Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cnoc1-c1ccc(F)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 5-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (9.50 g) in tetrahydrofuran (75 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 75 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (7.58 g, yield 95%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 106–107° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:36]([N:18]1[CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)OC(C)(C)C)cc1

Procedure:
tert-Butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate (0.425 g, 0.96 mmol) in dichloromethane at 25° C. (10 mL) was treated with triethylamine (0.28 mL, 2.02 mmol) followed by benzoyl chloride (0.12 mL, 1.06 mmol) and dimethylaminopyridine (10 mg). After 18 hours aqueous workup gave tert-butyl 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate. 1H NMR (dmso-d6, 300 MHz): 1.24 (s, 9H, t-bu), 1.82 (s, 3H, CH3), 2.0-4.0 (m, 8H, CH2), 4.65 (s, 1H, CH), 4.85 (s, 2H, CH2), 7.0-7.9 (m, 9H, ArH). Treatment with trifluoroacetic acid (4 mL) in dichloromethane (10 mL) for 6 hours gave, after concentration in vacuo followed by chromatography on silica gel eluting with dichloromethane/methanol, 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a foam (0.328 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6](O)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.OC1C2C=CC=CC=2OCC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: OC1CCOc2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OC1=CCOc2ccccc21
Product: Fc1ccc2c(c1)OCC=C2

Procedure:
Schema 5 illustrates the synthesis of an amino substituted 3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, starting with the reaction of an appropriately halo-substituted phenol with 3-bromopropanol under basic conditions in acetone, yielding the corresponding substituted phenoxypropanol (XI). The propanol is oxidized with Jones reagent in water and acetone, giving an acid, for example, 3-(3-fluorophenoxy)propanecarboxylic acid (XII). The acid is in turn cyclized with phosphorous pentachloride and aluminium chloride in methylene chloride, affording the corresponding 3,4-dihydro-7-substituted-2H-1-benzopyran-4-one (XIII), which is then treated with sodium borohydride in methanol, yielding the appropriate 3,4-dihydro-7-substituted-4-hydroxy-2H-1-benzopyran, for example, 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran (XIV). The 4-hydroxybenzopyran is dehydrated with molecular sieves in the present of p-toluenesulfonic acid, yielding the corresponding 7-fluoro-2H-1-benzopyran (XV). This compound is then hydrogenated in the presence of 5% palladium on carbon in ethanol, yielding 3,4-dihydro-7-fluoro-2H-1 -benzopyran (XVI), which is in turn treated with n-butyllithium and carbon dioxide at -78° C. in tetrahydrofuran, affording the corresponding 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid (XVII). The so-prepared acid is then refluxed with diphenylphosphoryl azide under mild basic conditions in t-butanol, giving the corresponding 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate (XVIII). The carbamate is then converted to the free amine by treating it with trifluoroacetic acid, yielding the 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran intermediate (XIX). The intermediate benzopyran is optionally halogenated in the 5-position by treatment with, for example, N-chlorosuccinimide in N,N-dimethylformamide, yielding the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XX) intermediate. Examples 11 and 12 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[NH2:21][C@H:22]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:46][CH:45]=1)[C:23]([NH:25][C@H:26]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][C:41]([I:43])=[CH:42][C:36]=2[N:35]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:54]([O:53][CH2:52][CH2:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([C@H:22]2[NH:21][C:2](=[O:1])[N:25]([C@H:26]([C:34]3[NH:38][C:37]4[CH:39]=[CH:40][C:41]([I:43])=[CH:42][C:36]=4[N:35]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23]2=[O:24])=[CH:49][CH:48]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](N)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OCCOc1ccc([C@H]2NC(=O)N([C@@H](Cc3ccccc3)c3nc4cc(I)ccc4[nH]3)C2=O)cc1
Temperature: -20 °C
Yield: 91.4 %

Procedure:
To a solution of diphosgene (29 μL, 0.24 mmol) in 1:1 v/v toluene/tetrahydrofuran (20 mL) at −78° C. under an atmosphere of nitrogen was added a solution of (R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-acetamide (210 mg, 0.34 mmol) and N,N-diisopropylethylamine (239 μL, 1.37 mmol) in tetrahydrofuran (6 mL) dropwise with stirring. The reaction was allowed to warm to −20° C. then quenched with ice water (10 mL) and stirred for 10 minutes. The mixture was poured into ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 60% v/v ethyl acetate/hexanes to give (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (140 mg, 64%).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:25])[C:6]([F:24])([F:23])[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>O.C(OCC)(=O)C.O1CCCC1>[N:4]1([C:5]([C:6]([F:24])([F:23])[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])([OH:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[O:25])[CH2:3][CH2:2]1
Reactant: O=C(NCCO)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CC1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 38 %

Procedure:
To 10 ml of dried tetrahydrofuran were added 0.36 g of N-(2-hydroxyethyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide, 0.39 g of triphenylphosphine and 0.26 g of diethyl azodicarboxylate. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 20 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 0.13 g of 1-aziridinylcarbonyl-2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propane.
Reaction SMILES: [OH-].[K+:2].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1>O>[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[K+:2]
Reactant: O=C(O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of KOH (1.12 g) in 10 ml of demineralised water, Nicotinic acid was added and stirred well at 50° C. for 3 h. Water was removed in a rotavapour. The solid was dried under vacuum at 120° C. to remove final traces of water to give 3.1 g of white solid with m.pt >325° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(Cl)(Cl)Cl>O>[CH:18]1([C:21]([NH:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
A mixture comprising 5.0 g (32.6 mmol) of 2-amino-4-methyl-3-nitropyridine and 5.2 g of pyridine was heated at 110° C. in a nitrogen atmosphere. 3.8 g (36 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110° C. for 5 hours. The reaction mixture was brought to room temperature, followed by the addition of chloroform (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined and washed with water (20 ml) and a saturated aqueous solution (20 ml) of common salt, successively. The resultant organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 5.4 g of the title compound (yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:15])([F:14])[C@@H:11]([OH:13])[CH3:12].CC([O-])(C)C.[K+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([O:13][C@@H:11]([CH3:12])[C:10]([F:15])([F:14])[F:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)C(F)(F)F
Reactant: Fc1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1ncccc1Cl)C(F)(F)F
Temperature: 60 °C
Yield: 64.5 %

Procedure:
To a solution of 3-chloro-2-fluoropyridine (115 mg, 0.88 mmol) and (25)-1,1,1-trifluoropropan-2-ol (45 wt % solution in TBME, 218 mg, 0.88 mmol) in THF (1 mL) was added potassium 2-methylpropan-2-olate (120 mg, 1.05 mmol) at room temperature under N2. The addition was slightly exothermic (˜40° C.). The resulting solution was warmed up to 60° C. for 10 minutes. The reaction mixture was diluted with water and extracted into DCM (3×5 mL) and the mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (128 mg, 65%) as colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[NH:10][C:9]([S:13][CH3:14])=[N:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]([S:13][CH3:14])=[N:8][C:7]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)NC(SC)=NC1c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)O
Product: CCOC(=O)c1c(-c2ccccc2)nc(SC)[nH]c1=O
Reaction time: 16 h

Procedure:
A mixture of 5-ethyloxycarbonyl-2-methylthio-4-phenyl-4,5-dihydro-6-oxopyrimidine (273 mg) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (200 mg) in isopropanol (5 ml) was stirred for 16 h. The reaction mixture was evaporated to dryness, the residue was dissolved in dichloromethane and stirred with 5% sodium thiosulfate for 5 min. The organic layer was washed with 5% sodium bicarbonate and water (2×), dried over sodium sulfate and evaporated to dryness. The pure title compound was obtained after chromatography on silicagel in dichloromethane/methanol 98/2 (v/v) as eluent.
Reaction SMILES: [I-].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:18])[CH3:17])[CH:13]=[C:12]([C:19](=[O:21])[CH3:20])[CH:11]=2)[CH:6]=[C:5]([CH3:22])[N+:4]=1[CH3:23].CO.O.[OH-].[Na+]>O>[NH2:2][C:3]1[N:4]([CH3:23])[C:5]([CH3:22])=[CH:6][C:7](=[N:9][C:10]2[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)[N:8]=1
Reactant: CC(=O)c1cc(Nc2cc(C)[n+](C)c(N)n2)cc(C(C)=O)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(N=c2cc(C)n(C)c(N)n2)cc(C(C)=O)c1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A suspension of 21 g (49.3 mmole) of 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium iodide (compound No. 2, synthesized as described in section 6.1) in 1:1 methanol/water (750 mL) at 60° C. was treated with excess 2N NaOH with cooling to maintain about 60° C. An additional 200 mL of water was added and the mixture was cooled in ice and filtered to give 14.69 g 2-amino-4-(3,5-diacetylphenyl) imino-1,4-dihydro-1,6-dimethylpyrimidine as yellow crystals, mp 219-220°.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](O)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][S:14][C:13]2=[S:24])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].O>Cl.CO>[C:1]([NH:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:13]2=[S:24])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N2C(=S)SCC2(O)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)NNc1ccc(-n2c(-c3ccccc3)csc2=S)cc1
Temperature: 80 °C

Procedure:
3-[4-(2-Acetylhydrazino)phenyl]-4-hydroxy-4-phenyl-thiazolidine-2-thione (1.0 g, 0.0028 mole) was added to water (25 ml) and methanol (5 ml). Concentrated hydrochloric acid (2 drops) was added; and the resulting mixture was stirred and heated at 80° C for 3 hours. The reaction mixture was chilled in ice, and the solid was filtered off. The product was washed with water, then ether, and allowed to dry. Yield 0.80 g (84%), m.p. 230°-232° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30]CC3C=CC=CC=3)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(O)cc1
Yield: 95.3 %

Procedure:
A solution of 2-(4-acetamidophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.190 g, 0.386 mmol) in 2 mL of EtOH/THF (1:1) was debenzylated with 10% Pd/C under an H2 atmosphere as described in Example 30.F to provide the title compound (0.148 g, 95% yield): ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C1(C)C=CC([C:17]#[N:18])=CC=1>>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)#[N:18]
Reactant: Cc1ccc(C#N)cc1
Reactant: N#CCc1ccc(I)cc1
Product: N#CCc1ccc(C#N)cc1
Yield: 34.2 %

Procedure:
4-bromomethylbenzonitrile (white crystal), 2.0 g (yield: 51.0%), were obtained according to the same method as that of synthesis of 4-iodophenylacetonitrile of Example 5 except that 2.34 g (20 mmole) of p-tolunitrile (purchased from Tokyo Kasei) were used. Subsequently, 438 mg (yield: 34.2%) of light yellow crystals of 4-cyanophenylacetonitrile were obtained according to the same method as that of synthesis of 4-iodophenylacetonitrile of Example 5 except that 1.76 g (9.0 mmole) of the above 4-bromomethylbenzonitrile were used and that purification was performed according to silica gel column chromatography and recrystallization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([CH:28]=[O:29])[C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[CH:15]=2)[CH2:12][C:11]([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])=[N:10]1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[N:24][C:23]([O:26][CH3:27])=[C:22]([CH2:28][OH:29])[CH:21]=3)[CH:15]=2)[CH2:12][C:11]([C:30]([F:36])([F:35])[C:31]([F:34])([F:32])[F:33])=[N:10]1
Reactant: COc1ncc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ncc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)cc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,4-difluoro-phenyl)-5-(3-(3-formyl-2-methoxy-pyridin-5-yl)-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20 mg, 0.04 mmol) prepared in Example 73 in ethanol (1 mL), was slowly added sodium borohydride (6.0 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with a 1N hydrochloric acid solution, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue as a pale yellow liquid. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 3.0 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:16]4[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([Cl:13])[CH:15]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: COc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1Cl
Reaction time: 0.75 h
Yield: 62 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.290 g), 1-(3-chloro-4-methoxyphenyl)piperazine (0.271 g), triethylamine (Aldrich; 0.159 g), and ethylene glycol (2 mL) is stirred at 80° C. for 40 min, at which time another 0.031 g of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine is added; after another 45 min, an additional 0.025 g of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine is added. When the mixture has stirred for a total of 2 h, it is cooled and partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.29 g of the title compound after crystallization from ethyl acetate/hexane; mp 99-100.5 ° C.; MS m/z 390, 392; IR (mineral oil) 1510, 1501, 795, 1072, 1321 cm-1. 1H NMR (CDCl3) δ2.75, 3.14, 3.78, 3.84, 6.83, 6.97, 7.13, 7.52, 7.55, 8.14.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.N1CCCCC1.CCCCC>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(C)=CC(=O)O
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1
Temperature: 107.5 °C

Procedure:
A heavy-walled screw-cap tube was charged with 3-methyl-2-butenoic acid (13.86 gm) 3,3-dimethylacrylic acid, (138.4 mmol), 4-methoxythiophenol (143.2 mmol), and piperidine (41.6 mmol) [Aldrich]. The mixture was heated to 105-110° C. for 32 hours, then cooled to room temperature. The reaction mixture was dissolved in ethyl acetate (EtOAc) (700 ml) with stirring, and the resulting solution was washed with 1M aqueous HCl (50 ml×2), water (50 ml), and saturated aqueous NaCl (50 ml). The organic solution was thereafter dried over NaSO4. Concentration of this organic solution under reduced pressure afforded an oil and 2 days incubation at −20° C. yielded a crystalline solid. Forty ml of pentane were added to the solid, which was then crushed and filtered. The solid was washed on filter paper with pentane (20 ml, 2 times) to yield the product 3-(4-methoxyphenylthio)-3-methyl-butyric acid, as pale yellow crystals (31.4 grams, 94.4% yield, m.p. 62-64° C.), [1H-NMR(CDCl3): d7.5 (t, 2H, J=8 Hz), d6.9 (t, 2H, J=6.7 Hz), d3.9 (s, 3H, J=16.1 Hz), d2.6 (s, 2H), d1.3 (s, 6H)].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH3:24])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH3:24])[CH:3]=1
Reactant: CSc1c(O)cccc1CN(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.6 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10%-sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.