Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[CH3:30].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[C:21]([CH3:30])[CH:22]=1)(=[O:27])=[O:28]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(C)c2)c(OC)c1
Yield: 59.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (590 mg, 2.40 mmol) prepared in Example 14a, 4-fluoro-3-methylbenzenesulfonyl chloride (WO 2010/079443; 1000 mg, 4.79 mmol), 1,4-diazabicyclo[2.2.2]octane (537 mg, 4.79 mmol) and THF (20 mL), to yield the title compound (598 mg, 50%) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=O)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH2:14]([N:13]([C:12]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:26][N+:23]([O-:25])=[O:24])=[CH:6][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:16][CH3:17])[CH3:15]
Reactant: C[N+](=O)[O-]
Reactant: CCN(CC)c1ccc(C=O)cc1NC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1NC(C)=O
Temperature: 100 °C
Yield: 36 %

Procedure:
A solution was prepared by dissolving 28 grams (0.12 mol) of 3-acetylamino-4-(N,N-diethylamino)benzaldehyde in 120 ml of nitromethane, and added with 4 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 10 grams of red crystals was obtained. The yield was 36%.
Reaction SMILES: C(O)C.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=O.O.[NH2:18]N>O>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:18]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccncc1
Solvent: CCO
Solvent: O
Product: c1cc(-c2cc[nH]n2)ccn1
Yield: 93 %

Procedure:
To 50 mL absolute ethanol was added (E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (20 g; Example 1, Step 1). When all solids dissolved, 6.33 mL hydrazine monohydrate was added dropwise with stirring. After 30 minutes an additional 1.1 mL hydrazine hydrate was added. After 2 hours the reaction was treated with water and the yellow solution was concentrated under vacuum until a slurry formed. The resulting solid product was collected by vacuum filtration, washed with water, and dried under high vacuum overnight to yield 15.27 g (93% yield) of product as off-white crystals. 1H NMR (CDCl3) was consistent with a tautomeric mixture of the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 146.4 by positive ESI.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][CH2:20][CH2:21][SH:22].CN(C)C=O>O>[CH2:21]([S:22][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:20][CH2:19][CH3:18]
Reactant: CCCCS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrobenzaldehyde (10.0 g), potassium carbonate (10.0 g), n-butylthiol (12.5 ml) and dimethylformamide (12.5 ml) was heated at 100° C. for a period of 16 hours, cooled and poured into water (250 ml). The aqueous mixture was extracted with diethyl ether (4×250 ml) and the combined organic phases were washed with aqueous 2% sodium hydroxide solution (5×100 ml) and finally with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation to give 4-(n-butylthio)benzaldehyde (10.8 g) as a reddish coloured oil. The product was characterized by proton nuclear magnetic resonance spectroscopy. Pmr (CDCl3 ; δ in ppm): 0.97 (3H, t); 1.60 (4H, m); 3.03 (2H, t); 7.32 (2H, d); 7.77 (2H, d); 9.89 (1H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[NH2:22][C@@H:23]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)[C@H:24]([OH:36])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:10]=[C:11]([C:14]([NH:22][C@@H:23]([CH2:37][C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[C@H:24]([OH:36])[CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(-c3ncco3)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: ClCCl
Product: CCCCn1ccc2c(-c3ncco3)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
To a mixture of 1-butyl-4-(1,3-oxazol-2-yl)-1H-indole-6-carboxylic acid (0.2 g) in methylene chloride (20 mL) was added 1,1-carbonyldiimidazole (0.114 g). The mixture was stirred at room temperature for 1 h at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.265 g) dissolved in methylene chloride (10 mL) was added. The mixture was stirred at room temperature for 18 h then poured into methylene chloride (50 mL), washed with water followed by brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 65% methylene chloride, 30% hexanes, and 5% methanol as eluent to give 0.0985 g of the title compound: MS (ESI+) for C35H38F2N4O3 m/z 601.99 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>CC(C)=O>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:3]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 50) (2 g, 8.60 mmol) and p-toluenesulfonyl chloride (1.640 g, 8.60 mmol) was taken up in acetone (12 mL) and stirred under nitrogen and cooled to between −5° C. and 5° C. To this solution was added 2.0M NaOH solution (5.50 mL, 10.99 mmol) while maintaining the internal temperature at less than 5° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The white solid was filtered off and washed well with acetone to afford 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.28 g, 99%) as a pale cream solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([O:25][CH3:24])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Product: COc1cccc(NC(=O)c2ccc(C)c(NC(=O)c3csc4c(N)ncnc34)c2)c1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-methoxyaniline to obtain the title compound (see Table 1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:37]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])=[O:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 513.9.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][C:4]1[C:5]([CH3:20])=[C:6]([CH3:19])[C:7]([Zr+2:10][C:11]2([CH2:16][CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12]2)([CH3:9])[CH:8]=1.C([Sn]([F:34])(CCCC)CCCC)CCC.CCCCC>ClCCl>[F-:34].[F-:34].[CH3:3][C:4]1[C:5]([CH3:20])=[C:6]([CH3:19])[C:7]([Zr+2:10][C:11]2([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=[CH:15]2)([CH3:9])[CH:8]=1
Reactant: CCCC[Sn](F)(CCCC)CCCC
Agent: CCCC1([Zr+2]C2(C)C=C(C)C(C)=C2C)C=CC=C1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCC
Product: [F-]
Temperature: -35 °C
Reaction time: 1 h

Procedure:
To a yellow solution of (tetramethylcyclopentadienyl)(propylcyclopentadienyl) zirconium dichloride [(Me4Cp)(PrCp)ZrCl2] (1.00 g, 2.47 mmol, 1.00 eq.) in dichloromethane (10 mL) was added tributyltin fluoride (1.60 g, 5.18 mmol, 2.09 eq.). The reaction quickly lightened, becoming almost colorless with a small amount of tributyltin fluoride still visible. The reaction was stirred 1 h and was then filtered to give a colorless solution and a small amount of white solid. The solution was evaporated in vacuo, leaving a damp, white solid. Pentane (15 mL) was added and the mixture was cooled to −35° C. The mixture was filtered, and resulting white solid was washed with pentane (3×3 mL) cooled to −35° C. The white solid was dried in vacuo to yield 0.88 g (96%). 1H NMR(CD2Cl2): δ 0.92 (t, 3H, CH2CH2CH3), 1.55 (m, 2H, CH2CH2CH3), 1.82 (s, 6H, Me), 1.99 (s, 6H, Me), 2.42 (t, 2H, CH2CH2CH3), 5.93 (s, 1H, ring-H), 5.96 (br m, 2H, ring-H), 6.17 (m, 2H, ring-H). 19F NMR(CD2Cl2): δ 17.5 (s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7](Cl)=[N:6][CH:5]=1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:18]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:13])[CH2:19]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: COC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
5,6-Dichloro-nicotinic acid methyl ester from step (a) above (1.23 g, 6.0 mmol) and (R)-(−)-2-methyl-piperazine (667 mg, 6.6 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a white solid. MS ESI, pos. ion) m/e: 270 (M+1).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[B:21]([OH:22])([OH:20])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc2cnccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to −78° C., was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45′. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5′ and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5% NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of 10% HCl at O° C. Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield=58%. 1H NMR (d6-DMSO, 200 MHz) δ 7.66 (1H, t, J=7.2 Hz), 8.07 (1H, d, J=5.8 Hz), 8.13 (1H, d, J=8.0 Hz), 8.34 (1H, d), 8.47 (1H, d), 8.50 (2H, bs), 9.29 (1H, s); [M+1] 174.1 (C9H8BNO2 requires 172.98)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH2:20]O)[N:17]([CH2:22][C:23]4[S:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)[C:16](=[O:32])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:33]([N:35](CC)[CH2:36]C)C.CS(Cl)(=O)=O.CNC>O1CCOCC1.ClCCl>[CH3:33][N:35]([CH2:20][C:18]1[N:17]([CH2:22][C:23]2[S:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[C:16](=[O:32])[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=1)[CH3:36]
Reactant: CCN(CC)CC
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(CO)n1Cc1ccc(C(F)(F)F)s1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)Cc1nc(N2CCN(c3ccc(F)cc3)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 9.9 %

Procedure:
To a dichloromethane solution (1.5 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-6-(hydroxymethyl)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (10.0 mg, 21.3 μmol) synthesized in Synthesis Example 458b, triethylamine (6.0 μL, 42.6 μmol) and methanesulfonyl chloride (2.4 μL, 32.0 μmol) were added and the resultant mixture was stirred at room temperature for 1 hour and 30 minutes. The volume of the reaction solution was divided in half. To one of the divided reaction solution, dimethylamine (20 μL) and 1,4-dioxane (4.0 mL) were added and the resultant mixture was stirred at 90° C. for 20 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.05 mg, yield: 20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:26][CH2:25][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:14])([F:15])[F:16])[CH2:11][N:12]=2)=[CH:7][C:2]=1[Br:1])(=[O:37])=[O:36]
Reactant: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of {2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl}methanol (0.95 g) and triethylamine (0.41 g) in dichloromethane was added methanesulfonyl chloride (0.35 g) gradually, and the mixture was stirred for 2 hours at room temperature. The reaction liquor was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-benzyl methanesulfonate (1.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]#[N:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.CC(O)=O.[C:25]([CH:27](C)[CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)#[N:26].[BH3-]C#N.[Na+]>CO>[C:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][C:25]#[N:26])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)#[N:13]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: CC(C#N)CCOc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CCCCOc1ccc(CNc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Pyridyl)-5-cyano-1-(4′-aminophenyl)pyrazole (0.5 mmol) was dissolved in MeOH (4 mL) and treated with HOAc (4 mL). The reaction was treated with a solution of 4-(3-cyanobutoxy)benzaldehyde (from Example above) (0.75 mmol) in MeOH (1 mL) and stirred at room temperature for 30 minutes. NaCNBH3 (1.25 mmol) was added in one portion. After 2 hr, volatiles were removed, the residue taken up in water, neutralized with NaHCO3 (aq) and extracted with dichloromethane. Organic extracts were combined, dried over MgSO4 and concentrated to leave a clear oil. Pure product was eluted from silica gel column using 50% dichloromethane in EtOAc giving a light yellow solid (140 mg, 64%), m.p. 128-129° C. 1H NMR (CDCl3): δ 1.98-2.04 (m, 2H), 2.63-2.66 (t, J=7.1 Hz, 2H), 4.00-4.04 (t, J=6 Hz, 2H), 4.27-4.29 (d, J=5.8 Hz, 2H), 6.72-6.79 (m, 3H), 6.92-6.94 (d, J=8.5 Hz, 2H), 7.31-7.33 (d, J=8.5 Hz, 2H), 7.42-7.44 (d, J=8.7 Hz, 2H), 7.50-7.53 (m, 1H), 7.96 (s, 1H), 8.24-8.26 (d, J=8 Hz, 1H), 8.60-8.61 (d, J=4.6 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[CH2:12]([O:19][C@@H:20]1[C@@H:28]([CH:29]=[O:30])[O:27][C@H:26]2[C@H:22]([N:23]=[C:24]([N:31]([CH3:33])[CH3:32])[S:25]2)[C@H:21]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C@@H:20]1[C@@H:28]([C@H:29]([CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[OH:30])[O:27][C@H:26]2[C@H:22]([N:23]=[C:24]([N:31]([CH3:33])[CH3:32])[S:25]2)[C@H:21]1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CSCSC1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C3SCCCS3)O[C@@H]2S1
Reaction time: 1 h

Procedure:
A solution of 1,3-dithiane (14.1 g, 117 mmol) in THF (100 mL) was treated with n-BuLi (44.9 mL, 112 mmol, 2.5M in hexane) at 0° C. for 1 hour, followed by the addition of a solution of the above aldehyde 95 in THF (20 mL) at −50° C. After kept additional 1 hour at 0° C., the reaction was quenched by saturated aqueous NH4Cl (150 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 20%-50% ethyl acetate in petroleum to afford the title compound as a yellow syrup (6.4 g, 62%, two epimers' ratio is 1:1 by 1H NMR); (ES, m/z) [M+H]+ 547.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.44 (m, 10H), 6.33 (d, J=6.6 Hz, 1H), 4.63-4.84 (m, 4H), 4.52-4.58 (m, 1H), 4.12-4.15 (m, 1H), 3.98-4.05 (m, 3H), 3.82-3.85 (m, 1H), 2.99 (s, 6H), 2.80-2.87 (m, 1H), 2.61-2.68 (m, 3H), 1.65-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12](C(C)=C)[C:11]1=[O:22])[CH2:7][CH2:8][CH3:9])[CH3:2].Cl>CO>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:22])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: C=C(C)n1c(=O)n(C(CCC)CC(=O)OCC)c2ccccc21
Agent: Cl
Solvent: CO
Product: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Temperature: 60 °C
Yield: 79.2 %

Procedure:
3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (1 g, 3.2 mmol) was dissolved in MeOH (30 mL) and HCl (30 mL) solution at room temperature. The solution was heated to 60° C. for 2 hours. The solution was cooled down and was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 5% MeOH in CH2Cl2 as the eluent to afford the desirable product 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 80%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:12][C:13]([F:17])=[N:14][C:15]=1F.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)(C)C>[Cl:9][C:10]1[C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][C:13]([F:17])=[N:12][C:11]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Fc1nc(F)c(Cl)c(N2CCOCC2)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Temperature: 110 °C

Procedure:
4-Chloroaniline (1.44 g) was added to a solution of the product from step (i) (0.88 g) and N,N-diisopropylethylamine (0.484 g) in 1,4-dioxane (15 ml) and isopropylalcohol (15 ml) and the mixture heated at 110° C. for 6 days. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4), and evaporated under reduced pressure. The solid was triturated with ethyl acetate, filtered and the filtrate purified by chromatography on silica eluting with 3% ethyl acetate in toluene. Yield 0.28 g
Reaction SMILES: [CH2:1]([CH:3]([C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH:18]=1)[OH:17])[CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[C:20]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]1=O)(=O)[CH3:21]>>[CH2:1]([CH:3]([C:12]1[CH:18]=[C:16]([OH:17])[C:15]2[CH:20]([CH3:21])[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]=3[O:19][C:14]=2[CH:13]=1)[CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCCC(CC)C(CC)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCC(CC)C(CC)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Condensation of 5-(1,2-diethylheptyl)resorcinol and 2-acetyl-5-methylcyclohexanone as described in the procedure of Example 1 gives the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([O:18][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:38])([F:39])[F:37])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4]
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (235 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (4 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 100% ethyl acetate in isohexane to give the product (430 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.62-3.70 (2H, m), 4.08-4.14 (2H, m), 6.04 (1H, t), 7.53-7.55 (1H, m), 7.68-7.77 (2H, m), 7.91 (1H, dd), 7.97 (1H, dd), 8.39 (1H, dd), 8.41 (1H, s), 8.56 (1H, s), 8.57-8.59 (1H, m), 9.02 (1H, s); m/z (ESI−) (M−H)−=496; HPLC tR=2.55 min.