Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[CH:18]=[C:17]([C@@H:26]([NH:28]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:27])[N:16]=1.O>C1COCC1>[Cl:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[C:15]([O:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)=[N:16][C:17]([C@@H:26]([NH2:28])[CH3:27])=[CH:18]2
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N)c1cc2cccc(Cl)c2c(OC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(methylsulfonyl)piperidin-4-ol (618 mg, 3.45 mmol, 1.6 eq) in THF (5 mL) at 0° C., NaH (60% in mineral oil, 173 mg, 4.32 mmol, 2.0 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate 69 (1.0 g, 2.16 mmol, 1.0 eq) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to RT and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)-1-(8-chloro-1-(1-(methylsulfonyl)piperidin-4-yloxy)isoquinolin-3-yl)ethanamine (175).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[Cl:47])=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:47][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:38]=1[NH:37][C:35]([N:24]1[CH2:25][CH2:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)=[O:36])[C:42]([OH:44])=[O:43]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CCC1c1ccccc1F)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To 274 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoic acid was added 3.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by stirring, separating, and then drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 157 mg of 3-chloro-4-({[4-(2-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}amino)benzoic acid as a colorless amorphous substance. The obtained amorphous substance was dissolved in chloroform, and hexane was added thereto to precipitate a white solid, which was collected by filtration to obtain 136 mg of 3-chloro-4-({[4-(2-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}amino)benzoic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O2 [(M+H)+] 676.318, observed 676.3176.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[N:8]=2)=[CH:3][CH:2]=1.[OH-].[NH4+:22]>CCOCC.O1CCCC1.O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([Cl:14])[N:10]=[C:11]([NH2:22])[N:12]=2)=[CH:5][CH:6]=1
Reactant: Clc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.9 %

Procedure:
A mixture of 2-[1,1′-biphenyl]-4-yl-4,6-dichloro-1,3,5-triazine (Example 63A) (0.804 g, 2.67 mmol) in 40 mL ether and concentrated ammonium hydroxide (2 mL, 30 mmol) in tetrahydrofuran (30 mL) was stirred at 0° C. for 60 minutes and at ambient temperature for 20 minutes. The reaction was reduced in volume, diluted with water, and the precipitate was collected, rinsed with water and ether, and dried to provide the desired compound (0.090 g, 12%).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:18]O>CS(O)(=O)=O>[CH2:1]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:16][OH:18])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCNC(=O)CCC(=O)O
Reactant: OO
Agent: CS(=O)(=O)O
Product: CCCCCCCCCNC(=O)CCC(=O)OO
Temperature: -15 °C
Yield: 89.3 %

Procedure:
A 500 mL beaker was charged with 50.0 g (0.205 mol) of 4-nonylamino-4-oxobutyric acid and 100 mL of 98% methanesulfonic acid. The resulting solution was cooled in an ice bath and, with stirring, 38.8 g of 90% hydrogen peroxide (34.9 g, 1.03 mol of hydrogen peroxide) was added dropwise at a rate such that the temperature of the reaction mixture did not rise above 20° C. (required 10 minutes). The solution was stirred at room temperature for 1.5 hours, cooled to -15° C., and poured over ice. The precipitated solid was collected by filtration and washed with water. The filter cake was reslurried with water, filtered, and washed with water. The wet filter cake was dissolved in 250 mL of 60° C. ethyl acetate, the water layer removed with a pipet, and the ethyl acetate solution cooled to -15° C. The crystals which formed were collected by filtration, washed with -15° C. ethyl acetate, and air dried to yield 47.5 g of 4-nonylamino-4-oxoperoxybutyric acid (1), mp 85°-91° C., analysis for available oxygen (AvO)=5.61%. Theoretical yield=53.2 g having an AvO of 6.17%.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>O>[CH2:1]([N:8]([CH3:9])[C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Solvent: O
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12

Procedure:
A solution of 12.2 gm (0.1 mol) of N-benzyl-methylamine in 50 ml of dioxane was slowly poured, while stirring, to a suspension of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine in about 250 ml of dioxane, and the resulting mixture was heated at 30°-40° C. for about 30 minutes. After taking up the reaction mixture in about 1 liter of water, the reaction product was obtained as a pale yellow precipitate which, after some standing, was suction filtered off, washed with water and dried at about 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:20]=[C:19]2[CH3:27])=[CH:14][CH:13]=1)=O.S(O)(O)(=O)=O.[CH3:38][O:39][C:40](=[NH:42])[NH2:41].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=[C:19]3[CH3:27])=[CH:14][CH:13]=2)[NH:42][C:40]([O:39][CH3:38])=[N:41]1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)c1ccc(-n2c(C)nc3cnccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(OC)=NC1c1ccccc1Cl
Yield: 46.6 %

Procedure:
A mixture of 3-(2-chlorophenyl)-2-ethoxycarbonyl-1-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]prop-2-ene-1-one (200 mg --see Preparation 1), O-methylisourea hydrogen sulphate (155 mg) and sodium bicarbonate (240 mg) was heated in dimethylformamide (DMF) (5 ml) at 70° C. for 16 hours. The cooled mixture was poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with water, dried (MGSO4), filtered and evaporated and the residue was chromatographed on silica eluting with methylene ebloride/metbanol. The fractions containing the product were combined and evaporated to give the title compound (105 mg), m.p. 228°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: CC(=O)Nc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with (3-acetylaminophenyl)boronic acid via General Procedure A to give crude N-(3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)phenyl)acetamide, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 124. MS (Q1) 449 (M+)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24]([OH:27])(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[Cl:20])=[O:5])C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>>[Cl:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[NH:12][C:11]1[N:10]2[N:21]=[CH:22][C:23]([S:24]([OH:27])(=[O:25])=[O:26])=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH2:36][CH2:37]1)=[O:5]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Yield: 87.1 %

Procedure:
Using 6-ethoxycarbonyl-7-(2,5-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.5 g, 1.16 mmol) obtained in Example 22 step 2 and 4-(4-fluorophenyl)piperidine (1.42 g, 7.94 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.57 g, 63%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.[C:20](OC(=O)CC)(=O)[CH2:21]C.O>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7](=[O:9])[CH2:20][CH3:21]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccc(C(=O)NC(CCCCCl)C(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Chloro-2-(p-toluoylamino)hexanoic acid (10.0 g) was dissolved in 15 ml of dry pyridine, and 15 ml of propionic anhydride was added and stirred for 2.5 hours at 90° C. To the mixture was added 15 ml of water slowly so that the maximum temperature did not exceed 85° C., and stirred for 20 minutes at 80° C. The reaction solution was cooled, poured into ice-cold water and extracted with diethyl ether. The extract was washed with 10% hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=8:1-4:1) to provide 6.0 g of the objective compound as colorless crystals. M.p. 85-86° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH3:12][C:13]1([CH3:44])[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:31]#[C:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=3)[CH:19]=2)[S:14]1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:31]#[C:32][C:33]4[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=4)[CH:19]=3)[S:14][C:13]([CH3:12])([CH3:44])[CH:22]=2)=[CH:5][CH:6]=1
Reactant: Cc1cccs1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CC(C)(C)S3)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2-methylthiophene (100.0 mg, 1.00 mmol) in 2.0 mL of THF was cooled to -78° C. and n-butyllithium (64.0 mg, 1.00 mmol, 0.63 ml of a 1.6M solution in hexanes) was added and the solution warmed to 0° C. during 1.5 hours. A solution of ZnCl2 (218.0 mg, 1.60 mmol) in 3.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature, stirred for 40 minutes, and transferred via cannula to a solution of ethyl 4-[(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-yl)ethynyl]-benzoate (Compound 224, 200.0 mg, 0.40 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 170.0 mg (96%), was isolated by column chromatography (5% EtOAc/hexanes) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.01 (2H, d, J=8.3 Hz), 7.63 (1H, s), 7.55 (2H, d, J=8.3 Hz), 7.35 (2H, s), 6.82 (1H, d, J=3.5 Hz), 6.72 (1H, m), 6.00 (1H, s), 4.38 (2H, q, J=7.1 Hz), 2.52 (3H, s), 1.46 (6H, s), 1.40 (2H, t, J=7.1 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH2:31][C:32]([O:34]C)=[O:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH2:31][C:32]([OH:34])=[O:33])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 99.9 %

Procedure:
A mixture of methyl [[6-(3,4,5-triphenyl-lH-pyrazol-1 -yl)hexyl]thio]acetate (1.01 g, 2 mmol), 3 N sodium hydroxide solution (2.1 mL, 6 mmol) and methanol (125 mL) was heated at reflux for 20 minutes. The solvent was removed and the residue treated with lN hydrochloric acid solution. Extraction with dichloromethane (three times) followed by drying of the organic phase over sodium sulfate and concentration in vacuo afforded an oil that crystallized on standing to give [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl) hexyl]thio]acetic acid (0.94 g, 96%); m.p. =92°-97° C. MS(CI): m/e =471 (MH+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1>C(Cl)Cl>[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:11]([CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)=[O:13])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (176 mg, 1 mmol) and triethylamine (0.25 ml) in methylene chloride (5 ml), isobutylchloroformate (136 mg, 1 mmol) was added. After 5 minutes N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine (260 mg, 1 mmol) in methylene chloride was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 2N potassium hydroxide solution. The organic layer was separated, washed with distilled water and dried (Na2SO4). Evaporation of the solvent gave a white solid which was crystallized from diethyl ether to afford the title compound (140 mg, 33%), m.p.=130-2°, Anal C27H34N2O2.0.25 H2O, Calc, C, 76.65; H, 8.22, N, 6.62; Found C,76.34; H, 8.32; N, 6.59.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:23]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:39][C:40]1[CH:41]=[C:42]([NH:48][C:2]2[N:7]=[CH:6][C:5]([C@H:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]3)[CH3:9])=[CH:4][C:3]=2[C:23]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:43]=[N:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(-c2cc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.673 g, 1.280 mmol) in THF (15 mL) under inert atmosphere was treated with a solution of 5-fluoro-6-methoxypyridin-3-amine (0.364 g, 2.56 mmol) in THF (10 mL) via syringe. The mixture was chilled to −20° C. in a diluted dry ice/acetone bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 3.84 mL, 3.84 mmol) was added slowly via syringe into the reaction mixture. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere for 1 h. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with 100% ethyl acetate to give tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.459 g, 0.709 mmol, 55.3% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.61 (s, 1H) 9.65 (t, J=1.96 Hz, 1H) 8.31 (dd, J=12.52, 2.35 Hz, 1H) 8.18-8.23 (m, 2H) 8.03 (d, J=2.35 Hz, 1H) 5.80 (dd, J=10.47, 2.05 Hz, 1H) 3.96 (s, 3H) 3.76 (s, 1H) 3.55 (d, J=6.85 Hz, 1H) 3.36 (s, 4H) 2.85 (s, 3H) 2.40 (d, J=3.33 Hz, 4H) 2.07 (s, 1H) 2.02 (s, 1H) 1.97 (s, 1H) 1.54-1.81 (m, 2H) 1.41 (d, J=6.65 Hz, 3H) 1.36 (s, 9H) 1.19 (s, 1H) 0.90 (d, J=6.65 Hz, 1H). m/z (ESI, +ve ion) 648.2 (M+H)+.
Reaction SMILES: C([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)C(C)C.[CH3:28][CH:29]([CH3:33])[CH2:30]C#C>>[C:29]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:33])([CH3:30])[CH3:28]
Reactant: C#CCC(C)C
Reactant: COCCCC[C@@](O)(c1cccc2cc(CC(C)C)oc12)[C@@H]1CCCNC1
Product: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCNC1

Procedure:
(S)-1-(2-isobutylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol using 4-methylpentyne in place of 3,3-dimethylbut-1-yne in Step 1.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:43])[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:43][CH:35]([CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)[CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCC(O)CN1CCCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCI, m/z): 530 [M+H]+.