Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl.[Cl-].[F:24][C:25]1[CH:30]=[CH:29][C:28]([S+:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>C(Cl)Cl.O.O1CCOCC1>[F:1][C:2]([F:19])([C:8]1([OH:18])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2)[C:3]([O-:5])=[O:4].[F:24][C:25]1[CH:30]=[CH:29][C:28]([S+:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(F)(F)C1(O)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C(F)(F)C1(O)C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of 2.6 g of ethyl difluoro-(2-hydroxyadamantan-2-yl)acetate, prepared in Synthesis Example 1-8, 30 g of 1,4-dioxane, 4.0 g of 25 wt % sodium hydroxide, and 10 g of water was stirred for 2 hours. To the reaction solution, 1.0 g of 35 wt % hydrochloric acid was added, and then 66 g of an aqueous solution of 4-fluorophenyldiphenylsulfonium chloride and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate. The supernatant was removed, leaving 2.4 g of the target compound, 4-fluorophenyldiphenylsulfonium difluoro-(2-hydroxyadamantan-2-yl)acetate as vitreous solids (yield 45%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[N:3]=1.COC1C=C2C(=CC=1)C=C(OCCO)C=C2.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=1)[CH:21]=[CH:20]2
Reactant: COc1ccc2cc(OCCOc3cncc(Cl)n3)ccc2c1
Reactant: C1CNCCN1
Agent: COc1ccc2cc(OCCO)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2cc(OCCOc3cncc(N4CCNCC4)n3)ccc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(6-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [0.94 g, 2.8 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(6-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.00 g, 11.6 mmol) and K2CO3 (0.50 g, 3.6 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.52 g (48%) which was obtained as a beige colored solid. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+ 380.1848, found 380.1845.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20]OS(C)(=O)=O)[N:18]=2)=[CH:10][CH:9]=1.ClCCl>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:18]=2)=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Temperature: 60 °C
Yield: 82 %

Procedure:
Add piperidine (1.3 g, 15 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.531 g, 1.47 mmol) in tetrahydrofuran (5 mL) in a sealed tube, and heat at 60° C. overnight. Cool to room temperature and add dichloromethane. Wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.421 g, 82%): MS (m/e): 349 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Br-].[K+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>C(OCC)(=O)C.O.CC1(C)N([O])C(C)(C)CCC1>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Yield: 97 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (50 g, 289 mmol) in ethyl acetate (400 mL) was cooled to 0° C. The resulting solution was then treated with solid TEMPO (0.5 g, 3.2 mmol, 0.011 equiv) and a solution of potassium bromide (KBr, 3.9 g, 33.2 mmol, 0.115 equiv) in water (60 mL) at 0-5° C. While keeping the reaction temperature between 0-5° C., a solution of saturated aqueous sodium bicarbonate (NaHCO3, 450 mL) and an aqueous sodium hypochlorite solution (NaClO, 10-13% available chlorine, 450 mL) were added. Once the solution of sodium hypochlorite was added, the color of the reaction mixture was changed immediately. When additional amount of sodium hypochlorite solution was added, the color of the reaction mixture was gradually faded. When TLC showed that all of the starting material was consumed, the color of the reaction mixture was no longer changed. The reaction mixture was then diluted with ethyl acetate (EtOAc, 500 mL) and two layers were separated. The organic layer was washed with water (500 mL) and the saturated aqueous sodium chloride solution (500 mL) and dried over sodium sulfate (Na2SO4). The solvent was then removed under reduced pressure to give the crude product, tert-butyl 3-oxoazetidine-1-carboxylate (48 g, 49.47 g theoretical, 97% yield), which was found to be sufficiently pure and was used directly in the subsequent reaction without further purification. 1HNMR (CDCl3, 300 MHz) δ 4.65 (s, 4H), 1.42 (s, 9H) ppm.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.02 g, 23.2 mmol) in dichloromethane (305 mL) was mixed with Dess-Martin Periodinane (9.55 g, 22.5 mmol) under cooling with ice and then stirred at room temperature for 3 hours. After addition of 10% aqueous sodium thiosulfate and saturated aqueous sodium hydrogen carbonate under cooling with ice, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 (v/v)) to give the title compound as a colorless solid (3.39 g, yield 85%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C(#N)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ncccn2)c(OC)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
Potassium carbonate (2.97 g, 21.5 mmol) was added to a mixture of 2-chloropyrimidine (2.1 g, 17.9 mmol), 2,4-dimethoxybenzylamine (3.0 g, 17.9 mmol) and acetonitrile (20 mL). The reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and partitioned between ethyl acetate (150 mL) and water (10 mL). The organic phase was washed with water (2 10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in diethyl ether (20 mL), washed with hexanes (20 mL) and purified by column chromatography, eluting with a 0-100% gradient of ethyl acetate in hexanes to afford N-(2,4-dimethoxybenzyl)pyrimidin-2-amine as a pale yellow solid in 84% yield (3.70 g): MS (ES+) m/z 245.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 ml reaction bottle equipped with magnetic stir bar were charged 5.0 g (35.2 mmole) 2,6-difluorobenzaldehyde in 20 ml acetone, added 50% NaOH (42 mmole) in 60 ml water (exothermic) and stirred room temperature. The reaction was monitored by GLC and after 2 hours worked up. The reaction mixture was extracted with 50 ml CHCl3, washed with 50 ml H2O, dried over anhydrous MgSO4, filtered, and removed solvent in vacuuo on a rotary evaporator to afford 5.7 g of 4-(2,6-difluoro-phenyl)-3-buten-2-one as a yellow oil (81% purity by GC) in 89.5% isolated yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CO)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzoic acid (800 mg) in THF (10 mL) was added dropwise a 1.0 M solution of borane-THF complex in THF (6.6 mL) at room temperature over 30 min, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction mixture under ice-cooling, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (480 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCNC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2 over 0.5 h. The reaction was stirred for 16 h and the volatiles were removed in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (4.43 g).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOC(C)=O>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCNC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over 0.5 h. The reaction benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over0.5 h. The reaction dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (4.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[NH:24][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:9]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12

Procedure:
Prepared from 4-chloro-δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (250 MHz, DMSO-d6) δ2.55-2.61 (2H, m), 3.07-3.13 (2H, m), 7.16 (2H, d, J 12.6 Hz), 7.41 (2H, d, J 12.6 Hz), 7.62-7.71 (3H, m), 11.52 (1H, br s), and 12.19 (1H, br s). m/z (ES+) 331, 333 (M+1).
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:8][C@H:7]([NH:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:8][C@H:7]([NH:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1
Reactant: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-N-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamide was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=O.[K+]>O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:14]([O:15][CH3:16])[CH:13]=2)=[O:18])[CH:20]=1
Reactant: COc1cc(C(O)c2cccnc2)ccc1OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
ba) 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanol suspended in 50 ml of water are treated with 2.5 g of potassium permanganate, whereupon the mixture is stirred at 90° for 30 minutes. After adding a further 1.0 g of potassium permanganate and stirring for a further 30 minutes at 90° the mixture is cooled to room temperature and extracted twice with 150 ml of ethyl acetate each time. The combined ethyl acetate phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromatographed on 50 g of silica gel with ethyl acetate. After recrystallization from methylene chloride/hexane there is obtained 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone of m.p. 76°.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O.[Sn]=O.[O-2].[Ca+2]>[O-2].[Fe+2].[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: CO
Agent: [Cr+3]
Agent: [Fe+2]
Agent: O=[Sn]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-cresol, methanol and water in a ratio of 1:2.5:2.5 were reacted in the same way as described in Example 1. The catalyst contained iron oxide, tin oxide, chromium oxide and calcium oxide in a molar ratio of 100:2:1:1. After working up, 2,6-xylenol was obtained with a selectivity of 98.9%. Even after 2000 hours, there was no change in the activity of selectivity of the catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+:12].[C:13](=[S:15])=[S:14].CCCCCC>C1COCC1>[C:13](=[S:15])([S-:14])[NH2:8].[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.[Na+:12]
Reactant: S=C=S
Agent: CNc1cccc(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=S)[S-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-methoxy-2-methylaminopyridine (25.6 g, 0.185 mol) was dissolved in 120 ml of dehydrated THF, and 60% sodium hydride (7.4 g, 0.185 mol) was added. This was then refluxed for 1 hour, and upon becoming transparent, allowed to cool to room temperature. Carbon disulfide (14.1 g, 0.185 mol) was added dropwise into this solution, which was then stirred for two hours at room temperature. 300 ml of hexane were added and stirring continued until crystals precipitated out. The precipitated crystals were filtered out, then washed with 200 ml of hexane, and dried overnight in a dessicator to obtain 43.6 g (yield 99.7%) of the titled compound in the form of a pale yellow powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1>CC(O)=O.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2ncc[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A solution of XIII (6.6 g, 0.035 mole) in glacial HOAc (40 mL) and 48% HBr (110 mL) was stirred at reflux for 7 hours and then evaporated to dryness in vacuo. The residue was stirred with saturated NaHCO3 (200 mL) for 16 hours at room temperature. The aqueous phase was decanted from the residue which again was stirred with saturated NaHCO3 for 2 hours. This aqueous phase was decanted and the residue was extracted with 3×100 mL of boiling H2O filtering from insoluble material. All of the aqueous phases were combined and evaporated to dryness in vacuo. The residue was extracted with 3×100 mL of CHCl3 --MeOH (60:40), filtering from inorganic material. Evaporation of the filtrate left the crude product as an oily brown solid that was purified by chromatography on silica gel, eluting with 90CHCl3 --10MeOH--1H2O; to yield XIV (74%); m.p. 188°-190° C. (CH3CN).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].CCOCC>C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 4 h
Yield: 83.6 %

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.5 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 49, and the solution is allowed to stand at room temperature for 4 hours. To the solution is added 200 ml of petroluem ether and the resulting mixture is shaken thoroughly. After the supernatant is removed by decantation, the residue is diluted with 50 ml of water and extracted three times with 100 ml each of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether is added to the viscous residue to give 0.37 g of 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as colorless crystals melting at 135°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].O1CCCC1.O.[OH-].[Li+]>C(OCC)(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a stirred solution of ethyl 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)-propanoate (458 mg, 1.51 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added lithium hydroxide (190 mg, 4.529 mmol). The reaction mixture was refluxed for 15 h, then cooled to room temperature, acidified to pH 3-4 with acetic acid. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (218 mg, 52%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(O)CC.[Pd]>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Fc1ccc(-c2ccccc2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of sodium carbonate (3.3 g, 0.031 mol) in demineralized water (25 mL) is added to a solution containing 4-fluorobromobenzene (4.55 g, 0.026 mol), phenylboronic acid (3.3 g, 0.027 mol), Pd (II) acetate (18 mg) and triphenylphosphine (65 mg) in n-propanol (50 mL). The reaction mixture is stirred at 80-90° C. for 1 hour. It is allowed to cool back to room temperature. Demineralized water (100 mL) is added and the aqueous layer is extracted with ethyl acetate (200 mL). The organic layer is concentrated and the residue is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 10:90) to furnish 4-fluorobiphenyl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0° C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid, (8.28 g, 36 mmol, 63%). 1HNMR (400 MHz, CD3OD): δ ppm 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).