Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].S(Cl)([Cl:14])=O>>[CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cnccc1C(=O)O
Product: CCc1cnccc1C(=O)Cl
Temperature: 25 °C

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([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C@@:33]([OH:38])([C:14]#[C:13][CH:10]1[CH2:12][CH2:11]1)[C:34]([F:36])([F:37])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide 3 M in ether (2 mL, 6.2 mmol) was added slowly to a solution of cyclopropyl acetylene (0.41 g, 6.2 mmol) in THF (5 mL) in an ice-bath under argon. The mixture was stirred at 0° C. for 1 hour and then 40° C. for 2 hours. Then (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)phenylamino)-2-oxo-1-phenylethyl pivalate (12, 0.55 g, 1.24 mmol) in THF (2 mL) was added slowly in an ice-bath. The mixture was stirred at 0° C. for 1.5 hours. 10% Citric acid was added to quench the reaction. The organic layer was washed with water and then evaporated to dryness to give (R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phe nylamino)-2-oxo-1-phenylethyl pivalate (13). This solid was shown to be 35.9% de by chiral HPLC. The pure product was isolated by chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2Cl)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Reactant: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2nc3ccccc3c(Oc3ccccc3)c2CC1
Reaction time: 40 h

Procedure:
A mixture of 15.0 gm (49.4 millimols) of 11-chloro-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and 28.2 gm (300 millimols) of phenol was melted at 150° C and held at that temperature for 40 hours. Then, the mixture was taken up in ethyl acetate, and the solution was extracted with dilute sodium hydroxide. The ethyl acetate phases were evaporated and chromatographed on a silicagel column with toluene/acetone (8:1) as the eluant. Subsequently, the crystals were triturated with ether/petroleum ether.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[N+](=[C:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])=[N-]>ClCCl.C(OCC)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:4][CH2:3][CH2:2][CH2:1][O:5][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: OCCCO
Reactant: [N-]=[N+]=C1CCOC1=O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1OCCC1OCCCO
Temperature: 25 °C

Procedure:
Propane-1,3-diol (0.050 g, 0.657 mmol) was dissolved in dichloromethane (6.5 mL) and treated with rhodium (II) acetate (3 mg) then solution was heated to reflux. One third of a solution (ca. 2 mL) of 3-diazodihydrofuran-2(3H)-one (0.283 g, 0.986 mmol) dissolved in a mixture of dichloromethane (3 mL) and diethyl ether (2.5 mL) was added dropwise to the hot solution then the solution was heated at reflux for 30 minutes. The solution of 3-diazodihydrofuran-2(3H)-one was added in two portions (ca. 2 mL each) to the refluxing mixture in a similar manner. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude oil was chromatographed on silica gel eluting with ethyl acetate/hexanes (2:1). 3-(3-Hydroxypropoxy)dihydrofuran-2(3H)-one was recovered as a colorless oil (47 mg, 45%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of 4 g (0.16 mol) of sodium hydride in 200 ml of DMF 20 at 0° C. was added 10 g (0.145 mol) of 1,2,4-triazole in 75 ml of DMF dropwise over a period of 30 minutes, and the mixture was allowed to warm to room temperature and stirred for 1 h. The above mixture was cooled to 0° C., 25 g (0.16 mol) of p-methoxybenzyl chloride was added, the mixture was allowed to warm to room temperature, and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica (hexane/ethyl acetate) to afford 21.9 g (64.5%) of 1-(p-methoxybenzyl)-1,2,4-triazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O.CCOC(C)=O>[C:14]([O:13][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[C:3]([C:1]#[N:2])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A flask was charged with tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (9.410 g, 40.00 mmol), methyl 4-hydroxybenzoate (7.303 g, 48.00 mmol), K2CO3 (6.634 g, 48.00 mmol), and DMSO (160 mL). The mixture was heated to 90° C. under a nitrogen atmosphere for 17 hours. The mixture was cooled to ambient temperature and poured into a mixture of EtOAc (250 mL) and 10% K2CO3 solution (250 mL). The resulting insoluble residue was dissolved in water and added to the EtOAc-aqueous mixture. The mixture was stirred for 1 hour and layers were separated. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with saturated K2CO3, water, and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to give 14.7 g of crude product as an oil. The crude material was purified by silica gel chromatography to provide methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (11.6 g, 79%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:34][C:33]4[CH:35]=[CH:36][C:37]5[O:38][CH2:39][CH2:29][O:30][C:31]=5[CH:32]=4)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 65 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28-7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1cccc(-c2cccnc2)c1F
Product: Fc1c(-c2cccnc2)cccc1-c1ccnc2nc(C(F)(F)F)ccc12
Yield: 44.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2-fluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (36 mg, 45%). δH (360 MHz, CDCl3) 7.40-7.55 (3H, m), 7.65-7.70 (2H, m), 7.84 (1H, d, J 8.4), 7.93 (1H, dq, J 8.1 and 1.9), 8.37 (1H, dd, J 2.3 and 8.6), 8.67 (1H, dd, J 1.6 and 4.7), 8.86 (1H, s), 9.34 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=O)C.O.[NH2:20]N>CCO>[NH:20]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[CH:4]=[N:2]1
Reactant: NN
Reactant: CN(C)C=C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cn[nH]c2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a stirred mixture of tert-butyl 4-((dimethylamino)methylene)-3-oxopiperidine-1-carboxylate (1.0 g, 4 mmol) in EtOH (10 mL) was added hydrazine hydrate (376 mg, 10 mmol). The mixture was stirred at 80° C. for 16 hours until the reaction was shown to be complete by LCMS. The mixture was then concentrated and the residue was extracted with EA (3×30 mL) from water (30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step (810 mg, 90% yield). LCMS: 224.1 (M+1), 114.1 (M+1−100), 168.1 (M+1−56).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27]>C(Cl)Cl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C=CC(C)(O)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12

Procedure:
Triethyl amine (6.2 mL, 0.045 mole) was added to a solution of 2,4-dichloro-3-nitroquinoline (10.9 g, 0.045 mole) in methylene chloride (60 mL). 4-Amino-3-methyl-1-butene-3-ol was added and the reaction mixture was heated at reflux for several hours before being concentrated under vacuum. The residue was chilled in an ice bath to give a solid. The solid was recrystallized from toluene to provide 17.1 g of the desired product as a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:30][N:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:30][N:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
N-[(4aR,7aR)-6-(5-Fluoropyrimidin-2-yl)-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (5 g, 11.5 mmol) is added to lithium hydroxide (530 mg, 12.6 mmol) in methanol (50 mL) at 22° C. The reaction mixture is refluxed for 3 hours and then cooled to 22° C. Hydrogen chloride, 2 M in water (20.3 mL) is added and then solvent is evaporated. The solution is washed with MTBE (50 mL). The aqueous solution is treated with charcoal (500 mg) and stirred 30 minutes at 22° C. The mixture is filtered over diatomaceous earth and the pH of the filtrate is adjusted to pH=9 with sodium hydroxide (2M aqueous solution). A white solid precipitates and is collected. The solid is dried under vacuum to a constant weight to give the title compound (1 g, 30%). ES/MS (m/e): 337 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1cc(-c2ccccc2F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-bromo-2-nitrobenzaldehyde (8.2 g, 36 mmol), 2-fluorobenzeneboronic acid (10.0 g, 71.6 mmol) and 2M K2CO3 (54 mL) in dioxane (250 mL) was degassed with nitrogen. Pd(PPh3)4 (3.9 g, 3.6 mmol) was added, and the resulting mixture was degassed again and heated to reflux for 90 minutes. The resulting mixture was then diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The EtOAc extract was dried with MgSO4, filtered, and concentrated in vacuo to yield a residue. The residue was purified by silica gel chromatography eluted with ethyl acetate and heptanes from 0:100 to 5:95 to yield a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a solution of 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.8 g, 13 mmoles) in THF (30 ml) and triethyl amine (5.5 ml, 39 mmoles) was added methanesulfonyl chloride (1.12 ml, 14 mmoles) and the reaction mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated and the residue was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous Na2CO3 solution and taken to dryness. The crude residue was purified by flash chromatography (CH2Cl2-methanol 96-4) to give 0.5 g of the title compound as a white solid. M.p. 162-170° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CS(C)=O>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:9]2[C:10]([CH2:12][CH3:13])=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1cc(-c2ccccc2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cc(-c2ccccc2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
To a solution of 3-phenyl-5-ethylpyrazole (1.0 g, 5.8 mmol) in DMSO (5 mL) was added potassium t-butoxide (0.72 g, 6.4 mmol) followed by 4-fluoronitrobenzene (0.65 mL, 6.4 mmol). The mixture was heated at 90° C. for 1 hour, cooled to rt, and quenched with water (50 mL). The precipitate was collected by filtration, redissolved in ethyl acetate (50 mL), treated with active carbon (3 g), and filtered through diatomaceous earth. The mixture was concentrated to 5 mL, and hexane (25 mL) was added. The 1-(4′-nitrophenyl)-3-phenyl-5-ethylpyrazole was collected by filtration (1.70 g, 92%): mp 112-113° C. NMR 8.39 (2H, d), 7.79 (2H, d), 7.90 (2H, m), 7.45 (2H, m), 7.38 (1H, m), 6.66 (1H, s), 2.86 (2H, q), 1.38 (3H, t).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([S:43][CH3:44])[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)=[O:18])=[C:11]([F:45])[C:10]=1[O:46][C:47]1[CH:52]=[C:51]([C:53]#[N:54])[CH:50]=[C:49]([Cl:55])[CH:48]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([S:43][CH3:44])[NH:22][CH:23]=2)=[O:18])=[C:11]([F:45])[C:10]=1[O:46][C:47]1[CH:52]=[C:51]([C:53]#[N:54])[CH:50]=[C:49]([Cl:55])[CH:48]=1
Reactant: CSc1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Yield: 75.2 %

Procedure:
N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(methylthio)-1-(triphenylmethyl)-1H-imidazole-4-carboxamide trifluoroacetate (0.030 g, 0.04 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (2 mL) and stirred for 2 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized to afford the title compound (0.017 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.43-7.52 (m, 3H), 7.30 (t, 1H), 4.45 (d, 2H), 2.55 (s, 3H). MS: m/z 451.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:24]#[N:25])=[CH:17][CH:16]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1Cc1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 58.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 2-cyanophenylboronic acid (0.034 g; 0.229 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.067 g; 0.450 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.052 g (56%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.[C:27](O)(=O)[CH3:28].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH2:27]([N:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:6])=[O:7])[CH2:2]1)[CH3:28]
Reactant: CC(=O)O
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(S(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CCN(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (STEP A, 25 mg, 0.066 mmol), acetic acid (11 microL, 0.20 mmol) and acetaldehyde (75 microL, 1.3 mmol) in dichloromethane (1 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (28 mg, 0.13 mmol) at room temperature. After 1 h, the mixture was concentrated. The residue was diluted with methanol (4 mL). The solution was filtered through SCX column and the column was washed with 1 mol/L ammonia in methanol solution (2 mL×2) to wash out the desired compound. The filtrate was concentrated in vacuo. The residue was purified by prep-LC-MS (“process A”).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14].C(N(CC)CC)C.C(O)C>C(#N)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:16](=[O:17])[N:15]([CH2:12][CH2:13][CH3:14])[C:4]2=[O:6]
Reactant: CCCN=C=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CCCn1c(=O)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.019 mol) 2-amino-5-iodobenzoic acid, 1.9 g (0.012 mol) n-propyl isocyanate, and 1.9 g (0.019 mol) triethylamine in 190 mL of acetonitrile was stirred at ambient temperature overnight. An additional 1.9 g (0.012 mol) of n-propyl isocyanate was added and stirring continued at ambient temperature for an additional 72 h. The reaction was then concentrated by atmospheric pressure distillation to deliver 7.8 g of an oil which solidified upon standing under reduced pressure. A 3.6 g portion of this crude material was subjected to heating neat at 190° C. for 0.75 h. The resulting reaction mass was cooled, treated with approximately 20 mL ethanol, agitated, and filtered. The filter cake was subsequently washed with ether and dried to deliver 1.8 g of the title compound, 1H NMR (300 MHz, Me2SO--d6): δ0.87 (s,3H); 1.50-1.69 (m,2H); 3.83 (t,2H); 6.99 (d,1H); 7.94 (dd,1H); 8.16 (d,1H); 11.50 (bs,1H).