solution. The excess SO2Cl was removed by distillation and the resulting yellow solid was dissolved in 5 mL of dry THF. Et3N (0.21 mL, 1.5 mmol) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (327 mg, 1.2 mmol) were added successively and the mixture was stirred 12 h. The reaction mixture was extracted with EtOAc to give 410 mg (87%) of 1-methyl-7-nitroindole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide.
Reaction SMILES: O=[C:2]([NH:13][C:14]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]>CC(O)=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:2]1[CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccn1
Solvent: CC(=O)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccn1
Reaction time: 72 h

Procedure:
A solution of (S)-tert-butyl 1-oxo-1-(3-(pyridin-2-ylamino)pyridin-2-ylamino)-propan-2-ylcarbamate (0.5432 g, 1.520 mmol) in AcOH (5.07 mL) was heated at 100° C. with stirring. After 3 days, the mixture was concentrated in vacuo to provide tert-butyl 1-(1-(pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethylcarbamate as a brown syrup: LC-MS (ESI) m/z 340.1 [M+H]+. Epimerization occurred. The crude product was used without further purification. 1-(1-(Pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethanamine
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([N:14]=[C:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1COCC1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:15]([NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: Nc1nccs1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nccs1

Procedure:
A 2-amino-thiazole derivative is condensed with a benzylisocyanate by heating with a basic catalyst (typically DMAP) in an inert organic solvent (typically THF or NMP) to afford the corresponding 1-(thiazol-2-yl)-3-benzyl-urea, which is purified by silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.[O:18](C(C(F)(F)F)=O)[C:19]([C:21]([F:24])([F:23])[F:22])=O>FC(F)(F)C(O)=O>[F:22][C:21]([F:23])([F:24])[C:19]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=[C:19]2[C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1)=[O:18]
Reactant: COc1ccc(Nc2ccc(N)nc2)c(N)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(NC(=O)C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of N5-(2-Amino-4-methoxy-phenyl)-pyridine-2,5-diamine (150 mg, 0.65 mmol) in trifluoroacetic acid (5 ml) was added (CF3CO)2O (5 ml). The resultant solution was allowed to stir at 80° C. for 4 hours. The reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). The mixture was concentrated under reduced pressure on a rotary evaporator. The reaction mixture was then quenched by adding 30 ml of 10% NaHCO3. The resultant solution was extracted three times with 50 ml of EtOAc and the organic layers were combined and dried over Na2SO4. After removal of the drying reagent by filtration, the crude product, 2,2,2-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyridin-2-yl]-acetamide (ff), was obtained by removal of the solvent under reduced pressure and it was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[Cl-].[NH4+:16]>C(O)C.N>[NH2:16][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Clc1ncncc1Oc1ccccc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: Nc1ncncc1Oc1ccccc1

Procedure:
4-Chloro-5-phenoxy pyrimidine is dissolved in absolute ethanol saturated with ammonia and added ammonium chloride, and heated in a stainless steel pressure bomb at about 160°C. for approximately 6 hours. The ethanol is removed under vacuum, and the oily residue taken up in ether. Concentration of the ether extract gives 4-amino-5-phenoxy pyrimidine as a yellow solid which is taken up in hot ethyl acetate, treated with activated charcoal, filtered and cooled to provide white crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[NH:40][CH:39]=[CH:38][C:35]3=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[NH:40][CH:39]=[CH:38][C:35]6=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5cc[nH]c5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (PepTech, Burlington, USA) to give the title compound as a white solid. (HPLC: tR 2.03 min (Method A); M+H=410 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.52 (s, 1H), 8.96 (s, 1H), 8.43-8.41 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.10 (m, 1H), 8.00-7.95 (m, 1H), 7.83-7.81 (m, 1H), 7.72-7.69 (m, 1H), 7.60-7.58 (m, 1H), 6.60-6.58 (m, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: BrC1C=CC=C2C=1C=C(O)N=C2.BrC1C=C2C(C=C(O)N=C2)=CC=1.[Br:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[CH:33](OC)OC)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:40]=[C:39]2[C:29](=[CH:28][CH:27]=1)[CH:30]=[N:31][C:32]([OH:38])=[CH:33]2
Reactant: COC(OC)C(=O)NCc1ccc(Br)cc1
Agent: Oc1cc2c(Br)cccc2cn1
Agent: Oc1cc2ccc(Br)cc2cn1
Product: Oc1cc2cc(Br)ccc2cn1

Procedure:
The title compounds was obtained as a yellow solid following the procedure for 5-bromoisoquinolin-3-ol and 7-bromoisoquinolin-3-ol, using N-(4-bromobenzyl)-2,2-dimethoxyacetamide. 1H NMR (400 MHz, DMSO-d6): δ=6.87 (s, 1H), 7.42 (dd, J=2.0 & 8.4 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 8.93 (s, 1H), 11.07 (brs, 1H). MS(ES+): m/z=224.04/225.93 (88/100) [MH+]. HPLC: tR=2.41 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-])=O)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 8 h

Procedure:
To a 100 mL RBF was added (S)-tert-butyl methyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate (1.75 g, 4.34 mmol) and palladium, 10 wt. % on activated carbon wet (0.923 g, 0.868 mmol) under nitrogen. MeOH was added via syringe, and the atmosphere was purged with hydrogen from a balloon. The reaction was allowed to stir rapidly under hydrogen for 8 h. The flask was purged with nitrogen, filtered through celite, rinsing with 100 mL MeOH, and concentrated to give (S)-tert-butyl 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate as a gray solid. MS m/z=374 [M+H]+. Calc'd for C18H26F3N3O2: 373.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([CH3:33])[C:11]([NH:13][CH:14]2[C:20](=[O:21])[NH:19][C:18]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:17]=3[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([CH3:33])[C:11]([NH:13][CH:14]2[C:20](=[O:21])[N:19]([CH3:34])[C:18]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:17]=3[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: CI
Product: C[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O

Procedure:
Prepared from (2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(7-chloro-2-oxo-5phenyl-2,3dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide by treatment with methyl iodide (c.f Step 2B, Scheme 2) (1H, CDCl3) 1.27 (3H, d, J=7 Hz), 2.68 (2H, m), 2.96 (1H, m), 3.43 (3H, s), 5.41 (1H, d, J=7.9 Hz), 7.05 (1H, m), 7.14 (1H, m), 7.32–7.36 (4H, m), 7.41 (2H, m), 7.48 (1H, m), 7.54–7.58 (3H, m); MS(CI+): MH+:516.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].C([O-])([O-])=O.[Ca+2]>OCC(CO)O>[OH:6][C:5]1[C@@H:7]([C@@H:9]([OH:10])[CH2:11][OH:12])[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: OCC(O)CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 20 h

Procedure:
3 ml of the seed culture were transferred into 500 ml Erlenmeyer flasks containing 50 ml of the production medium containing 8.0% L-sorbose, 5.0% baker's yeast, 0.05% glycerol, 0.25% MgSO4.7H2O, 3.0% corn steep liquor, 1.5% CaCO3 and 0.15% antifoam. The cultivation was carried out at 30° C. with 180 rpm for 20 h on a rotary shaker. As a result, 407.1 mg/L of vitamin C was produced.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:22]=[C:15]3[C:16]([O:18]C(=O)[NH:20][C:14]3=[CH:13][CH:12]=2)=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:16](=[O:18])[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([S:8](=[O:9])(=[O:10])[NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:22]=2)[NH2:20])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CCCCC3)cc2c(=O)o1
Solvent: CCO
Product: CN1CCN(C(=O)c2cc(S(=O)(=O)NC3CCCCC3)ccc2N)CC1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-cyclohexylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-cyclohexylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 167°-168° (from ethanol). The hydrochloride melts at 263°-264°.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.[OH-].[Li+].CO>O1CCOCC1.O>[Br:10][C:8]1[C:7]([O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1ncc(C(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson et al., J. Org. Chem. 49 (1984), 5237-5243; 2.00 g, 8.13 mmol) was dissolved in dioxane (40 ml), lithium hydroxide (40 ml of a 1 M solution in water) was added and subsequently sufficient methanol to achieve complete dissolution. The mixture was stirred at 60° C. for 2 h.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.Cl.[Pd]>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[C:11]3([O:14][C:15](=[O:23])[C:16]=2[CH:21]=1)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1OC2(CCNCC2)c2ccc(F)cc21
Temperature: 25 °C
Yield: 94.9 %

Procedure:
1′-Benzyl-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (0.622 g, 2 mmol) was suspended in ethanol (6 ml). The mixture was acidified with a few drops of HCl 37%. Pd/C 10% (65 mg, 0.06 mmol) was added. The mixture was refluxed under an hydrogen atmosphere for 1 hour then cooled to room temperature, purged with argon and diluted with dichloromethane. The catalyst was filtered and the filtrate was concentrated in vacuo. The white solid was dissolved in water (20 ml). The solution was basified with a 2M Na2CO3 solution and extracted 3 times with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield 0.42 g (96%) 5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one as a white solid. MS m/e: 222 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2.12 g (32.5 mmol) of potassium cyanide were added to 6.90 g (16.3 mmol) of the compound from Example 52A in 345 ml of DMF. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 5.05 g (87% of theory) of the target compound were obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38]>CN(C=O)C>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:38]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccccn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccn1

Procedure:
Reaction of the 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole described in Example 1 above with sodium hydride in DMF, and reaction of the resulting sodium salt with 2-pyridine carbonyl chloride using the procedure described above in Example 1 affords 1-(2-pyridylcarbonyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C.[Cl:29][C:30]([F:35])([F:34])[C:31](O)=[O:32]>ClCCl>[Cl:29][C:30]([F:35])([F:34])[C:31]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:32]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)(F)Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reaction time: 8 h
Yield: 23.9 %

Procedure:
In 5 ml of dichloromethane, 200 mg (2.13 mmol) of 2-aminopyridine was dissolved. To this solution, 491 mg (2.55 mmol) of EDC-HCl, 311 mg (2.55 mmol) of dimethylaminopyridine, and 187 μl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added in this order, followed by stirring overnight. After completion of the reaction, the reaction liquid was diluted with dichloromethane, washed with water and with 1% hydrochloric acid, and then dried over anhydrous magnesium sulfate. Thus, 105 mg of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide was obtained (Percentage Yield: 24%).