Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].O.[C:16](=O)(O)[O-].[Na+].C[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]=1[C:33](Cl)=[O:34]>CC(C)=O>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[CH:6]([NH:9][C:33]([C:23]3[C:24]([C:27]4[CH:28]=[C:29]([CH3:16])[CH:30]=[CH:31][CH:32]=4)=[N:25][O:26][CH:22]=3)=[O:34])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3conc3-c3cccc(C)c3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68849.8 %

Procedure:
7-Aminodesacetoxycephalosporanic acid (7-amino-3-methylceph-3-em-4-carboxylic acid; 21.4 g., 0.1 mmole) was dissolved in 800 ml. of water by the action of sodium bicarbonate (27.9 g., 0.33 mmole). The solution was diluted with 800 ml. of acetone, and cooled to 0° C. 5-Methyl-3-phenylisoxazole-4-carbonyl chloride (27.7 g., 0.33 mmole) was added and the reaction mixture stirred for 2 hours at 0° C., then held at refrigerator temperature for approximately 16 hours. The acetone was removed by evaporation in vacuo, the aqueous residue extracted several times with ethyl acetate. Layering the aqueous phase with ethyl acetate and adjusting down to 2.0 precipitated the desired product. Filtration with ethyl acetate wash gave 3-methyl-7-(5-methylphenylisoxazole-4-carboxamido)ceph-3-em-4-carboxylic acid [27.5 g., pnmr (TMS/DMSO-d6) delta: includes 2.0 (s, 3H); 2.4 (s, 3H); 3.4 (m, 2H); 7.2-7.8 (m, 5H)].
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]#[C:26]Br>CO.C(#N)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:26](=[NH:25])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Solvent: CC#N
Solvent: CO
Product: N=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (202 mg, 0.62 mmol) in MeOH (1.5 mL) was added 130 μL of 5.0 M solution of cyanogen bromide in acetonitrile. The resulting mixture was stirred at r.t. under N2 for 24 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 174 mg (80%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.35-1.46 (m, 2H), 1.50-1.67 (m, 3H), 2.04-2.12 (m, 2H), 2.539 (d, 2H, J=7), 2.773 (t, 2H, J=6), 3.00-3.03 (m, 2H), 3.50 (bs, 1H), 4.035 (t, 2H, J=6), 6.243 (dd, 1H, J=8; 3), 6.317 (d, 1H, J=3), 6.614 (d, 1H, J=8), 7.12-7.30 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1sc(-c2ccc(F)cc2)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
A vigorously stirred mixture of 2-amino-5-(4-fluorophenyl)- 3-thiophenecarboxamide (0.01 mole) and pyridine (20 ml) at 0° was treated dropwise with acetyl chloride (0.011 mole). The resulting solution was stirred a further 30 minutes at 0° and then poured on to cold water. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from ethanol yielded 2-acetamido-5-(4-fluorophenyl)- 3-thiophenecarboxamide (90°/o, m.p. 230°-3°).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1)=[O:5].[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[O:37]1[C:29]2[CH:28]=[CH:27][C:32]([CH2:33][N:10]3[CH2:11][C@@H:7]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[CH2:8][C@H:9]3[C:12]([O:14][CH3:15])=[O:13])=[CH:31][C:30]=2[O:35][CH2:36]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Reaction time: 0.75 h

Procedure:
A solution of methyl(2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (19b) (138 mg, 0.38 mmol), piperonal (58 mg, 0.39 mmol) and glacial acetic acid (225 μL, 3.93 mmol) in tetrahydrofuran (2.8 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (125 mg, 1.88 mmol) was added in small portions and stirring was continued for 45 min at the same temperature. After dilution with ethyl acetate (5 mL), the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution (2×5 mL) and brine (5 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 100% dichloromethane and dichloromethane-ethylacetate (4:1, v/v) to give the title pyrrole (20):
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.C(Cl)Cl.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O>[C:11]([O:10][C:9]([NH:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][N:3]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C@@H:2]1[CH3:1])=[O:15])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:10][C:9]([NH:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][N:3]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C@H:2]1[CH3:1])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1NCCCC1NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %
Yield: 19 %

Procedure:
(R)-tert-Butyl 2-methylpiperidin-3-ylcarbamate (307) (8.2 g, 38 mmol) was suspended in a solution of DCM (500 mL) and DIEA (13.4 mL, 76.9 mmol). Benzyl chloroformate (6.6 mL, 46 mmol) was then added drop-wise over 5 minutes and the reaction was stirred at 0° C. for 30 minutes. Water was then added and the mixture was allowed to come to room temperature and stirred for 30 minutes. The organic phase was separated, washed with 1M HCl (aq), saturated NaHCO3 (aq), and brine. On TLC, the trans-isomer (309) displayed a higher silica Rf value than the cis isomer (308). The two diastereomers were separated by silica flash column chromatography (EtOAc/hexanes). The mixed fractions from the first purification were combined and subjected to a second purification. After two purifications, (2R,3R)-benzyl 3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (308) (2.5 g, 7.2 mmol, 19% yield) and (2S,3R)-benzyl 3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (309) (8 g, 23 mmol, 61% yield) were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][N:35]=[N+]=[N-])[O:31][C:30]4=[O:38])=[CH:25][C:24]=3[F:39])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([C:53]2[CH:58]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:59]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][NH:35][C:58](=[O:59])[CH3:53])[O:31][C:30]4=[O:38])=[CH:25][C:24]=3[F:39])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCN(C4CCN(C(=O)OCc5ccccc5)CC4)CC3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C4CCN(C(=O)OCc5ccccc5)CC4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 2.65 g of 4-{4-[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-piperazin-1-yl}-piperidin-1-carboxylic acid benzyl ester (4.93 mmol), 1.55 g triphenylphosphine (5.91 mmol) and 0.88 g water (49.3 mmol) in 40 ml THF was stirred at reflux for 22 hrs. The reaction was controlled by TLC. The THF was evaporated and the residue dissolved in 10 ml acetic acid and 2 ml of acetic anhydride. the reaction was monitored by TLC. The solvents were evaporated and the residue crystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH:15]=[CH2:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19].[Na].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH2:15][CH2:16][NH2:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: C=CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
24.2 g of 3-(4'-fluoro-4-biphenylyl)-1-buten-3-ol (obtainable from 4-acetyl-4'-fluorobiphenyl and vinylmagnesium bromide) are heated with 8 g of ammonia and 0.25 g of sodium for 8 hours at 180° - 200°, and the mixture is cooled and worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1.F[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:16]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=2[CH:18]=[O:19])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 65 °C
Yield: 23.5 %

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid methyl ester (1 g, 5.2 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (1 g, 5.2 mmol), and potassium carbonate (1.3 g, 10.4 mmol) were combined in THF (10 mL) and heated to 65° C. for 8 hours. After working-up the mixture with H2O and EtOAc, the crude material was purified by silica gel chromatography to give the desired product as a white solid (0.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: BrCCCCCBr
Product: COC(=O)C1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 90 %

Procedure:
Using the procedure and molar proportions of example 71, 1 g of racemic-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was alkylated with 1,5-dibromopentane giving racemic-6-[(5-bromopentyl)-oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 72.5°-74.5° C. in 90% yield after purification by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[CH:3]=1.O.[NH2:22][NH2:23]>CO>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH:22][NH2:23])=[O:16])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(Oc2cc(N)nc(SC)n2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CSc1nc(N)cc(Oc2ccc(C(=O)NN)cc2)n1

Procedure:
Compound 6 was prepared from commercially available 4,6-dichloro-2-(methylthio)pyrimidine followed scheme 4. To prepare compound 6.1,4,6-Dichloro-2-(methylthio)pyrimidine was reacted with ammonia in THF in a sealed tube to provide 4-Amino-6-chloro-2-(methylthio)pyrimidine in good yield. Amino group of the resulting compound was protected with suitable protecting group such as BOC to afford compound 6.1. Compound 6.1 was then reacted with methyl 4-hydroxybenzoate in the presence of base to provide the amine protected intermediate, 2 which upon deprotection under acidic condition to afford methyl 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzoate (3). Reaction of compound 3 with hydrazine hydrate in methanol provided 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzohydrazide (6.4) in good yield. The hydrazide was then reacted with S-methyl N-[3-(trifluoromethyl-phenyl)thiourea in the presence of base to yield compound 6.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([C:36]2[N:37]=[C:38]([CH2:47][CH2:48][NH2:49])[O:39][C:40]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:30]1([C:36]2[N:37]=[C:38]([CH2:47][CH2:48][NH:49][CH:24]3[C:25]4[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:22][CH2:23]3)[O:39][C:40]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[C:30]1([C:36]2[N:37]=[C:38]([CH2:47][CH2:48][NH:49][CH:19]3[C:20]4[C:25](=[C:24]([OH:29])[CH:23]=[CH:22][CH:21]=4)[CH2:26][CH2:27][CH2:28]3)[O:39][C:40]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: NCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC2NCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Product: Oc1cccc2c1CCCC2NCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(t-butyldiphenylsilyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalene (0.52 g), 2-(4,5-diphenyloxazol-2-yl)ethylamine (0.33 g) and p-toluenesulfonic acid (catalytic amount) in toluene (30 ml) was refluxed for 15 hours with Dean-stark equipment. The solution was evaporated in vacuo and MeOH (10 ml) was added to the residue. To the MeOH solution, NaBH4 (0.21 g) was added at 0° C. After being stirred for 30 minutes at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-(t-butyldiphenylsilyloxy)naphthalene (0.25 g) and 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.11 g). To a solution of 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-(t-butyldiphenylsilyloxy)naphthalene (0.25 g) in THF (2 ml) was added 1M-THF solution (2 ml) of tetra-n-butyl ammonium fluoride (TBAF). After being stirred for 1 hour at room temperature, the reaction mixture was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ClC(OCC)=O.C(N(CC)CC)C.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]=[CH:9][C:10]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:12])=[CH:13][CH:14]=1
Reactant: CC(C)N
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
The precursor 4-(4-chlorophenyl)-N-(1-methylethyl)-4-oxo-2-butenamide (7A) was prepared by the procedure shown in the previous examples by treating 1A with ethyl chloroformate and triethylamine in toluene at 0°, then adding at 0° a solution of isopropylamine in toluene. 7A was obtained as a solid, m.p.: 162°-163°. It was converted to 7 by treatment with hydrogen peroxide, by the procedure described in Example 1, 7 being obtained as a solid, m.p.: 128°-129°.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[K+:6].[K+].[Cl-:8].[K+].[S:10](=[O:14])(=[O:13])([OH:12])[OH:11]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[K+:6].[K+:6].[S:10](=[O:12])(=[O:11])([OH:14])[O-:13].[K+:6].[ClH:8]
Reactant: O=S(=O)(O)O
Reactant: [Cl-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: Cl
Product: O=S(=O)([O-])O

Procedure:
As a general process of producing potassium sulfate, there is known such a process that, as is shown by the reaction formulae (1) and (2), potassium chloride is reacted with sulfuric acid to obtain potassium sulfate through potassium bisulfate and hydrogen chloride as a by-product.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:16][CH:17]=[CH2:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:3]([CH2:16][CH2:17][CH3:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: C=CCc1c(O)ccc2[nH]c(C(=O)OCC)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2[nH]c(C(=O)OCC)cc12
Yield: 74.2 %

Procedure:
Ethyl 5-hydroxy-4-(2-propenyl)-1H-indole-2-carboxylate (2.16 g) was dissolved in dry ethanol (100 ml) and hydrogenated at atmospheric pressure in the presence of 5% palladium on charcoal (0.2 g) until hydrogen uptake had ceased. The catalyst was filtered off, washed with hot ethanol, the filtrate evaporated and the residue recrystallised from aqueous ethanol to give 1.616 g of the desired product mp 185°-186°:
Reaction SMILES: S1C=CC=C1.[CH3:6][O:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1.C1(C[NH2:27])C=CC=CC=1.[H][H]>[Pd].CO.C(O)C>[NH2:27][C@H:13]1[CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C@H:8]1[O:7][CH3:6]
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1

Procedure:
To 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol were added 126 parts of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate, 70 parts of benzenemethanamine and 400 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After up-take of one equivalent of hydrogen, the catalyst was filtered off and hydrogenation was continued with another 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue contained some oil drops which were separated, yielding 92.9 parts of ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate (intermediate 54).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:30][O:29][CH2:28][C@:27]([C:32]3[CH:33]=[C:34]([NH:39][C:40]([C:42]4[C:47]([Cl:48])=[CH:46][C:45]([C:49]#[N:50])=[CH:44][N:43]=4)=[O:41])[CH:35]=[CH:36][C:37]=3[F:38])([CH3:31])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[ClH:48].[NH2:24][C:25]1[CH2:30][O:29][CH2:28][C@:27]([C:32]2[CH:33]=[C:34]([NH:39][C:40]([C:42]3[C:47]([Cl:48])=[CH:46][C:45]([C:49]#[N:50])=[CH:44][N:43]=3)=[O:41])[CH:35]=[CH:36][C:37]=2[F:38])([CH3:31])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(NC(=O)c4ncc(C#N)cc4Cl)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)COCC(N)=N1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-5-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide (80 mg, 0.12 mmol) in dichloromethane (2 ml) was treated at room temperature with trifluoroacetic acid (0.89 ml, 1.16 mmol); the yellow solution immediately turned to orange. The reaction mixture was stirred at room temperature for 16 hours. For the workup, it was poured into a sodium carbonate solution (1 M, 2 ml), then extracted with dichloromethane (10 ml). The organic layer was washed with brine (5 ml), dried over sodium sulfate, and evaporated. After chromatography on silica gel using a gradient of dichloromethane and methanol=100/0 to 93/7 the 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide was obtained. For further purification the product was dissolved in dioxane and hydrochloric acid (4 N, 0.15 ml) was added. After evaporation at reduced pressure the salt was triturated in diethylether (2 ml), the solid material filtrated and dried. The title compound was obtained as a white solid (5 mg, 10% of theory). Mass (calculated) C18H15ClFN5O2.ClH [424.260]; (found) [M+H]+=388.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[C:12]=1[CH3:13].COC(OC)[N:18]([CH3:20])C.O.[NH2:24]N>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][C:8]3[C:7](=[N:24][NH:18][CH:20]=3)[C:6]=2[C:12]=1[CH3:13]
Reactant: NN
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)c(C)c2c1SCc1c[nH]nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
2.80 g (10 mmol) of the title compound of Step B and 1.79 g(15 mmol) of N,N-dimethylformamide dimethyl acetal were dissolved in 16 mL of ethyl acetate and heated to reflux. The methanol/ethyl acetate mixture was removed via a Dean Stark trap and was replaced with fresh ethyl acetate. After heating to reflux for 4 hours, the reaction was cooled to room temperature and allowed to stand overnight. It was then reluxed further for 2 hours, cooled to 60° C., and 0.75 g (15 mmol) of hydrazine monohydrate was added. The reaction was reheated to reflux for 1 hour, cooled to room temperature, and diluted to 100 mL with ethyl acetate. The organic phase was washed twice with 100 mL of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 3.10 g of an oily yellow solid. This solide was triturated with hexanes, collected by filtration, washed further with hexanes, and dried to yield 2.79 g of the title compound of Step C as a pale yellow solid melting at 162-164° C. 1H NMR (CDCl3): δ2.34 (s, 3H), 2.79 (s, 3H), 3.84 (s, 2H), 7.35 (s, 1H), 7.46 (s, 1H), 10.4 (br s).