Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:14])(=[O:13])[C:5]2=[CH:6][CH:7]=[CH:8][C:9]3=[CH:10][CH:11]=[CH:12][C:3](=[C:4]23)[NH:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)[CH3:21]>CN(C)C=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH:20]([CH3:21])[CH2:19][CH2:18][N:2]3[C:3]4[CH:12]=[CH:11][CH:10]=[C:9]5[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=45)[S:1]3(=[O:13])=[O:14])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: CC(CCBr)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCN1c2cccc3cccc(c23)S1(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of naphtho[1,8-cd]isothiazole 1,1-dioxide (3.25 g) in dimethylformamide (50 cc) is poured over 30 minutes into a mixture of sodium hydride (0.76 g) in a 50% dispersion in vaseline oil and dimethylformamide (10 cc), under a current of argon. The reaction medium is stirred for 2 hours at a temperature of about 20° C. 1-(4-bromo-2-butyl)-4-(4-fluorophenyl)piperazine (5 g) in dimethylformamide (100 cc) is added over 10 minutes. The reaction mixture is stirred for 15 hours at a temperature close to 20° C., then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (80-20 vol) as eluant. After recrystallization from boiling acetonitrile (13 cc), 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.8 g) is obtained, m.p. 122° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1.C([O-])(=O)C.[K+].O>C(O)C.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[F:18][C:19]1[C:24]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: C=Cc1cnc(F)c(B(O)O)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(F)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (984 mg, 3.89 mmol), 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 5.28 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (138 mg, 0.195 mmol), and potassium acetate (1.212 g, 12.35 mmol) were suspended in ethanol (12.0 mL) and water (2.4 mL) and the flask was fitted with a reflux condenser and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was put in a preheated oil bath (80° C.) and stirred under nitrogen for 1 h. The reaction was cooled to room temperature, diluted with water (20 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/2N ammonia in MeOH) to afford 6-(2-fluoro-5-vinylpyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine, which was taken on to the next step. MS (ESI pos. ion) m/z 340 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]O.CCCCC.C(Cl)(Cl)(Cl)[Cl:42]>>[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][Cl:42]
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Product: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
Triphenylphosphine (371 mg, 1.41 mmol) was added to a solution of 3,5-bistrifluoromethylbenzyl alcohol (257 mg, 1.05 mmol) in dry CCl4 (2 ml). The mixture was refluxed for 1 h, then cooled to room temp. Pentane (2 ml) was added, and the mixture stirred for a further 5 min., then filtered. The solid was washed with pentane (2 ml), and the filtrate concentrated in vacuo. The crude product was purified by column chromatography [SiO2: hexane-ethyl acetate 4:1] to give 3,5-bistrifluoromethylbenzyl chloride (162 mg, 59%); TLC (hexane-ethyl acetate 1:1) rf=0.73.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].CO>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:26]
Reactant: COCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added methoxyacetyl chloride (0.08 g, 0.70 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.111 g (87%) of product as an off-white solid: mp 244-246° C.; 1H NMR (DMSO-d6) 11.07 (s, 1H), 10.26 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 4.10 (s, 2H), 3.47 (s, 3H), 2.77-2.51 (m, 3H), 2.09-2.04 (m, 1H), 1.90 (s, 3H); 13C NMR (DMSO-d6) 172.12, 171.99, 169.15, 168.99, 167.38, 136.22, 135.68, 131.06, 124.25, 117.90, 115.91, 71.43, 59.06, 58.88, 29.01, 28.53, 20.92; Anal. Calcd. For C17H17N3O6: C, 56.48; H, 4.81; N, 11.62. Found: C, 56.10; H, 4.55; N, 11.39+0.12H2O.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:34][O:35][CH3:36])[N:4]=1.Br.CCOCC>CC(O)=O>[CH3:36][O:35][CH2:34][C@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:5]1[NH:4][C:3](=[O:2])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1
Reactant: COC[C@H]1CCCN1c1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC[C@H]1CCCN1c1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 61.2 %

Procedure:
(R)-4-methoxy-2-(2-(methoxymethyl)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidine (96 mg, 0.20 mmol) was dissolved in AcOH (3 mL) and then 48% hydrobromic acid (0.1 mL) was added. The mixture was heated at 90° C. FOR 3.5 hours. The mixture was concentrated and the residue was treated with NaHCO3 solution. The solution was extracted with EtOAc (3×) and the organic was washed with NaHCO3, dried over Na2SO4, filtered and concentrated to obtain the crude. The material was treated with ether and sonicated. The solid was filtered, washed with ether and dried under vacuum to obtain (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (58 mg, 60.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.15 (br s, 1H), 8.73 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.28 (br s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.53 (m, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.62 (m, 1H), 4.34 (m, 1H), 3.85 (s, 3H), 3.52-3.40 (m, 4H), 3.28 (s, 3H), 2.35 (s, 3H), 1.95 (br d, J=27.5 Hz, 4H); MS (ESI) m/z: 474.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=O)[CH3:19].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=[N:32][NH:31][C:29]([C:28]1[CH:33]=[CH:34][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=1)=[O:30])[CH3:19]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cn2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2c(C)nn(-c3ccc(C(F)(F)F)cn3)c2O)cc1
Yield: 71.5 %

Procedure:
0.2 mmol of 1-{5-hydroxy-3-methyl-1-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}ethanone and 0.2 mmol of 4-methoxycarbonylbenzhydrazide were heated in 2 ml of DMF at 100° C. for 9 hours with stirring. After the solvent was removed by evaporation, the resulting crude product was dissolved in chloroform and recrystallized from hexane to obtain 66 mg of the desired product, methyl 4-{([2-(1-{5-hydroxy-3-methyl-1-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}ethylidene)hydrazino]carbonyl}benzoate (yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH2:29][CH3:30]
Reactant: CCC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: CCC(CO)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 63 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.6 mmol) was converted, using rac-2-amino-1-butanol instead of 2-amino-2-methyl-1-propanol, to the title compound (155 mg, 63%) which was obtained as a colorless gum. MS: m/e=403.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1.[C:15]1([CH:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C.[Cl-].[Na+]>CN(C)C=O>[C:33]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=4)[N:7]=3)[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)c1nc2ccc(Cl)nn2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
0.92 g of methyl 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylate and 1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of N,N-dimethylformamide; 1.49 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing at 80° C. for 15 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the residue was recrystallized from ethanol-ethyl acetate (1:2) to yield 639 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([S:11][CH3:12])[CH:4]=1.[CH:13](O)=[O:14]>>[CH3:10][S:9][C:7]1[N:6]=[C:5]([S:11][CH3:12])[CH:4]=[C:3]([CH2:2][NH:1][CH:13]=[O:14])[N:8]=1
Reactant: O=CO
Reactant: CSc1cc(CN)nc(SC)n1
Product: CSc1cc(CNC=O)nc(SC)n1

Procedure:
Using the method of Example 5, 6-aminomethyl-2,4-bis(methylthio)pyrimidine from Example 1, part E or Example 8 was reacted with formic acid to provide 2,4-bis(methylthio)-6-formylaminomethylpyrimidine as a light yellow solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([N:15]2[C:19]([C:20]3C=CC=CC=3)=[N:18][N:17]=[N:16]2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.FC1C=CC(C(C2C=CC(F)=CC=2)=C(N2C(C)=NN=N2)C(OCC)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:9]([N:15]2[C:19]([CH3:20])=[N:18][N:17]=[N:16]2)[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1C
Product: Cc1nnnn1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
The general procedure of Example 5 was repeated, except that the ethyl 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenoate utilized therein was replaced by 4.87 g of ethyl 3,3-bis(4-fluorophenyl)-2-(5-methyl-1H-tetrazol-1-yl)-2-propenoate [prepared in Example 14] and there was thereby produced 4.45 g of the title compound which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]4[CH2:24][CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16]4)=[CH:6][CH:7]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1CCc2ccccc2C1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H+].[B-:24]([F:28])([F:27])([F:26])[F:25]>C(Cl)Cl.C(OCC)C>[F:25][B-:24]([F:28])([F:27])[F:26].[CH2:1]([S+:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: c1ccc(CSc2ccccc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(C[S+](Cc2ccccc2)c2ccccc2)cc1
Yield: 87 %

Procedure:
A solution of 75.0 g (0.374 mol) of benzylphenyl sulfide, 60.73 g (0.561 mol) of benzyl alcohol in 350 ml of methylene chloride is introduced into a reaction vessel provided with a stirrer and thermometer. 182.45 g (1.12 mol) of 54% by weight HBF4 in diethyl ether are added dropwise at an internal temperature of 20°-30° C. in the course of 35 min, while stirring. The reaction mixture is then stirred at RT for 2 h. The reaction mixture is diluted with 300-400 ml of methylene chloride and extracted 4 times with water (pH ~6). The organic phase is then dried over MgSO4 and the solvent is removed on a rotary evaporator. The yellow-brown oil which remains is stirred in 400 ml of toluene and the mixture is left to crystallize at 0°-5° C. for about 1 h. The suspension is filtered and the residue is washed with a little cooled toluene (0°-5° C.). The pure product is dried under a high vacuum at RT overnight. 123.8 g (87% of theory) of dibenzylphenylsulfonium tetrafluoroborate are obtained as white crystals of melting point 110°-115° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.C(S[C:16]1[N:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=2)[C:18](=[O:27])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:20]=2[N:21]=1)CC.O>O1CCCC1>[F:3][C:4]1([F:11])[CH2:9][CH2:8][CH:7]([O:10][C:16]2[N:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:32][CH:33]=3)[C:18](=[O:27])[C:19]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:20]=3[N:21]=2)[CH2:6][CH2:5]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OC3CCC(F)(F)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 19 mg) in tetrahydrofuran (5 ml) was added 4,4-difluorocyclohexanol (109 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (75 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:14].[H][H]>CO.O.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)c1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cccc(CN)c1
Reaction time: 48 h

Procedure:
To a solution of 3-cyano-N-methyl-benzenesulfonamide (4.88 g, 2.49 mmol) in MeOH (160 mL) is added concentrated HCl in water (16 mL) followed by the addition of Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g). With magnetic stirring, the reaction is alternately placed under vacuum and 1 atmosphere of hydrogen (balloon) for three cycles. The reaction is then left under 1 atmosphere of hydrogen with stirring for 2 days. The reaction is filtered through celite and fresh Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g) is added. The reaction is stirred for 24 hours under 1 atmosphere of hydrogen. The reaction is filtered through celite and the filtrate is concentrated in vacuo to provide 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride, as a solid (99%). MS: 201 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.12 (d, 2H), 7.23-7.57 (m, 2H), 7.70 (d, 1H), 7.81 (d, 1H), 8.49 (broad-s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C)C=O>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 82.2 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil 92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, 4-methylbenzylbromide (426 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(4-methyl-benzyl)-3-nitro-1H-pyrazole (316 mg, 82%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 2.36 (3H, s), 5.32 (2H, s), 6.87 (1H, d, J=2.3 Hz), 7.19 (4H, s), 7.34 (1H, d, J=2.3 Hz).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17].[NH4+].[Cl-]>CCOCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])=[CH:8][CH:9]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
n-Butyllithium (2.4M solution in hexane; 92.7 mL, 0.222 mol) was added dropwise (20 min) to a solution of p-dibromobenzene (50.0 g, 0.212 mol) in Et2O (1.2 L) at -60° C. After completion of the addition, the reaction was left at -50° C. for 30 min and hexafluoroacetone (42.2 g, 0.254 mol) was bubbled through the heterogeneous mixture, at the same temperature. The resulting solution was allowed to warm to -30° C. over 30 min before saturated aqueous NH4Cl was added. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were successively washed with 25% aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure (bp 85°-90° C./12 mmHg) to afford the title compound as colorless crystals (53.5 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:7][C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(Cl)cc1CBr
Product: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 5-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol in the manner described in Example 4A. This product is distilled at 210° C., 0.15 mm, leaving an orange oil. The oil is dissolved in ether where it is converted to its hydrochloride salt which is recrystallized thrice from an ethyl alcohol-ether mixture to provide the product, 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol hydrochloride, mp 217°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH2:12])=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:12]=[C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:13]([F:14])([F:15])[F:16])[O:11][CH:20]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc(F)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1ccc(C=Cc2nc(CCl)co2)c(C(F)(F)F)c1
Yield: 70.9 %

Procedure:
3-(4-Fluoro-2-trifluoromethyl-phenyl)-acrylamide (1.0 g, 4.29 mmol), dichloro acetone (2.18 g, 17.15 mmol) and toluene (10 ml) were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1) yielding 0.93 g (71%) 4-chloromethyl-2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-oxazole as tan solid.