Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:11])([F:10])[F:12])[CH:5]=[CH:4][N:3]=1
Reactant: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(OCCCc2nnn[nH]2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reaction time: 48 h
Yield: 86.8 %

Procedure:
2-(2-Chloro-pyridin-4-yl)-3-{2-chloro-4-[3-(1-trityl-(1H)-tetrazol-5-yl)-propoxy]-phenyl}-1,1,1-trifluoro-butan-2-ol (80 mg, from previous step) was dissolved in CH2Cl2 (2.5 mL). To the solution was added trifluoroacetic acid (1.25 mL) at RT and the mixture was allowed to stir for 48 hours; almost complete conversion was observed. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate and water. The layers were separated and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compounds as a white solid (46 mg). MS (m/e)=476.1 (MH+).
Reaction SMILES: ONC([C@H:5]([C@@H:15]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:16]([NH:18][N:19](S(C)(=O)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:34](=[O:37])([O-:36])O.[Na+].Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(OCC)C>[C:9]([O:36][C:34]([C@H:5]([C@@H:15]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:16]([NH:18][N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:37])([CH3:14])([CH3:10])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])O
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CCCc1ccccc1)C(=O)NO
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NN(C(=O)OCc1ccccc1)c1ccccc1)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
0.5 g of 2(R)-[1(S)-(tert-butoxycarbonyl-4-phenylbutyl]-4-methyl-2′-phenylvalerohydrazide, prepared as described in Example 1, part (i), was dissolved in 10 ml of diethyl ether and stirred with 10 ml of saturated aqueous sodium hydrogen carbonate solution and 1.0 ml of benzyl chloroformate. After 24 hours the ether layer was separated, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After removal of the solvent the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (9.1) for the elution. There was obtained 0.767 g of benzyl 3-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleryl]-2-phenylcarbazate in the form of a white solid.
Reaction SMILES: [OH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[S:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CS(C)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:22]([O:1][C:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[S:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:24])[CH3:23]
Reactant: Cc1ccc(C2Sc3cc(C)ccc3NC(=O)C2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1=C(c2ccc(C)cc2)Sc2cc(C)ccc2NC1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 70.6 %

Procedure:
A mixture of 2,3-dihydro-3-hydroxy-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one (30.0 g), acetic anhydride (50 ml), dimethylsulfoxide (100 ml), pyridine (3 ml) and toluene (100 ml) is stirred at room temperature for 4 days, and the mixture is treated in the same manner as in Reference Example 1-(1) to give 3-acetoxy-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one (24.0 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[Br:20]([O-])(=O)=O.[K+]>O>[Br:20][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:14])([F:13])[F:1])[NH2:10]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 80 °C

Procedure:
4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 h., and the mixture was heated at 80° C. for a further 2 h. The mixture was cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue) was dissolved in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) was added. The mixture was heated under reflux for 2 h., cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (3:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H]2CCCC[C@@H]2N)ccc1OC

Procedure:
40.0 g of (+/−)-cis-2-ethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound C1) are dissolved in 1000 ml of ethanol and 500 ml of tetrahydrofuran, treated with 10 g of Raney nickel and hydrogenated in an autoclave for 4 days at a hydrogen pressure of 100 bar. After filtration and removal of the solvent in vacuo, 35.9 g of the title compound are obtained as a solidifying oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[N:25]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Temperature: 160 °C

Procedure:
159 (500 mg, 1.6 mmol), 2,6-Dichloro-pyridine (360 mg, 24 mmol) are dissolved in 15 ml of dimethylformamide. After addition of potassium carbonate (340 mg, 24 mmol) and a catalytic amount Cu-powder the mixture is heated to 160° C. for 3 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is solved in dichloromethane and after evaporation crystallized with cyclohexane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][CH:48]2[N:51]([CH2:52][C:53](O)=[O:54])[C:50](=[O:56])[CH2:49]2)=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:53](=[O:54])[CH2:52][N:51]2[CH:48]([S:47][C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH2:49][C:50]2=[O:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(SC2CC(=O)N2CC(=O)O)cc1
Reactant: NCCCCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(SC2CC(=O)N2CC(=O)NCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (1.4 g, 8 mmol) in DMF (50 ml) was added to DCC (1.6 g, 8 mmol), hydroxybenzotriazole (1.0 g, 8 mmol) and (4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid (2.1 g, 8 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (x2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:3). Evaporation of the appropriate fractions gave the product as a colourless oil, 77% yield. 1H NMR δ (CDCl3) 1.34-1.47 (10H, m, (CH2)5), 2.59 (2H, t, J=7.7 Hz, CH2), 2.83 (1H, dd, J=2.2, 15 Hz, H3a), 3.18-3.36 (3H, m, CH2H3b), 3.78 (3H, s, OCH3), 3.80, 3.99 (each 1H, d, J=15 Hz, NCH2), 4.95 (1H, m, H4), 6.23 (1H, bt, NH), 6.87 (2H, d, J=6.8 Hz, 2, 6 Ph--H), 7.14-7.39 (7H, m, 3, 5 Ph--H, Ph--H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29]Cl)[CH3:27]>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCOCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a mixture of diisopropylamine (2.1 ml, 15 mmol) and tetrahydrofuran (30 ml) was added dropwise n-butyllithium (2.4M n-hexane solution, 5.0 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred for 30 minutes. To the mixture was added dropwise tributyltin hydride (3.3 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred at 0° C. (external temperature) for 40 minutes. The reaction mixture was cooled to −78° C. (external temperature), and ethoxymethyl chloride (1.1 ml, 12 mmol) was added dropwise to the reaction mixture. After the reaction mixture was raised to room temperature, to the reaction mixture were added diethyl ether and an aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=30:1) to obtain the title compound (2.8 g, 7.9 mmol, 66%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(NC(=NC(C)C)O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)C>C(#N)C>[CH2:19]([O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)N=C(NC(C)C)OCc1ccccc1
Solvent: CC#N
Product: Cc1sc(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 81.7 %

Procedure:
A mixture of 5-methyl-4-nitro-thiophene-2-carboxylic acid (1.0 g, 5.3 mmol) and 1,3-diisopropyl-2-benzylisourea (1.54 g, 6.4 mmol) in acetonitrile (25 mL) was stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture was cooled, the solvent was removed under reduced pressure, and the residue was triturated in diethyl ether and cooled. The precipitate was filtered off and rinsed with cold ether. The filtrate and washings were combined, and rotary evaporated under reduced pressure. The resulting residue was dissolved in a minimum of ethyl acetate, and the solution was filtered through a column of silica gel, eluting with more ethyl acetate. The filtrate was rotary evaporated to dryness under reduced pressure to afford 1.2 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid benzyl ester. A sample was chromatographed on silica gel in ether/petroleum ether 1:1, then recrystallized from ethanol to give product with a mp 57-58° C.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([NH2:28])=[O:18])[CH2:15][N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 11.1 %

Procedure:
To a solution of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.090 g) in N,N-dimethylformamide (6 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.034 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.049 g), and the mixture was stirred at 50° C. for 45 min. 28% Aqueous ammonia (2 ml) was added to the reaction, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=100:0-90:10), and recrystallized from hexane-ethyl acetate to give the title compound (0.010 g, yield 11%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Nc1ccc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyridine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a white solid (210 mg, 53%). MS (ISP) 379.2 [(M+H)+]; mp 241-244° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1[C:21]2[N:20]([CH3:22])[C:19]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[N:30]=[CH:31][NH:32][C:33]=4[CH3:34])[C:26](=[O:27])[C:18]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:12][C:13]1[C:21]2[N:20]([CH3:22])[C:19]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[N:30]=[CH:31][N:32]([C:2]([O:4][CH2:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:3])[C:33]=4[CH3:34])[C:26](=[O:27])[C:18]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (0.47 ml) in dichloromethane (1 ml) was added to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl -1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (496 mg) and triethylamine (0.67 ml) in dry dichloromethane (50 ml) at 20° under nitrogen, and the mixture was stirred overnight. The cooled reaction mixture was then added to 2N sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (200:8:1) to give the title compound (442 mg) as a solid. A sample was recrystallised from hot ethyl acetate, and the resultant solid was triturated with ether to give a crystalline solid, m.p. 126°-128°.
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:20]3[C:16]([S:17][C:18]([C:24]([O:26]CC)=[O:25])=[C:19]3[CH:21]([CH3:23])[CH3:22])=[N:15][C@:14]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:9][C:8]=1[F:37]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:20]3[C:16]([S:17][C:18]([C:24]([OH:26])=[O:25])=[C:19]3[CH:21]([CH3:22])[CH3:23])=[N:15][C@:14]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:9][C:8]=1[F:37]
Reactant: CCOC(=O)C1=C(C(C)C)N2C(=N[C@@](C)(c3ccc(Cl)nc3)[C@H]2c2ccc(Cl)c(F)c2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C1=C(C(=O)O)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 60 °C
Yield: 77.6 %

Procedure:
1 N aqueous sodium hydroxide solution (6 ml) was added to an ethanol (30 ml) solution of the compound (2.06 g, 4.17 mmol) obtained in Step 12 above and the resulting mixture was stirred under heating at 60° C. for 16 hours. After cooling, the solvent was concentrated under reduced pressure and the residue obtained was diluted with water and then washed with diethyl ether. The aqueous layer was made into an acidic solution by the gradual addition of 1 N aqueous hydrochloric acid solution under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, a diethyl ether/n-hexane mixed solvent was added to the residue and the resulting precipitate was collected by filtration and dried to give the title compound (1.51 g, 87%) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([OH:2])=[O:10])=[O:11])=[CH:15][CH:14]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
To a stirred mixture of 25 parts of 1,3-isobenzofurandione and 108.5 parts of fluorobenzene were added portion-wise 50 parts of aluminium chloride. Upon completion, the whole was heated slowly to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled and poured onto a mixture of crushed ice and 60 parts of concentrated hydrochloric acid. The product was extracted twice with dichloromethane. The combined extracts were washed with a sodium hydroxide solution 10%. The aqueous phase was separated, washed with 2,2'-oxybispropane and acidified with concentrated hydrochloric acid while cooling. The whole was stirred for 1 hour at room temperature. The precipitated product was filtered off and dissolved in benzene. The solution was distilled azeotropically to dry. The solid residue was stirred in hexane. The product was filtered off and dried in vacuo at about 50° C., yielding 33.5 parts (80.7%) of 2-(4-fluorobenzoyl)benzoic acid; mp. 129.2° C. (intermediate 90).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:6].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-fluoro-4-methylbenzoyl)pyrrolidine-1-carboxylate (1.35 g, 4.38 mmol), which had been obtained in Example 1 (1a), in methanol (5 mL), sodium borohydride (0.20 g, 5.23 mmol) was added under ice cooling, and stirred at room temperature for 0.5 hours. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound as an orange oily substance (1.30 g, yield 96%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Solvent: c1ccccc1
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F

Procedure:
2,4,5-Trifluoro-3-methyl-6-nitrobenzoic acid was suspended in 490 ml of benzene to which was subsequently added dropwise 30.4 ml (0.42 mol) of thionyl chloride at room temperature. After completion of the dropwise addition, the reaction solution was heated under reflux for 22 hours. After evaporation of benzene, the resulting residue was subjected twice to azeotropic treatment with 200 ml of benzene to yield crude 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. A 6.13 g (0.25 mol) portion of magnesium was mixed with 200 ml of ethanol. Thereto was added dropwise 10 ml of carbon tetrachloride at room temperature, followed by 6 hours of stirring at the same temperature. When magnesium was dissolved, 44 ml (0.29 mol) of diethyl malonate dissolved in 150 ml of tetrahydrofuran was added dropwise thereto, spending 1 hour. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was evaporated and the resulting residue was dried under a reduced pressure. The thus obtained solid matter was mixed with 300 ml of tetrahydrofuran to which was subsequently added dropwise 150 ml of tetrahydrofuran solution of the acid chloride obtained above in 1.5 hours. After completion of the dropwise addition, the reaction solution was stirred for 2 hours at room temperature. After completion of the reaction, the reaction solution was mixed with 400 ml of ethyl acetate and washed with 10% citric acid (500 ml×1), water (500 ml×1) and saturated brine (500 ml×1) in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was mixed with 1.5 liters of water and 1.5 g of p-toluenesulfonic acid, and heated under reflux for 1.5 hours. After completion of the reaction, the reaction solution was spontaneously cooled and extracted with benzene (500 ml×5). The organic layers were combined, washed with 500 ml of saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was subjected to a silica gel column chromatography to yield 37.65 g (44%) of the title compound from the eluate of hexane:ethyl acetate=95:5.