Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]2[CH:12]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)CO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]4[CH:12]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2nc(CCl)cn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Cc1ccc2nc(CN3CCN(c4ccc(F)cc4)CC3)cn2c1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 55.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine (0.302 g), 1-(4-fluorophenyl) piperazine (Aldrich; 0.319 g), triethylamine (Aldrich; 0.26 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. The cooled mixture is then poured into saturated aq. sodium bicarbonate and extracted several times with dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide (4/96/0.25) and crystallized from ethyl acetate/hexane to give 0.300 g of the title compound; mp 112-112.5° C.; ms m/z 324; IR (mineral oil) 1511, 804, 1234, 1246, 1345 cm-1 ; 1H NMR (CDCl3) δ2.31, 2.74, 3.15, 3.76, 6.90, 7.46, 7.86.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].O>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:10](=[O:5])[C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(=O)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 24 h

Procedure:
97.2 g of a 75% strength aqueous N-methylmorpholine N-oxide solution were added with ice-cooling to a solution of 100 g (0.38 mol) of the compound of Example 1 in 400 ml of dimethyl sulfoxide (DMSO). After the mixture had been stirred for 24 hours at 20 to 25° C., it was poured into water and extracted with methyl tert-butyl ether (MtBE). After the organic phases had been dried, stripped from the solvent and chromatographed on silica gel (cyclohexane/MtBE [3:1]), 69 g of the title compound was obtained.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:35][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (250 mg, 2.2 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) in dioxane (10 mL) was added. The resulting mixture was then heated at 85-95° C. for 16 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 1:1) afforded the title compound (150 mg, 63%) which was obtained as a white solid. MS: m/e=482.2 [M+H]′.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[C:4]([O:6]CC)=O.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[CH3:11][C:2]([CH3:1])([CH3:10])[C:3](=[N:20][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])[C:4]([NH:20][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:6]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C(=O)C(C)(C)C
Solvent: Cc1ccccc1C
Solvent: O
Product: C[C@H](N=C(C(=O)N[C@@H](C)c1ccccc1)C(C)(C)C)c1ccccc1
Yield: 44.7 %

Procedure:
A solution of 15 g (95 mmol) of ethyl trimethyl-pyruvate and 50 g (413 mmol) of (S)-1-phenylethylamine in 50 ml of xylene was boiled under reflux on a water separator for 18 hours. Subsequently, the solvent was distilled off and excess amine was removed at 120° C. in a vacuum. After crystallization of the distillation residue from 125 ml of hexane there were obtained 14.3 g (45%) of (S)-3,3-dimethyl-N-[(S)-1-phenylethyl]-2-(1-phenylethylimino)-butyramide of melting point 96°-97° C. [α]=-58.9 (c=1.0, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1noc(C2CNCC(c3ccc(CC(F)(F)F)cc3)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 52 mg (0.14 mmol) of the compound from Example 61A in dichloromethane (1.6 ml) was admixed with 0.07 ml (49.7 mg, 0.49 mmol) of triethylamine and then, at 0° C., 28 mg (0.14 mmol) of 4-nitrophenyl chloroformate were added. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 75.8 mg (95% of theory)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:15]=2[F:28])[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].[Br:34]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:34][C:8]1[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:15]=2[F:28])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH3:11]
Reactant: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.48 g) and sodium acetate (0.36 g) in acetic acid (20 mL) was added bromine (0.22 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.07 g, 60%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=1[CH3:35])[CH2:19][CH2:20]C(OC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH:18]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9][N:10]([CH3:11])[C:6]=2[CH2:5][C:4](=[O:3])[CH2:20][CH2:19]1)[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)Cc1c(C(CCC(=O)OC)c2ccc(C(=O)OC)cc2C)c(-c2ccccn2)nn1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)O)ccc1C1CCC(=O)Cc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A flask fitted with a Dean-Stark apparatus containing dry molecular sieves was charged with a solution of methyl 4-(1-(5-(2-ethoxy-2-oxoethyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-methoxy-4-oxobutyl)-3-methylbenzoate (0.590 g, 1.20 mmol) in toluene (120 mL). The mixture was heated to reflux for about 16 h. The Dean-Stark apparatus was removed and the mixture was cooled to about 0° C. 1 M lithium bis(trimethylsilyl)amide in toluene (1.20 mL, 1.20 mmol) was added in dropwise manner. The mixture was allowed to slowly warm to rt in the cold bath. After about 2 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.60 mL, 0.60 mmol) was added dropwise. After about 4 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.30 mL, 0.30 mmol) was added dropwise and the reaction was stirred at rt for about 16 h. The mixture was cooled to about 0° C. then HOAc (10 mL) was added. The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (4 mL) and 6 N aqueous HCl (8.0 mL, 48.0 mmol). The mixture was heated at about 100° C. for about 16 h then cooled to rt and concentrated in vacuo to remove the dioxane. The mixture was neutralized with saturated NaHCO3 then adjusted to pH 5 with HOAc. The mixture was extracted with EtOAc (2×100 mL). The combined organic solutions were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, O-5% MeOH/DCM) to give 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoic acid (0.277 g, 58%): LC-MS (Table 1, Method g) Rt=1.66 min, m/z 376 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.57 (s, 1H), 8.32-8.25 (m, 1H), 7.72-7.57 (m, 3H), 7.43-7.39 (m, 1H), 7.07-7.03 (m, 1H), 6.68 (d, J=8.0 Hz, 1H), 5.32-5.27 (m, 1H), 4.23 (d, J=15.6 Hz, 1H), 3.97 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 2.64-2.55 (m, 4H), 2.40-2.27 (m, 2H), 2.18-2.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([CH2:18][CH2:19][CH:20]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[C:21]([O:23]C)=[O:22])[C:14]([O:16]C)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].O.Cl>C(O)C>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH:20]([CH2:19][CH2:18][CH:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:14]([OH:16])=[O:15])[C:21]([OH:23])=[O:22])[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COC(=O)C(CCC(C(=O)OC)c1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(CCC(C(=O)O)c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc(OC)c1OC
Yield: 97 %

Procedure:
A mixture of dimethyl α,α'-bis(3,4,5-trimethoxyphenyl)adipate (11.0 g, 21.7 mmoles), potassium hydroxide (13.0 g, 202 mmoles), water (163 ml), and ethanol (65 ml) was heated at 90° in a nitrogen atmosphere for 3 hours. After cooling the clear solution was added slowly to 250 ml of 1N hydrochloric acid with vigorous stirring. The slurry was stirred and warmed to 50° for several minutes. After cooling in an ice bath the solid was filtered, washed with water (4 times) and dried to give 10.07 g (97%) of α,α'-bis(3,4,5-trimethoxyphenyl)adipic acid, m.p. 226°-233°. NMR (DMSO-d6) indicates a 9:1 mixture of meso and racemic isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([NH:45][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:29])[F:30])[C:9]=3[CH:17]=2)=[CH:26][CH:25]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Product: O=C(NC(c1ccccc1)c1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z=613.00 (M+H+); retention time=1.06 minutes.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].O.C(=O)([O-])[O-].[K+:38].[K+]>CO>[K+:38].[C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 1 h

Procedure:
A 100 mg (0.23 mM) quantity (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Preparation No. 6, 5Ba) is stirred at room temperature under nitrogen in 3 mL MeOH. Added 0.1 mL water and 43 mg (0.31 mM) potassium carbonate. After 1 hour, TLC shows no starting material left. Store in freezer overnight. The next morning the solvent is evaporated to give (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (6Ba). The residue is partitioned between methylene chloride and water containing 0.9 mL 1N HCl. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated. This leaves (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7Ba) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:12][C:10](=[O:11])[NH:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)NNc1ccc(Br)cc1
Reactant: CCOC(OCC)OCC
Product: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
A solution of compound 52a (10 g, 43 mmol) and triethoxymethane (300 mL) was stirred at 120° C. for 2 h and allowed to cool to rt. The solids were collected by filtration and washed with Et2O (2×50 mL) to obtain compound 52b as a grey solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H6BrN3O: 240.0 (M+H). Found 240.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH2:30])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH:30][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:28][CH2:29]2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NC1(c2cccc(Br)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(c2cccc(Br)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.500 g, 1.94 mmol), 1-(3-bromophenyl)cyclopropanamine (453 mg, 2.14 mmol) and N,N-diisopropylethylamine (1.73 mL, 9.72 mmol) in DMF (18 mL) is added TBTU (0.780 g, 2.43 mmol). After 2 hours, the mixture is concentrated in vacuo, dissolved in ethyl acetate (200 mL), and washed with 2N sodium hydroxide (3×100 mL), saturated aqueous ammonium chloride (2×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL). The organic layer is dried over MgSO4, filtered through a pad of silica gel eluting with ethyl acetate (3×100 mL), and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 50-70% ethyl acetate in heptane to give a solid that is triturated with methylene chloride to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.[F:40][C:41]([F:51])([F:50])[O:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl>[Cl:21][C:11]1[CH:12]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:14]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[NH:47][C:46]1[CH:48]=[CH:49][C:43]([O:42][C:41]([F:40])([F:50])[F:51])=[CH:44][CH:45]=1
Reactant: O=C(O)CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)Nc1ccc(OC(F)(F)F)cc1
Yield: 72 %

Procedure:
p To a solution of 0.26 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)butyric acid and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise 0.14 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, while stirring under ice cooling. After stirring for 30 minutes, a solution of 0.12 g of 4-trifluoromethoxyaniline dissolved in 5 ml of dichloromethane was added dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.26 g of 3,5-dichloro-4-(3-(N-(4-trifluoromethoxyphenyl)carbamoyl)-propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (70% yield), m.p., 88.8° C.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:41][C:42]([N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]1([CH3:53])[CH3:52])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]2([CH3:53])[CH3:52])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 5.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.0 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([NH:14][C:15](=[O:17])[CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:19]>>[CH3:19][N:14]([CH:12]1[CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13]1)[C:15](=[O:17])[CH3:16]
Reactant: CI
Reactant: CC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Product: CC(=O)N(C)C1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
Reaction SMILES: [BH4-].[Na+].[Br-].[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N+:16]([CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CCO>[C:4]([O:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:9]([O:8][CH2:4][CH3:5])=[O:10])([CH3:28])[CH3:27])[CH2:15][C:14]=2[CH:13]=[CH:12]1)=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)CCCCCC(c1ccccc1Cl)[n+]1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Portions of sodium borohydride (0.16 g, 4.28 mmol) were added to a solution of 1-tert-butoxycarbonyl-5-[1-(2-chlorophenyl)-7-methyloctyl]-1H-pyrrolo[3,2-c]pyridin-5-ium bromide (1.3 g, 2.14 mmol) in 70% EtOH (30 mL) at room temperature over 30 minutes. Once the addition was complete, the mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure and water (60 mL) was added. The product was extracted with dichloromethane (3×80 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The resultant tertiary amine was purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to yield 5-[1-(2-chlorophenyl)-7-ethoxycarbonyl-7-methyloctyl]-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.53 g, 46.9%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.52 (d, 1H, J=7.8 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=6.6 Hz), 7.19 (t, 1H, J=7.5 Hz), 7.12 (d, 1H, J=3.3 Hz), 5.95 (d, 1H, J=3.3 Hz), 4.16-4.13 (m, 1H), 4.09 (q, 2H, J=7.2 Hz), 3.31 (d, 1H, J=13.8 Hz), 2.85-2.59 (m, 4H), 1.95-1.76 (m, 2H), 1.55 (s, 9H), 1.45-1.40 (m, 2H), 1.28-1.14 (m, 6H), 1.21 (t, 3H, J=7.2 Hz), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.00, 149.47, 139.70, 134.90, 129.45, 129.15, 127.89, 127.60, 126.80, 120.94, 119.76, 109.18, 83.24, 63.80, 60.30, 48.78, 42.32, 40.88, 33.20, 30.56, 28.31, 26.45, 25.44, 25.38, 25.03, 14.52. HRMS (FIR): Calculated for C30H43ClN2O2 (M+H)+: 531.2990, found 531.2933.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[F:5][C:6]1[CH:36]=[CH:35][C:9]2[S:10][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[S:25][CH:26]=[C:27](CO)[N:28]=4)=[CH:20][C:19]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:16])=[O:15])=[C:12]([CH3:13])[C:8]=2[CH:7]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[Cl:4][CH2:1][C:27]1[N:28]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][S:14]([C:11]3[S:10][C:9]4[CH:35]=[CH:36][C:6]([F:5])=[CH:7][C:8]=4[C:12]=3[CH3:13])(=[O:15])=[O:16])=[C:19]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:20]=2)[S:25][CH:26]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CO)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CCl)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Into 20 mL of chloroform was suspended 159 mg of Compound 63, and 47 μL of thionyl chloride was added at 0° C., followed by 21 hours of stirring at room temperature. Further, 1 mL of thionyl chloride was added, followed by 1 hour of heating under refluxing. After 2 mL of triethylamine was added at 0° C. and the mixture was stirred for 3 hours, the reaction was terminated with 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, successively and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain 104 mg of the title compound as light brown powder.