Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2SC(C(OCC)=O)=C(C)N=2)=CC=1[N+]([O-])=O.[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:35]([N+:45]([O-:47])=[O:46])[CH:34]=2)[S:26][C:27]=1[C:28]([O:30]CC)=[O:29]>N1CCCCC1>[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[C:35]([N+:45]([O-:47])=[O:46])[CH:34]=2)[S:26][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)c1sc(-c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)nc1C
Agent: CCOC(=O)c1sc(-c2ccc(Cl)c([N+](=O)[O-])c2)nc1C
Solvent: C1CCNCC1
Product: Cc1nc(-c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)sc1C(=O)O
Yield: 63 %

Procedure:
As described in Example 37, ethyl 2-(4-chloro-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate was reacted in piperidine, and the resulting ethyl 4-methyl-2-(3-nitro-4-piperidinophenyl)-5-thiazolecarboxylate was hydrolyzed by a conventional process to give 135 mg of 4-methyl-2-(3-nitro-4-piperidinophenyl)-5-thiazolecarboxylic acid (yield: 63%).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[S:25]1C=CC=C1CN>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[S:25][CH:22]=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1cccs1
Agent: Cl
Product: Cc1nc(NCc2cccs2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (2-thienylmethyl)amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.35 (m, 5H), 1.65-1.79 (m, 5H), 1.89 (s, 3H), 2.23 (s, 3H), 4.08 (bs, 1H), 4.71 (d, J=4.57 Hz, 2H), 6.96 (s, 1H), 7.05 (s, 1H), 7.40 (d, J=4.57 Hz, 1H), 7.70 (d, J=6.72 Hz, 1H), 8.07 (s, 1H); MS (ESI) m/z 317.7 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.CCOC(C)=O>[C:21]([C:18]1[N:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(C#N)nc2)cc1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
4-Methoxycarbonylphenyl boronic acid (0.5 g) and 5-bromo-2-pyridinecarbonitrile (0.5 g) in a mixture of THF (5 ml) and water (5 ml) were treated with tetrakis(triphenyl phosphine)palladium(0) (0.32 g) and potassium carbonate (1 g). A further amount of THF (5 ml) was added and the reaction was heated at 80° C. for 1 h. After cooling the reaction mixture was diluted with EtOAc (30 ml) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried (magnesium sulfate) and concentrated to give a crude residue that was purified by column chromatography (silica-gel, gradient 0-100% EtOAc in hexane) to give the title compound (D8) as a white solid (0.5 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: B.C1COCC1.Cl.[CH3:8][C@H:9]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[C@@H:13]([CH3:29])[C:12]2[S:30][CH:31]=[CH:32][C:11]=2[CH2:10]1>>[CH3:8][C@H:9]1[N:14]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[C@@H:13]([CH3:29])[C:12]2[S:30][CH:31]=[CH:32][C:11]=2[CH2:10]1
Reactant: C[C@@H]1Cc2ccsc2[C@H](C)N1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H]1Cc2ccsc2[C@H](C)N1CCNCc1ccc([N+](=O)[O-])cc1
Yield: 58.3 %

Procedure:
A borane/THF (48 ml, 48 mmol) solution of the amide from Example 28 (3.50 g, 9.74 mmol) was stirred at reflux for 12 hours under nitrogen. After the solution was quenched with 6N HCl, the THF was removed in vacuo. The acidic residue was warmed on a steambath for 15-20 min and then it was treated with 50% NaOH to afford a pH of 10. The aqueous mixture was extracted with CH2Cl2 and the combined extract was washed with brine and dried (Na2SO4). Solvent removal produced the crude product that was purified by flash silica gel column chromatography using 0.5-4% MeOH in CH2Cl2. There was obtained 1.96 g (58%) of the title compound that was treated with oxalic acid (1.1 eq) in acetone to produce a tan solid: mp 211°- 213° C.; IR (KBr) 3040, 2840, 1720, 1625, 1520, 1345, 1210, 855, 715 and 700 cm-1.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:20][CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=C(CCNCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl acrylate (2 g) in ethanol (15 mL) was added benzylamine (1.75 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (2.91 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.10 g, 6.81 mmol), triethylamine (1.21 mL, 8.67 mmol) in DCM (25.2 mL) was cooled in an ice/water bath and treated with methanesulfonyl chloride (675 μL, 8.67 mmol) added dropwise under an atmosphere of nitrogen. The mixture was stirred at 25° C. overnight. The mixture was treated with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2×50 mL). The extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo leaving a beige oil which was recrystallized from hexanes (22 mL) to give 1.59 g (98%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.61-1.68 (m, 2H), 1.82-1.90 (m, 2H), 1.94-2.08 (m, 4H), 3.02 (s, 3H), 3.91-4.00 (m, 4H), 4.82-4.88 (m, 1H); MS (ESI): 237.10 [M+H]+; HPLC tR=2.54 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15]I.[OH-].[K+]>CN(C=O)C.O>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 197.7 %

Procedure:
Indole-5-carboxylic acid (200 mg, 1.24 mmol) was dissolved in DMF (2 mL), and the solution was added with 60% sodium hydride-mineral oil dispersant (164 mg, 4.1 mmol), followed by stirring at room temperature for 10 minutes. The mixture was added with methyl iodide (0.258 mL, 0.410 mmol), stirred at room temperature for 3 hours and then added with 4 mol/L aqueous potassium hydroxide solution (2 mL), followed by stirring at 80° C. for 5 hours. The reaction mixture was added with water, and the organic layer was separated from aqueous layer. The aqueous layer was added with 1 mol/L hydrochloric acid to adjust the pH to 1, followed by stirring at room temperature for 1 hour. The obtained solid was collected by filtration and dried under reduced pressure to obtain 1-methylindole-5-carboxylic acid (142 mg, yield 65%).
Reaction SMILES: NN.C([C:11]1[C:15]([NH:16][C:17](=[O:30])[CH2:18][N:19]2C(=O)[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=O)=[C:14](C2C=CC=CC=2)[NH:13][C:12]=1[CH3:37])(=O)C1C=CC=CC=1>>[C:21]1([C:20]2[C:11]3[C:15](=[C:14]([C:21]4[CH:22]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:13][C:12]=3[CH3:37])[NH:16][C:17](=[O:30])[CH2:18][N:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:22]=1
Reactant: Cc1[nH]c(-c2ccccc2)c(NC(=O)CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1
Agent: NN
Product: Cc1[nH]c(-c2ccccc2)c2c1C(c1ccccc1)=NCC(=O)N2

Procedure:
To a solution of 7 g. of anhydrous hydrazine in 350 ml. of methano 27.8 g. of 3-benzoyl-2-methyl-5-phenyl-4-(phthalimidoacetamido)pyrrole are added and the mixture is refluxed for one hour. The solvent is evaporated off and 150 ml. of concentrated hydrochloric acid are added to the residue. After refluxing for one hour the solid precipitated is eliminated by filtration and the filtrate is diluted with water and then alkalinized with 10% sodium hydroxide. The precipitate is crystallized twice from methanol yielding 9 g. of the title product which melts at 310°-12° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:7][NH:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[CH:7][N:8]2[CH2:31][CH2:32][CH2:33][C:34]#[N:35]
Reactant: COc1ccc(-c2c[nH]c3c(OC)ccc(OC)c3c2=O)cc1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(CCCC#N)c3c(OC)ccc(OC)c3c2=O)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
400 mg (1.28 mmol) of compound 29 are added to 10 ml of anhydrous N,N-dimethylformamide under a nitrogen atmosphere. 1.35 g of anhydrous potassium carbonate (7.5 eq) and then 0.35 ml of 4-chlorobutyronitrile (3 eq) are successively added to this suspension. The reaction is stirred at 90° C. for 18 hours. The solvents are evaporated off. The residue is taken up in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica treated with triethylamine (eluent: 7/3 CH2Cl2/EtOAc) to give 180 mg (37%) of compound 80 and 274 mg (56%) of derivative 81.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OC(O)C)C>[OH:23][CH2:22][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3)c2cc1OC

Procedure:
A stirred mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (7.46 g, 30 mmol), 3-aminobenzyl alcohol (7.39 g, 60 mmol), pyridine (2.43 ml, 30 mmol), and 90 ml of ethoxyethanol was refluxed for 5 h, cooled, and stirred with aqueous sodium bicarbonate. The resulting solid was filtered, washed with water, and dried. Recrystallization from methanol gave a brown solid, mp 250-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH2:12][CH3:13].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH2:17][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(F)cc21
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2c(Cl)cc(F)cc21

Procedure:
The title compound is prepared according to process H using processing method 1 from 7-chloro-3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)-piperazine.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:34][S:35]([NH:38][C:30]([CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:33])=[CH:6][CH:5]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:31])(=[O:37])=[O:36]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)NS(C)(=O)=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98.1 %

Procedure:
[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3B-1) (203 mg), methanesulfonamide (84 mg), 1,3-dicyclohexylcarbodiimide (101 mg) and 4-dimethylaminopyridine (59 mg) were dissolved in dichloromethane (5 mL). The solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, dichloromethane-methanol (10:1)] to give the title compound (233 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NCc1ccco1
Yield: 90.8 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethylene)amine (1.86 g, 5.81 mmol) in 20 mL of methanol was treated with NaBH4 (0.659 g, 17.4 mmol) and stirred under an atmosphere of nitrogen. After 18 h the reaction was quenched by addition of 20 mL of water. The reaction mixture was concentrated under reduced pressure and dissolved in CHCl3. The organic portion was washed with 2% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethyl)amine (1.70 g) as a thick orange syrup.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[CH:7]=1
Reactant: FC(F)(F)c1cnn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C(F)(F)F)cn1
Yield: 18.8 %

Procedure:
0.60 g of 1-(chloromethyl)-4-(trifluoromethyl)-1H-pyrazole and 0.54 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.99 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-chloroform to obtain 0.19 g of {[4-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (22), hereinafter) shown by below formula.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([NH:38][S:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][S:39]([C:42]1[CH:47]=[C:46]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=4)[CH:11]=[C:10]([C:30]([F:32])([F:31])[F:33])[N:9]=3)[CH:3]=2)[CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-{4-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromophenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.38 g, 0.69 mmol) and commercially available 3-(tert.-butylsulfamoyl)phenylboronic acid (0.23 g, 0.89 mmol) according to the general procedure VI. Obtained as light yellow solid (0.45 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[N:11]([CH2:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([S:38]P([O-])(OCC)=S)C.O>C1COCC1>[C:29]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:11]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10](=[O:35])[NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]([NH2:2])=[S:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#Cc1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Temperature: 40 °C
Reaction time: 27 h

Procedure:
70 mg (0.15 mmol, 1 eq.) of 3-(3-cyanophenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 19) are dissolved in 0.5 mL of THF under argon. 142 μL (0.90 mmol, 6 eq.) of diethyldithiophosphate and 50 μL (0.01 mmol, 0.1 eq.) of water are added. The mixture is stirred for 27 hours at 40° C. Water is added to the medium and the aqueous phase is extracted with dichloromethane, washed twice with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is subjected to chromatography over silica gel (eluent: 97/3 dichloromethane/methanol) in order to obtain the expected product in the form of a yellow powder (55 mg, yield=73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[C:7]2[NH:8][CH:12]=[CH:13][C:6]=12
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cnc(Cl)c2[nH]ccc12
Temperature: -20 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 2,5-dichloro-3-nitropyridine (5.00 g, 25.9 mmol) in tetrahydrofuran (164 ml) was added a solution of 1 mol/L vinylmagnesium bromide in tetrahydrofuran (82.9 ml, 82.9 mmol) at −78° C. The mixture was stirred at −20° C. overnight, and then to the reaction solution was added saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→7:3), and then washed with diisopropyl ether to give 4,7-dichloro-1H-pyrrolo[2,3-c]pyridine (1.12 g, 23%) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:16])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(OC(=O)C(C)(C)C)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (5.0 g, 14.9 mmol) was dissolved in DMF (100 mL) and sodium hydride (1.8 g, 45 mmol) was added, and the mixture stirred at RT for 15 min. Pivaloyl chloride (3 g, 25 mmol) was added dropwise at the same temperature, and the mixture stirred for 45 min. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into 400 mL ice water to obtain a solid that was filtered. The solid was dissolved in DCM, dried over sodium sulfate and concentrated to obtain the crude product that was purified by column chromatography (silica gel: 100-200 mesh, Eluent: −4-6% MeOH in DCM) to obtain 1.8 g of 2,2-dimethyl-propionic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethyl ester. The product was further purified by chiral preparative HPLC to give enantiomers II-16a and II-16b. 1H NMR (CDCl3, Free base): δ (ppm): 8.55 (d, 1H), 8.5 (s, 1H), 7.2 (d, 1H), 7.18 (m, 3H), 6.9 (d, 1H), 4.3 (dd, 2H), 3.65 (d, 1H), 3.52 (d, 1H), 2.65 (m, 2H), 2.5 (m, 2H), 2.5 (s, 3H), 2.4 (s, 3H), 2.3 (d, 1H), 2.0 (s, 3H), 2.0 (m, 1H), 1.2 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].OS(O)(=O)=O.[CH3:21]O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH3:21])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1

Procedure:
To a solution of 2-(4-isobutyl-phenyl)-propionic acid (5.00 g, 24.2 mmol) in anhydrous MeOH (150 mL) was added conc H2SO4 (catalytic) and heated to reflux for 5 hrs. After cooling, the solution was evaporated to dryness, the residue dissolved in methylene chloride, dried (MgSO4), filtered and evaporated to yield methyl 2-(4isobutyl-phenyl)-propionate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.19 (2H, d, J=8,1 Hz), 7.09 (2H, d, J=8.1 Hz), 3.71 (1H, q, J=7.2 Hz), 3.66 (3H, s), 2.44 (2H, d, J=7.2 Hz), 1.84 (1H, app. septet, J=6.7 Hz), 1.48 (3H, d, J=7.2 Hz), 0.90 (6H, d, J=6.6 Hz).