Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC1
Reactant: ClCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Under an N2 atmosphere at ˜7° C., BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) was added drop wise to a solution of iPr2NH (18.52 mL, 132 mmol, distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixture was allowed to warm to rt, stirred for 0.5 h, cooled to −60° C. and then, ethyl 1-cyclobutanecarboxylate (prepared according to Török, B.; Molnár, Á., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804, 14.05 g, 110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resulting mixture was allowed to warm to 0° C. in 20 min., cooled again to −60° C. and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) in dry THF (30 mL) was added dropwise in 20 min, after which the temperature was raised to −20° C. in 15 min. After 1.5 h, the temperature was raised to −10° C. and stirring was continued for 1 h. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (500 mL). The organic layer was washed with brine (250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin, colorless oil. 1H NMR (CDCl3): δ=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4. HRMS calcd for C11H20(37Cl)O2 (MH+): 221.1122. found: 221.1116.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1.[Na].C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1.O>[CH:26]([C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1)=[O:27]
Reactant: Clc1cc2nc(-c3ccc(Br)s3)[nH]c2cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To a solution of 2-(2-bromothiophen-5-yl)-5,6-dichlorobenzimidazole (100 mg, 0.287 mmol) in tetrahydrofuran (6 mL) was added sodium hydryde (60% oil dispersion; 14 mg, 0.35 mmol) at 0° C. under nitrogen atmosphere. After cooling to −78° C., n-butyllithium (1.6 mol/L in hexane; 0.36 mL, 0.57 mmol), dimethylformamide (0.085 mL, 1.1 mmol) were added, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (19:1 to 9:1 chloroform/acetonitrle) to afford 2-(2-formylthiophen-5-yl)-5,6-dichlorobenzimidazole (36 mg, 42%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:15]([CH2:14][CH2:13][Cl:12])=[O:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the known Schotten-Baumann procedure using 3-(trifluoromethyl)-aniline and 3-chloro-propionyl chloride.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.N.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
A mixture of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate (27.2 g, 78.5 mmol), trifluoroacetic acid (75 ml) and dichloromethane (250 ml) was stirred at 0°C. for 3 hours, slowly poured into cold aqueous ammonia, and then extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, after which the residue was dissolved in pyridine (150 ml) and the resulting solution was cooled to 5° C. p-Toluenesulfonyl chloride (22.4 g, 118 mmol) was added to the cooled solution in small portions and the resulting mixture was stirred at 5° C. for 3 hours and then allowed to stand overnight at room temperature. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/9) to obtain 27.6 g of ethyl 1-[2-(4-methylphenylsulfonyl) aminoethyl]-4-methyl-1H-indole-2-carboxylate
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]([CH:23]=2)=[N:20][O:21][N:22]=3)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:22]1[O:21][N:20]=[C:19]2[CH:23]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=3)[CH:16]=[CH:17][C:18]=12
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nonc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2ccc3nonc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
510 mg (1.57 eq.) (4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-methyl-carbamic acid tert-butyl ester are dissolved in 10 mL dichloromethane, treated with 0.126 mL (1.05 eq.) trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture is evaporated and the residue column chromatographed (hexane, hexane/ethyl acetate 4:1 then 3:1) to yield the desired product as an orange solid. MS(ES+): 226 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CCO>[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]2=[O:13])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCC(Br)C(=O)C1
Reactant: Fc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(Sc2ccc(F)cc2)C(=O)C1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of ethyl 4-bromo-3-oxocyclohexanecarboxylate (5.2 g, 20.9 mmol) in EtOH (120 mL) at 80° C. was added a solution of 4-fluorobenzenethiol (2.22 mL, 20.9 mmol) and KOH (1.29 g, 22.9 mmol) in EtOH (50 mL). The suspension was stirred for 30 min then filtered. The filtrate was concentrated in vacuo then diluted with water and extracted with diethyl ether. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel (15% EtOAc in hexane) afforded the title compound (3.08 g, 51%) as a white solid: mp 96-97° C.; MS (+) 297 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-pyridine (1.0 g) in dry dichloromethane (10.6 mL) under nitrogen at 0° C. was treated with triethylamine (1.63 mL) followed by slow addition of chloroacetyl chloride (0.93 mL). The reaction mixture was allowed to warm up to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-30% ethyl acetate/cyclohexane to give the title compound (1.43 g) as a pink solid. Further purification was achieved by trituration with 40-60 petroleum ether to give 1.15 g of the desired product. Crystallisation of a 0.94 g portion of the material from refluxing acetonitrile (2.4 mL) gave the sub-titled compound as a pink solid (0.73 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 7 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 19.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([Cl:18])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(OCC(=O)Cl)cc1

Procedure:
Filling in a dry 250 ml flask respectively 57.42 g (0.276 mol) of para-t-butylphenoxyacetic acid synthesized in Example 17 and 80.5 ml of thionyl chloride, the reaction mixture was heated and refluxed for 5-6 hours.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][C@H:12]([NH2:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:21][C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: C[C@H](N)CCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(Br)c1C#N
Yield: 60.2 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), (S)-1-Methyl-3-phenyl-propylamine (58.1 mg, 0.382 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) at 120° C. for 30 min to give the desired product as a clear oil (76 mg). LC/MS (316/318, [M−H]/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=5.5 Hz, 1H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 3H), 6.81 (d, J=5.3 Hz, 1H), 5.06 (br. s., 1H), 4.33 (dt, J=14.0, 6.9 Hz, 1H), 2.71 (t, J=8.0 Hz, 2H), 1.98-1.83 (m, 2H), 1.32-1.25 (m, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:11][C:3]1=2.[CH2:18]([C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([C@H:25]1[CH2:29][N:28]([C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:3]3[O:2][CH2:7][CH2:6][O:5][C:4]=3[CH:8]=2)[C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCCc1ccc2c(c1)OCCO2
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CCCc1ccc2c(c1)OCCO2
Yield: 23.5 %

Procedure:
Proceeding as in Example 1, but substituting 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 33, (2S,4R)-4-benzyl-1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (8.4 mg, 23.5%). 1H-NMR (400 MHz, DMSO-D6): σ 9.93 (s, 1H), 7.54 (d, 2H), 7.26 (t, 2H), 7.18 (m, 5H), 6.98 (m, 4H), 6.71 (d, 1H), 6.45 (m, 2H), 4.45 (m, 1H), 4.17 (m, 4H), 3.57 (m, 1H), 3.14 (m, 1H), 2.64 (m, 3H), 2.64 (t, 2H), 2.19 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H). MS (EI) for C36H35FN2O5: 595.7 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])[CH3:2].IC.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C@:6]1([CH3:24])[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a solution of (3S,4S)-3-ethoxycarbonyl-4-fluoromethyl-1-[(1R)-1-phenylethyl]-2-pyrrolidone (8.30 g, 28.3 mmol) and iodomethane (2.47 mL, 39.6 mmol) in tetrahydrofuran (170 mL), potassium bistrimethylsilyl amide (67.9 mL, 34.0 mmol, 0.5M solution in toluene) was added at −78° C., and the mixture was stirred at the same temperature for 10 minutes. While stirring, the temperature was gradually increased to −10° C. in 30 minutes. Saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×2), and the organic layer was washed with saturated aqueous solution of sodium chloride (150 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 7.91 g (91%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C1(C)C=CC=CC=1>[CH2:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Brc1n[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1nn(Cc2ccccc2)c2ccccc12
Yield: 50 %

Procedure:
3-bromo-1H-indazole (90.4 g, 0.459 mol, 1.0 eq.) and toluene (450 mL) were placed in a 1 liter flask fitted with a mechanical stirrer under an atmosphere of nitrogen. Then potassium t-butoxide (t-BuOK, 54.2 g, 0.483 mol, 1.05 eq.) was added at room temperature over about half an hour and benzyl bromide (86.3 g, 0.505 mol, 1.1 eq.) was added over approximately 1.5 hours. The mixture was left stirred at the same temperature until the reaction was complete (checked by TLC, approximately 3 hours). Then 0.1 M HCl (45 mL) and water (90 mL) were added and the resulting phases were separated. The organic phase was washed with water, and the solvent was evaporated off at reduced pressure in order to obtain a red oily residue. The product was then precipitated through the addition of n-heptane, filtered and dried under vacuum at room temperature. Yield: 65.9 g of beige solid (yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH:13]1([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:18]=[CH:17][C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:8])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: c1cc(N2CCNCC2)ncc1C1CC1
Product: O=C(c1c(F)cc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2,6-difluorobenzoic acid (1.20 g) and 1-(5-cyclopropylpyridin-2-yl)piperazine (1.15 g) described in Preparation Example 187, the title compound (1.90 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[C:14]([N+:16]([O-])=O)[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35]>ClCCl>[Cl:39][C:38]([Cl:41])([Cl:40])[CH2:37][O:36][C:34](=[O:35])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:13]2[S:12][C:11]([C:9](=[O:10])[NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:15][C:14]=2[NH2:16])=[CH:21][CH:22]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Sc2sc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)sc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
To the product from Example 356C dissolved in dichloromethane was added pyridine followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate. The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water, the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried followed by reduction of the nitro group according to the procedure described in Example 356E to provide the title product.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][CH2:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:6][CH2:7][CH:8]2[CH2:10][CH2:9]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1NCC1CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4-bromo-N-(cyclopropylmethyl)-2-nitroaniline (Step A, 1.7 g, 6.2 mmol), iron (1.7 g, 31.2 mmol) and ammonium chloride (33 mg, 0.62 mmol) in ethanol (18 mL) and water (6 mL) was stirred under reflux for 4 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (40 mL) and the mixture was washed with water containing aqueous ammonia. The organic layer was separated, dried over sodium sulfate and concentrated to afford the title compound (1.48 g, 98%) as a brown oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10]>C1COCC1>[Br:3][C:4]1[C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
1.3 800 ml of 2N NaOH are added to a solution of 150 g of methyl 5-bromo-2,4-dibenzyloxybenzoate in 500 ml of THF, and the mixture is stirred at 50° for 2 hours and subsequently stirred at room temperature for 16 hours. The red alkaline phase is separated off and cooled, and conc. hydrochloric acid is added dropwise to pH 2-3. The precipitated product is separated off and dried, giving 132 g of 5-bromo-2,4-dibenzyloxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18][CH2:19]O>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C

Procedure:
(3-Bromo-4-hydroxy-phenyl)-acetic acid (5.6 mmol) in EtOH (20 mL) was treated with sulfuric acid (1 mL) and stirred at room temperature over the weekend. The mixture was concentrated to give the title compound.