Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH2:10]([S:17][C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25](O)[N:20]2[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCCCCC.P(Cl)(Cl)([Cl:37])=O>C(OCC)(=O)C>[CH2:10]([S:17][C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([Cl:37])[N:20]2[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)n2nc(SCc3ccccc3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(Cl)n2nc(SCc3ccccc3)nc2c1

Procedure:
N,N-Dimethylaniline (21.9 g, 0.18 mol) was added slowly to a mixture of 2-benzylthio-5-hydroxy-7-methyl[1,2,4]triazolo[1,5-a]pyridine (44.5 g, 0.164 mol) in 150 mL of phosphorus oxychloride with stirring. The mixture was heated at reflux with stirring for 20 hours. The excess phosphorus oxychloride was then removed by evaporation under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed well with water and quickly concentrated by evaporation under reduced pressure to drive off the excess water. The residue was again dissolved in ethyl acetate and the resulting mixture was filtered with suction through a bed of silica gel. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained was mixed with hexane. The resulting mixture was filtered to recover the solids and dried to obtain the 37.5 g (79 percent of theory) of the title compound as a tan powder melting at 108°-110° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][N:7](C(OCC)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][NH:7][CH2:6]1
Reactant: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)SCN2C3CNCC3CC21

Procedure:
6 g (22.2 mmOl) of ethyl 9,9-dimethyl-10-thia -1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 12 g of Ba(OH)2. 8H2O in 100 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction and the filtrate is extracted ten times using 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>CN(C=O)C>[Cl:39][CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2cccnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (270 mg, 1.09 mmol) in 2.5 mL DMF was added triphenylphospine (285 mg, 1.09 mmol) and carbon tetrachloride (167 mg, 1.09 mmol). The reaction was allowed to stir 16 h at ambient temperature. The solution was concentrated and purified by silica gel chromatography (0-50% ethylacetate/hexanes) to give tert-butyl 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (8.6%). 1H NMR (400 MHz, CDCl3): δ 8.56-8.55 (d, J=4.9 Hz, 1H), 8.02-8.00 (d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.26-7.24 (m, 1H), 5.30 (s, 2H), 1.54 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:27][CH2:28][CH3:29])=[C:4]([C:17]([CH2:24][CH2:25][CH3:26])=[CH:18][C:19]=1[C:20](=[O:23])[CH2:21][CH3:22])[O:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>>[OH:1][C:2]1[C:3]([CH2:27][CH2:28][CH3:29])=[C:4]([C:17]([CH2:24][CH2:25][CH3:26])=[CH:18][C:19]=1[C:20](=[O:23])[CH2:21][CH3:22])[O:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCCc1cc(C(=O)CC)c(O)c(CCC)c1OC(C(=O)OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1cc(C(=O)CC)c(O)c(CCC)c1OC(C(=O)O)c1ccccc1

Procedure:
The ester of step 2 (18.6 gm) was hydrolyzed with NaOH (98 ml) as for example 1, step 5.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[C:9](OC)(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:9]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: N[C@H]1CCCC[C@@H]1N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1N
Yield: 63.8 %

Procedure:
(S,S)-1,2-Diaminocyclohexane (1.14 g) and 2.96 g of methyl oleate were reacted in the same manner as in Reference Example 26 to obtain 2.41 g of the objective compound (yield: 65%)
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:33])[C@@H:10]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[C:24]=1[CH3:32])[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:31][C:25]1[C:24]([CH3:32])=[C:23]([NH:22][C@@H:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)propyl amino)-2-chloro-3-methylbenzonitrile (242 mg, 0.49 mmol) was deprotected using tetrabutylammonium fluoride (1.0 M solution in THF, 0.97 mL, 0.97 mmol) in a procedure analogous to that used for the preparation of example 7. After column chromatography (50% EtOAc/hexanes) the title compound was isolated as a white solid (182 mg, 97%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.96 (m, 2H), 7.51 (m, 4H), 6.85 (d, J=8.8 Hz, 1H), 5.89 (d, J=7.7 Hz, 1H), 5.15 (dd, J=7.6 Hz, 3.9 1H), 5.03 (d, J=4.4 Hz, 1H), 4.53 (m, 1H), 2.35 (s, 3H), 1.28 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C@@:8]12[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][C@H:9]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17](/[CH:19]=C/C3C=CC=CC=3)[N:16]=[CH:15][C:14]=12.[O:35]1CCOCC1.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=O.[Na+]>O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]12[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:35])[N:16]=[CH:15][C:14]=12
Reactant: C(=C/c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3)\c1ccccc1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: O=Cc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3
Yield: 79 %

Procedure:
A flask with stir bar and nitrogen line was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-3-((E)-styryl)-5,6,7,7a,8,10,11,11a-octahydro spiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane] (145, R2=Pyridin-2-ylmethyl) (5.9 g, 13.04 mmol), 1,4-dioxane (150 mL), water (50.0 mL), 2,6-dimethylpyridine (3.04 mL, 26.1 mmol) and osmium(VIII) oxide (2.5 wt % in tert-butanol) (4.91 mL, 0.391 mmol). Sodium periodate (11.15 g, 52.1 mmol) was added and the mixture was stirred at rt for about 15 h. The mixture was diluted with water (200 mL) and EtOAc (50 mL). The layers were separated then the aqueous layer was extracted four times with EtOAc (50 mL). The combined organics were washed twice with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The material was triturated with EtOAc and the solids collected by filtration and dried to yield rac-(7aR,11 aR)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane]-3-carbaldehyde (146, R2=Pyridin-2-ylmethyl) (3.89 g, 79%); LC/MS, method 3, Rt=2.00 min, MS m/z 379 (M+H)+. 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.29-8.27 (m, 1H), 8.22 (s, 1H), 7.69 (s, 1H), 7.40-7.36 (m, 1H), 7.05-7.02 (m, 1H), 6.41 (d, J=7.8 Hz, 1H), 3.94-3.84 (m, 4H), 3.50 (d, J=13.3 Hz, 1H), 3.44-3.36 (m, 1H), 3.20 (d, J=13.4 Hz, 1H), 3.07-3.02 (m, 1H), 2.19-2.11 (m, 2H), 2.06-1.94 (m, 2H), 1.94-1.83 (m, 2H), 1.75-1.66 (m, 3H), 1.62-1.57 (m, 1H), 1.49-1.34 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH3:26])=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=3)[N:11]=[C:10]([C:31]#[N:32])[C:9]=2[N:8]=[CH:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[C:10]([C:31]#[N:32])[C:9]3[N:8]=[CH:7][N:6]([CH3:5])[C:14]=3[CH:13]=2)=[CH:16][C:17]=1[C:27]([F:30])([F:29])[F:28])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(C)CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.011 ml) was added dropwise to a solution of 1-methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) and diisopropylethylamine (0.045 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to give 6-{-4-[3-(N-acetyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (9.2 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[CH:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[CH2:19]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([CH:18]=[CH2:19])=[CH:21][CH:22]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: C=Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 61.3 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.200 g, 0.75 mmol) was reacted with 4-vinylaniline (0.098 g, 0.83 mmol) to afford the title compound (0.160 g, 62%) as a light yellow solid. MW=347.84. 1H NMR (DMSO-d6, 500 MHz) δ 8.82 (s, 1H), 8.31-8.23 (m, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.55-7.47 (m, 4H), 6.77-6.68 (m, 1H), 5.77 (d, J=17.5 Hz, 1H), 5.19 (d, J=11.0 Hz, 1H), 2.96-2.87 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 348 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:21]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc3c2C1
Yield: 12.8 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 17.0 mg (0.085 mMol) 4-methanesulfonylbenzoic acid, 2.0 mg (13%) of the title compound were recovered as a beige solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1.O.[OH-].[Na+]>C(OCC)C>[OH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a stirred suspension of LiAlH4 (0.070 g, 1.85 mmol, 5 eq) in diethyl ether (1.9 mL) was added dropwise at 0° C. a solution of 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile (0.12 g, 0.37 mmol) in diethyl ether (5.5 mL). The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was cooled to 0° C. and, successively, a solution of water, sodium hydroxide (15% w/v, 0.08 mL) and water again were carefully dropped. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by flash chromatography (10 g silica gel, DCM/MeOH (10% NH3) to provide 0.050 g of title compound. 1H NMR (400 MHz, DMSO-D6) δ10.6 (bs, 1H), 7.42 (d, 2H), 7 (d, 2H), 4.1-3.95 (m, 2H), 3.6-3.2 (m, 5H), 3.03-2.87 (m, 2H), 2.15-1.8 (m, 10H), 1.65-1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH:5]=[C:6]2[C:10]([OH:12])=[O:11].[C:14]1([C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N+]=[N-])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([CH:20]([O:11][C:10]([C:6]2[CH:7]3[CH:3]([CH2:4][CH:5]=2)[C:2]([Cl:13])([Cl:1])[C:8]3=[O:9])=[O:12])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1=CCC2C1C(=O)C2(Cl)Cl
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2C1C(=O)C2(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
The crude 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid (61 g) from Example 3 was stirred as a suspension in 300 mL of ethyl acetate and treated portionwise with 57 g of diphenyldiazomethane over a 45 min period. The resulting solution was stirred at room temperature for 1 hr. Evaporation of the solvent and trituration with ether afforded 76.9 g (71.9%) of 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester. Material prepared by essentially the same procedure had the following characteristics: IR (Nujol mull): 1625, 1730, 1800 cm-1 ; NMR (CDCl3): δ 3.07 (1H, dddd, J=20, 8, 2, 2), 3.20 (1H, broad d, J=20), 3.64 (1H, ddd, J=8, 8, 2), 4.89 (1H, ddd, J=8, 4, 2), 6.86 (1H, s), 6.95 (1H, dd, J=4, 2), and 7.2-7.5 (10H, m). HRMS: Calcd for C21H16O3Cl2, 386.0475; found, 386.0495.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:23]([CH:25]([C:33]#[N:34])[C:26]([CH3:32])([CH3:31])[C:27](OC)=[O:28])#[N:24].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[NH2:24][C:23]1[C:25]2[C:26]([CH3:32])([CH3:31])[C:27](=[O:28])[NH:34][C:33]=2[N:17]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][C:11]([CH3:14])=[N:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1

Procedure:
400 mg (1.11 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 277 mg (1.33 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 175 mg (1.56 mmol) of potassium tert-butoxide, and the mixture was heated to reflux for 24 h. A little water was added and the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). The product-containing fractions were concentrated and the residue was stirred with water/isopropanol. The solids were filtered off and purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 170 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][Si](C)(C)C)=[CH:15][CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:18]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2=[O:24])#[CH:19]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#C[Si](C)(C)C)cc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1
Yield: 65.6 %

Procedure:
To a solution of Compound Q (205 mg, 0.5 mmol) in THF (2.5 mL) was added a 1M solution of TBAF in THF (554 μL, 0.55 mmol). After thirty minutes the reaction was concentrated in vacuo. Purification by flash chromatography on silica gel afforded 110 mg (65%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.28 (d, J=1.84 Hz, 1H), 7.77-7.69 (m, 3H), 7.54-7.5 (m, 2H), 6.67 (d, J=8.8 Hz, 1H), 4.22-4.19 (m, 3H), 1.28-1.23 (m, 3H); ES-MS [M+1]+: 336.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[N:12]1([C:8]([CH3:9])=[CH:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)CC(=O)c1cccs1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(=CC(=O)c1cccs1)N1CCCC1

Procedure:
A mixture of 0.01 mole of 1-(2-thienyl)butan-1,3-dione was reacted with pyrrolidine in ethyl acetate to give 3-(1-pyrrolidinyl)-1-(2-thienyl)-2-buten-1-one, mp 154°-156° C.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]1([F:60])[CH:55]2[CH2:56][C:51]3([CH2:58][OH:59])[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:51]23[CH2:56][CH:55]4[CH2:54][CH:53]([CH2:57][CH:49]([C:48]4([F:47])[F:60])[CH2:50]2)[CH2:52]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(C1)C(F)(F)C(C3)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4,4-difluoro-1-(hydroxymethyl)adamantane, the title compound was obtained as a colorless solid (0.21 g, 44%): 1H NMR (300 MHz, CDCl3) δ 8.64 (br s, 1H), 8.16-8.03 (m, 1H), 6.73-6.60 (m, 1H), 3.63 (s, 2H), 3.03 (s, 6H), 2.37-2.25 (m, 2H), 2.11-1.84 (m, 5H), 1.81-1.66 (m, 6H); MS (ES−) m/z 479.2 (M−1), 481.1 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.992 g, 2.5 mmol), tert-butyl 4-piperidinylcarbamate (1.00 g, 5 mmol), and DIPEA (0.65 g, 5 mmol) in THF (100 mL) was stirred at room temperature for 30 min. The solution was then concentrated and diluted with water (100 mL) containing 1 mL of acetic acid. The resulting solid was collected, washed with water, and dried to give 1.38 g (98%) of tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinylcarbamate: mp (MeOH) 208-209° C.; 1H NMR (CDCl3) δ 7.88 (d, J=8.1 Hz, 1H), 7.48 (t, JHF=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.66 (br d, J=13.4 Hz, 2H), 4.46 (m, exchangeable with D2O, 1H), 4.04 (s, 3H), 3.87 (m, 4H), 3.78 (m, 5H), 3.12 (m, 2H), 2.07 (br d, J=14.0 Hz, 2H), 1.46 (s, 9H), 1.45-1.33 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.85; H, 6.1; N, 20.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[OH:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Fc1ccccc1Br
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1F
Yield: 70.8 %

Procedure:
With 5.00 g of 5-chloroisatin and 6.92 g of 1-bromo-2-fluorobenzene as starting materials, 5.41 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([C:4]1[C:5]([O-:14])=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Na+].N1C[CH2:19][CH2:18][CH2:17]1>CC(C)=O>[CH3:17][C:18]1([CH3:19])[O:14][C:5]2=[N:6][C:7]([C:10]([F:12])([F:11])[F:13])=[CH:8][CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1
Reactant: C1CCNC1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)nc2O1
Yield: 243.1 %

Procedure:
A mixture of Example 105A (2.62 g, 12.8 mmol), acetone (26 mL), 3 Å molecular sieves (1.55 g), and pyrrolidine (0.211 ml, 2.55 mmol) was stirred at ambient temperature for four days. The volatiles were removed in vacuo and the mixture was purified by flash column chromatography (SiO2, 0-50% EtOAc/hexanes gradient) provided the title compound (1.52 g, 6.20 mmol, 49% yield). MS (DCI+) m/z 246 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[C:20]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O.C(OCC)(=O)C.O1CCCC1.N1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH:4][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[C:29]([NH:28][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:30]=1
Reactant: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
At room temperature, 2.0 g of 2,6-dimethyl-4-[1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline, 2.7 g of 3-(benzoylamino)benzoyl chloride and 1.2 g of pyridine were introduced to 50 ml of tetrahydrofuran, and the resulting solution was stirred at room temperature. After disappearance of the starting raw material was confirmed by means of TLC, saturated baking soda solution was added to the reaction solution which was stirred for a while. Ethyl acetate and water were added to the reaction solution for solution separation. To a separated organic layer was added anhydrous magnesium sulfate, and the organic layer was dried and filtered off. The filtrate was evaporated to be dried under a reduced pressure and the resulting solid was pulverized to obtain 3.4 g of the desired product (Yield: 95%) in the form of powder.