Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:8]([Li])[CH2:9][CH2:10]C.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.C1(Br)CCCC1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([CH:6]2[CH2:5][CH2:7][CH2:10][CH2:9][CH2:8]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CC(C)NC(C)C
Agent: BrC1CCCC1
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.4 M in hexanes, 5.4 mL, 12.9 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydrofuran (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via syringe, and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×15 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×15 mL), and the combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 40% EtOAc/hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclohexyl)acetic acid as a clear oil. HRMS: calcd for C13H15ClO2−H, 237.06823; found (ESI, [M−H]−), 237.0682
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:23]([F:26])([F:25])[F:24])[C:3]=1[C:27](=[O:29])[NH2:28].CO[C:32](=O)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].[O-]CC.[Na+]>CCO>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][C:32]1[NH:28][C:27](=[O:29])[C:3]2[C:4]([C:23]([F:26])([F:25])[F:24])=[N:5][N:6]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:11][CH2:12]3)[C:2]=2[N:1]=1
Reactant: NC(=O)c1c(C(F)(F)F)nn(C2CCN(C(=O)OCc3ccccc3)CC2)c1N
Reactant: COC(=O)Cc1ccccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Cc1nc2c(c(C(F)(F)F)nn2C2CCN(C(=O)OCc3ccccc3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a stirred solution of 117 (327 mg, 0.795 mmol) in EtOH (3.2 mL) was added 2-Methoxyphenylacetic acid methyl ester (0.26 mL, 1.59 mmol), and then Sodium ethoxide (21% in EtOH, 0.6 mL, 1.59 mmol) and the resulting solution was allowed to stir for 1 h at room temperature, then for 3 h at 75° C. After the usual work-up the crude material was purified via Biotage (10% to 60% EtOAc/Hexane; 12M column) to afford 118 (98 mg, 22.8% yield) as white solid, LRMS (ESI): calc. 541.5; found 542.3 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:13]2[C:8](=[CH:9][C:10]([O:34][CH3:35])=[C:11]([O:32][CH3:33])[CH:12]=2)[N:7]1[C:36]([O:38][CH:39]([CH2:41][CH3:42])[CH3:40])=[O:37])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:50]([O:52][CH3:53])=[O:51]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([N:16]([CH2:17][C:18]2[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[C:50]([O:52][CH3:53])=[O:51])[C:13]2[C:8](=[CH:9][C:10]([O:34][CH3:35])=[C:11]([O:32][CH3:33])[CH:12]=2)[N:7]1[C:36]([O:38][CH:39]([CH2:41][CH3:42])[CH3:40])=[O:37])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 4) (approximately 500 mg, 0.83 mmol) and pyridine (195 mg, 2.5 mmol) were dissolved in anhydrous dichloromethane (100 mL) and cooled to 0° C. Methyl chloroformate (195 mg, 2.1 mmol) was added slowly. The reaction was stirred at 0° C. for 1 h, then at room temperature for 18 h. The reaction mixture was then diluted with chloroform, and washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title product (400 mg). MS m/z 664.2 (M+); 1H NMR (CDCl3) δ 0.9 (t, 3H), 1.3 (t, 3H), 1.5 (m, 2H), 3.85 (s, 3H), 4.0 (t, 2H) 6.3 (s, 1 H), 7.8 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6])[CH3:2].CN(C=O)C.[NH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([Cl:28])=[CH:20][C:19]=1[OH:29].C(N(CC)CC)C>O>[Cl:28][C:21]1[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]([NH:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][N:10]=[CH:11][C:3]=2[CH2:1][CH3:2])=[C:19]([OH:29])[CH:20]=1
Reactant: CCc1cnccc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cnccc1C(=O)Nc1cc(C(F)(F)F)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.62 g of 3-ethyl isonicotinic acid 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-ethyl isonicotinic acid chloride. A mixture of the resultant 3-ethyl isonicotinic acid chloride and 3 ml of DMF was added dropwise to a mixture of 0.87 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.83 g of triethylamine and 3 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for two hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]-3-ethyl isonicotinamide.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH:53][CH:54]([CH3:56])[CH3:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:53]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH:54]([CH3:56])[CH3:55])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)NC1CCCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C(C)C)C2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-cyclohexyl-N-isopropylamine (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C45H60Cl2N5O3 [(M+H)+] 788.4068, observed 788.4062.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[CH3:12][O-:13].[Na+].[CH3:15][OH:16]>>[Cl:11][C:4]1[C:5]([S:9][CH3:10])=[C:6]([O:13][CH3:12])[N:7]=[C:2]([O:16][CH3:15])[N:3]=1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1nc(Cl)c(SC)c(OC)n1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of 2,4,6-trichloro-5-methylsulfanyl-pyrimidine (5.00 g, 21.73 mmol.) was added dropwise to a slurry of sodium methoxide (2.47 g, 45.65 mmol, 2.1 eq) in MeOH (80 ml) in ice bath at 0° C., then the reaction mixture was stirred at r.t, for 2 hrs and dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and 0.1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 9:1) to give a gray solid 3.36 g (70.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[N:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=4)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ncc([N+](=O)[O-])cn4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 30.2 %

Procedure:
A 100 mL flask was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 3.71 mmol obtained from Example 5, step B), 2-chloro-5-nitropyrimidine (0.592 g, 3.71 mmol), cesium carbonate (1.21 g, 3.71 mmol) and DMF (20 mL). The solution was allowed to stir overnight at room temperature for 16.5 hours. The crude product was isolated by filtration and flash chromatography (EtOAc/Hexane 1:2) to afford 0.44 g (29%) of the desired product. LRMS M+1 (393.0) observed.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:18]=[C:19](N=C=O)[CH:20]=C[CH:22]=1)#[N:16].[CH3:26][N:27]([CH3:30])[CH:28]=[O:29]>O>[C:15]([C:17]1[CH:22]=[C:26]([N:27]([CH:30]2[CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]2)[C:28]([NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)=[O:29])[CH:20]=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NC1CCCN(Cc2ccccc2)C1
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(N(C(=O)NC2CCCN(Cc3ccccc3)C2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4.3 g of N-benzyl 3-aminopiperidine (22.6 mmol) and 3-cyanophenyl isocyanate (3.58 g, 24.9 mmol) in dimethylformamide (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The organic solution was washed with water (5×100 mL), dried and evaporated. This material was purified further by flash chromatography on silica gel using a gradient of 1:1 to 3:1 ethyl acetate:hexane. There was obtained 3.18 g of the pure urea (9.52 mmol); LRMS (M+H)+ m/z=335.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (840 mg, 3.35 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (663 mg, 3.05 mmol) were combined in anhydrous DCM (10 ml) and anhydrous MeOH (2 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.03 g, 9.12 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1 g, 71%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1>ClCCl>[CH:3]12[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH:2]1[CH:15]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C1C=CCCC1
Reactant: C1=CCCCCCC1
Solvent: ClCCl
Product: O=C1CCCC2C3CCCCCCC3C12
Yield: 83 %

Procedure:
A solution of 29.4 g. (0.3 mol.) of cyclohexenone and 200 ml. of cyclooctene in 2600 ml. of dichloromethane was irradiated at -65° C. in the low temperature photolysis apparatus described in Organic Prep. Proc. Int. 3, 61 (1971) with a 1000 watt G.E. mercury arc through a Corning 9700 glass filter for 4 hours. At the end of the photolysis the solution was concentrated in vacuo and the product was distilled through a short Vigreux-column to yield 51.8 g. (0.249 mol., 83% yield) of a mixture of four isomers having b.p. 108°-127° C./0.4 mm.Hg. IR: 1695 cm-1 confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2, 16.50 g, 59.25 mmol) in 250.0 mL of N,N-dimethylformamide, sodium hydride (3.10 g, 60% in mineral oil, 77.5 mmol) was added. The reaction was stirred at room temperature for 90 minutes, then triisopropysilyl chloride (3, 13.00 mL, 61.36 mmol) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (4, 10.0 g). 5-fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine is prepared similarly from 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:31]([O-])=O)=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:8].[H][H]>[Ni].C(O)(=O)C>[NH2:31][C:3]1[C:2]([Cl:1])=[CH:28][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:16][CH2:17]2)=[O:8])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [Ni]
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 4.2 parts of 5-chloro-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-methoxy-4-nitrobenzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with a diluted sodium hydroxide solution. The precipitated product is filtered off and crystallized from methanol. The product is filtered off (the filtrate is set aside) and dried, yielding a first fraction of 0.8 parts of 4-amino-5-chloro-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-methoxybenzamide; mp. 230.1° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>C(O)(C)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isoporpyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 121° C (from ethanol).
Reaction SMILES: C(N)CN.ClC1C=CC([N+]([O-])=O)=CC=1C.Cl.[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([NH:24][CH2:25][CH2:26][NH2:27])=[C:22]([CH3:30])[CH:21]=1)([O-:19])=[O:18].[N-:31]=[C:32]=[O:33].[K+]>>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([NH:24][CH2:25][CH2:26][NH:27][C:32]([NH2:31])=[O:33])=[C:22]([CH3:30])[CH:21]=1)([O-:19])=[O:18]
Reactant: [N-]=C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCN
Agent: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [K+]
Solvent: NCCN
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(N)=O

Procedure:
4-nitro-2-methyl-N-(β-aminoethyl) aniline monohydrochloride is obtained by reacting ethylene diamine with 2-chloro-5-nitro-toluene. This monohydrochloride is then reacted with potassium isocyanate to produce 4-nitro-2-methyl-N-(β-ureidoethyl) aniline, which is reduced with hydrazine and Raney's nickel to 4-amino-2-methyl-N-(β-ureidoethyl) aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:17])[C:3]=1[O:18][CH3:19].ClC1C=CC=C(F)C=1OC.C([Li:34])CCC>>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([F:17])[C:5]([Li:34])=[CH:6][CH:7]=1
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: [Li]CCCC
Agent: COc1c(F)cccc1Cl
Product: [Li]c1ccc(Cl)c(OC)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](=O)[C:25]([F:28])([F:27])[F:26])[C:20](=O)[C:19]2=[O:31])=[CH:14][CH:13]=1.C(O)C.Cl>C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20]3[C:19](=[O:31])[N:18]([C:15]4[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=4)[CH2:23][CH2:22][C:21]=3[C:24]([C:25]([F:28])([F:26])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2c(c(C(F)(F)F)nn2-c2ccc(F)c(Cl)c2)CCN1c1ccc(I)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Part A. 3-chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mol) and 1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione (12.8 g, 31.14 mmol) were added together with 120 mL of ethanol and 4 mL of hydrochloric acid (12 M). The mixture was stirred at reflux under N2 for overnight. The reaction was cooled down to rt. The solvents were removed, and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL×2) and brine (50 mL). It was then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography on silica gel using 4:1 hexane:ethylacetate to give 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one as a brown solid (12.5 g, 75% yield). LRMS (AP+): 536.1 (M+H)+. 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.67-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.19 (t, 3H), 7.06 (d, 2H), 4.12 (t, 2H), 3.17 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: OCc1cccc(Cl)c1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of (2-bromo-3-chloro phenyl)methanol (4.73 g, 21.24 mmol), which had been obtained in Reference example 5(5a), in methylene chloride (120 mL) was added with 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (10.8 g, 25.49 mmol) under ice cooling, and stirred at room temperature for 2 hours. The reaction solution was added with a mixture of saturated aqueous sodium hydrogen carbonate solution (60 mL) and saturated aqueous sodium thiosulfate solution (30 mL), and then stirred at room temperature for 0.5 hours. The mixture obtained was extracted with dichloromethane (90 mL×2). After that, the organic layers were combined 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=5/1) to give the title compound as a white solid (4.36 g, yield 94%).