Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[O-:13][S:14]([O-:16])=[O:15].[Na+].[Na+].O>CCO>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([S:14]([OH:16])(=[O:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Yield: 73.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 1,4-difluoro-2-methyl-5-nitrobenzene (1.2 g, 6.93 mmol) in EtOH (10 ml) and Na2SO3 (1.98 g, 15.7 mmol) in EtOH:water (40 ml:25 ml) at 70° C. for 16 h gave the title compound (1.2 g, 73%) which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:7]([CH:14]3[CH2:16][CH2:15]3)[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25]>>[CH:14]1([C:7]2[C:8]([CH3:13])([CH3:12])[O:9][C:10]3[C:5]([C:6]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:4][CH:3]=[C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:11]=3)[CH2:15][CH2:16]1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C1CC1)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (1) described above (112 mg) and tert-butyl carbamate (240 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (117 mg) as a pale brown powder.
Reaction SMILES: [CH2:1]([CH:8]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:12]([O:24]CC2C=CC=CC=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Pd]>[CH2:1]([CH:8]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:12]([OH:24])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(CC(Cc3ccccc3)C(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1CN(c2ccc(CC(Cc3ccccc3)C(=O)c3ccccc3)cc2O)S(=O)(=O)N1
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(2-benzyl-3-oxo-3-phenylpropyl)-2-benzyloxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.069 mmol) and 7 mg of Degussa 5% Pd/C in 4 mL of ethanol/water (1:1) is hydrogenated at 1 atm for 8 h at RT. The catalyst is filtered through Celite, washed with 1:1 ethanol/water and the filtrate concentrated under reduced pressure. The resulting residue is stripped four times with ethanol and the resulting solid is triturated with ether and dried to afford the title compound as a solid: (M−1)−=449. HPLC retention time=0.88 min (Method C).
Reaction SMILES: [F:1][C:2]([F:21])([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[B]1OC2C(=CC=CC=2)O1>C(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)Cl>[F:21][C:2]([F:1])([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: CSc1ccc(OC(F)(F)C(=O)c2ccc(F)cc2)cc1
Agent: [B]1Oc2ccccc2O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CSc1ccc(OC(F)(F)[C@H](O)c2ccc(F)cc2)cc1
Temperature: -70 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
To a solution of 2,2-difluoro-1-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanone (2.76 g, 8.84 mmol) and S-methyl-CS-oxazaborolidine in a mixture of DCM/Toluene (1/1, 40 ml) under nitrogen, at −70° C., a solution of catecholborane (1.27 g, 10.6 mmol) in DCM (2 ml) was slowly added. After stirring at −70° C. for 18 h, the reaction mixture was quenched by adding 4M solution of HCl in dioxane (3 ml). The heterogeneous mixture was stirred for 15 min at −70° C., then warmed to room temperature. Solvent was removed on a rotary evaporator and the resulting solution was diluted with hexanes (80 ml). Water (0.5 ml) was added and the mixture was stirred for 15 min. The solids were filtered and the filter cake was washed with hexanes. The filtrate was washed with 10% aqueous sodium metabisulfite (15 ml) and brine (15 ml). The organic phase was dried over sodium sulfate and the crude purified by flash chromatography, using EA/H (1/10) as eluent to give 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanol (1.55 g, 56%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=[C:5]([CH2:23][CH3:24])[CH:4]=1)[CH3:2].[C:25]1([CH2:31][C:32]([NH:34][NH2:35])=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:32]([CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:34][N:35]=3)[C:7]=2[CH:6]=[C:5]([CH2:23][CH3:24])[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(C2=NCC(=S)Nc3cc(CC)cc(CC)c32)c1
Reactant: NNC(=O)Cc1ccccc1
Solvent: CCO
Product: CCc1cccc(C2=NCc3nnc(Cc4ccccc4)n3-c3cc(CC)cc(CC)c32)c1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,8-diethyl-1,3-dihydro-5-(m-ethylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with phenylacetic acid hydrazide and the resulting product heated to 250° C. to give 7,9-diethyl-1-benzyl-6-(m-ethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][C:22]([CH3:24])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:22]([CH3:24])[CH3:21])[NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)=O
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.11 mL acetone in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.26 g. MS (ES+): 350 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].C1COCC1.CN(C=O)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>C1COCC1>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:36]([C:31]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=2)(=[O:38])=[O:37])[C:8]=1[CH3:16]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled stirring suspension of NaH (60% dispersion in mineral oil; 63 mg, 1.6 mmol) in THF (3 mL) is added a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (200 mg, 1 mmol) in 3:1 THF/DMF (4 mL). After 45 minutes, a solution of 3,4-dichloro-benzenesulfonyl chloride (214 μL, 1.4 mmol) in THF (3 mL) is added. After 10 minutes, the reaction mixture is added to ice/water and extracted with EtOAc. The organic layer is washed with brine and evaporated. The crude product is purified by flash chromatography (3:1 iso-hexane/EtOAc elution), to afford [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=413.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol and 6.7 g (0.067 mol) of triethylamine in 20 ml of methylene chloride cooled to 0° is added 6.5 g (0.054 mol) of pivaloyl chloride in a dropwise manner. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over magnesium sulfate. Filtration and removal of the solvents gives crude 2-fluoro-4-pivaloyloxy-nitrobenzene which is dissolved in 200 ml of absolute ethanol. To the solution is added 0.9 g of 5% palladium on carbon, and the mixture is then hydrogenated under 30 psi hydrogen for two hours. The catalyst is filtered and the solvent removed to give 2-fluoro-4-pivaloyloxyaniline.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:10][C:11]2[C:20](=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzylamine (3.21 g, 30.0 mmol) in anhydrous tetrahydrofuran (25 ml) was added to a stirred mixture of methyl 3,4-bis-(bromomethyl)benzoate (9.66 g, 30.0 mmol) (obtained from Fluorochem) and triethylamine (9 ml, 64.7 mmol) in anhydrous tetrahydrofuran (50 ml) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo at 40° C. and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with a further portion of water (100 ml), separated and the solvent removed in vacuo at 40° C. to afford methyl 2-benzyl-2,3-dihydro-1H-isoindole-5-carboxylate as a pale orange solid that was used immediately without further purification as described below. 1H NMR (DMSO-d6) 7.82 (2H, m), 7.40-7.25 (6H, m), 3.90 (3H, s), 3.88 (2H, s), 3.84 (4H, s). MS: [M+H]+ 268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([Cl:12])=[C:8]2[C:4]=1[C:5]([C:13](=[O:17])[C:14]([O-:16])=O)=[CH:6][NH:7]2.[K+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:14](=[O:16])[C:13]([C:5]2[C:4]3[C:8](=[C:9]([Cl:12])[N:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)=[O:17])[CH2:29][CH2:28]1)=[O:26]
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Reactant: O=C(c1ccccn1)N1CCNCC1
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccn4)CC3)c12

Procedure:
Precursor 51, 1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, and picolinoyl-piperazine. 1H NMR (500 MHz, DMSO-d6) δ 8.63-7.45 (m, 7H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z: (M+H)+ Calc'd for C20H19ClN5O4: 428.11; Found 428.11. HPLC retention time: 1.09 minutes (column A).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>CCOC(C)=O>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][CH2:3]2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)N1CCC(NC(=O)c2ccc(C#N)cc2)CC1)C(F)(F)F
Yield: 36.6 %

Procedure:
To a solution of (R)-[4-amino-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine] (Example 21, 170 mg, 0.71 mmol) and triethylamine (0.12 mg, 0.86 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzoylchloride (130 mg, 0.78 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc/DCM as eluent to give the title compound as a solid (97 mg, 0.26 mmol). NMR: 1.45 (m, 2H), 1.65 (s, 3H), 2.1 (m, 2H), 3.05 (m, 2H), 4.2 (m, 1H), 4.4-4.6 (m, 2H), 5.1 (s, 1H), 6.2 (d, 1H), 7.65 (d, 2H), 7.8 (d, 2H); m/z 368.
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCOC>[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17][O:13][C:10]1[CH:9]=[C:5]([C:6]([NH2:7])=[O:8])[C:4]([OH:3])=[CH:12][CH:11]=1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)[N+](=O)[O-]
Reaction time: 9 h

Procedure:
A mixture of 84.3 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 144.2 g of methanesulfonic acid-(2-methyl-2-nitropropyl)-ester and 121 g of anhydrous potassium carbonate in 440 ml of diethylene glycol dimethyl ether is stirred for 9 hours in a bath at about 150°. The reaction mixture is cooled, poured into 4000 ml of water, and extracted with 3000 ml of ethyl acetate. The oil, obtained by concentrating the organic phase by evaporation, is dissolved in 250 ml of dioxane, and about 750 ml of 2N hydrochloric acid is added until an acid reaction occurs. The solution is held for 11/2 hours at 80°-100°; it is then concentrated under reduced pressure to half its volume, and extracted three times with 500 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of water, then with saturated sodium bicarbonate solution, and finally with saturated sodium chloride solution; they are subsequently dried over magnesium sulfate and concentrated by evaporation. The dark brown oil thus obtained is chromatographed on 500 g of silica gel. Elution with ether yields crystalline 5-(2-methyl-2-nitropropoxy)-salicylamide, m.p. 145°-148°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][C@H:34]([F:33])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: F[C@H]1CCNC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CC[C@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using (S)-3-fluoropyrrolidine in Step 2. LC-MS Method 3 tR=0.962 min, m/z=531.1; 1H NMR (CDCl3) 0.80-0.92 (m, 1H), 1.46-1.57 (m, 4H), 1.59 (s, 3H), 2.16-2.40 (m, 6H), 2.75-3.09 (m, 3H), 5.10-5.38 (m, 1H), 5.70 (m, 1H), 7.01-7.13 (m, 6H), 7.30-7.49 (m, 4H), 7.46 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]([CH3:15])=[CH:9][C:7]=1[OH:8].[C:16]1([CH:22]2[O:27][C:25](=[O:26])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCCl>[CH3:15][C:10]1[C:11](=[O:14])[C:12]([CH3:13])=[C:6]([CH3:5])[C:7](=[O:8])[C:9]=1[CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C1CCC(c2ccccc2)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
Aluminum chloride (1.4 g, 0.01 mole) was added to a 1,2-dichloroethane solution (20 ml) of 2,3,5-trimethylhydroquinone (1.5 g, 0.01 mole) and the mixture was heated at 80° C. A 1,2-dichloroethane solution (10 ml) of 4-phenylbutyrolactone (1.6 g, 0.01 mole) was added dropwise to the mixed solution over the 2-hours period, and the reaction was carried out under the same conditions for further 18 hours. After cooling, 2N-hydrochloric acid (40 ml) was added to the reaction solution, followed by stirring for 10 minutes, and the reaction product was extracted with isopropyl ether. The organic layer was washed with water, dried and evaporated and the residue was dissolved in tetrahydrofuran (30 ml). A 10% aqueous solution (5 ml) of ferric chloride was added to the solution, followed by stirring at room temperature for 10 minutes, and the reaction product was extracted twice with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether to give 4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-4-phenylbutyric acid (1.2 g, 38%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 36 to 38 were prepared.
Reaction SMILES: C1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][O:37][CH:38]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:39])[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:41]([O:40][CH:38]([O:37][NH:36][C:35]([C:33]1[S:32][C:31]2[CH:46]=[C:27]([CH2:26][NH:25][CH2:24][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C@@H:8]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([OH:47])=[O:6])=[CH:23][CH:22]=3)[CH:28]=[CH:29][C:30]=2[CH:34]=1)=[O:45])[CH3:39])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)O)cc3)cc2s1
Temperature: 50 °C

Procedure:
(S)-2-[4-({[2-(1-Isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-methyl)-benzylamino]-3-phenyl-propionic acid cyclopentyl ester (40 mg, 0.06 mmol) was dissolved in THF (2 mL) and water (2 mL). LiOH (8 mg, 0.30 mmol) was added and the reaction mixture heated to 50° C. for 36 h. THF was removed by evaporation and the residue partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was isolated and the pH adjusted to 3 by addition of 1M HCl. This was extracted with EtOAc (3×20 mL), the organic layers combined and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Br)c2cc[nH]c12
Temperature: -40 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-nitro-benzene (8.7 g, 0.037 mol) in THF at −40° C. was added vinylmagnesium bromide (132 ml, 0.132 mol) dropwise, and the mixture was stirred at −40° C. for a further 2 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford the title compound (1.35 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19](OCC)=[O:20]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:7])[NH:8][C:19](=[O:20])[O:11][C:4]=2[CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 22L, five neck, round bottom flask was equipped with an overhead stirrer, reflux condenser, addition funnel, thermocouple temperature read out, and a heating mantle. The reactor was purged with nitrogen. Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782 g, 10.4 mol) were charged to the reaction flask and the stirring was started. Pyridine (1133 mL, 14.0 mol) was charged to the reactor. The resulting reaction slurry was cooled to less than 10° C. with an ice bath. Ethyl chloroformate (1091 mL, 1237 g, 11.4 mol) was placed in the addition funnel and charged slowly to the stirred reaction mixture such that the temperature of the reaction mixture did not exceed 15° C. during the addition. The temperature of the reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours. Liquid chromatographic analysis of the reaction mixture indicated that the reaction was only 80% complete. Approximately half of the solvent was removed by atmospheric distillation. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Additional pyridine (215 mL, 2.65 mol) was added to the reaction mixture. Ethyl chloroformate (235 g, 2.17 mol) was added slowly via an addition funnel to the cold reaction mixture. The reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours, after which time liquid chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Water (1600 mL) was added slowly via an addition funnel and the resulting slurry held at <10° C. for 90 minutes. The solid product was collected by vacuum filtration through a large sintered glass funnel. The product filter cake was washed with deionized water and vacuum dried at 50° C. for 18 hours to give 1914 g of 7-chloro-2H-1,3-benzoxazine-2,4(3H)-dione as a tan solid. The yield was 83%.