Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:25]=[C:24]2[O:26][CH2:27][CH2:28][C:23]2=[CH:22][CH:21]=1>ClCCCl.C(Cl)Cl>[Cl:1][C:21]1[CH:22]=[C:23]2[CH2:28][CH2:27][O:26][C:24]2=[N:25][C:20]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13]
Reactant: Brc1ccccc1-c1ccc2c(n1)OCC2
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Clc1cc2c(nc1-c1ccccc1Br)OCC2
Reaction time: 8 h
Yield: 206.3 %

Procedure:
Trichloroisocyanuric acid (0.63 g, 2.7 mmol) was added as a solid to a solution of 6-(2-bromophenyl)-2,3-dihydrofuro[2,3-b]pyridine (1.5 g, 5.4 mmol) in 1,2-dichloroethane (30 ml). The mixture was allowed to stir overnight and then a small additional amount of the chlorinating agent was added and the solution refluxed for 1.5 h. The mixture was diluted with methylene chloride and washed with water, brine (sat.), dried (over MgSO4), filtered and concentrated to afford 1.73 grams of the desired product, m.p. 106°-117° C.
Reaction SMILES: [CH:1]([C:3]1(O)[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)=[CH2:2].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)(=O)C>[C:14]([S:15][CH2:2][CH:1]=[C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)(=[NH:13])[NH2:16]
Reactant: C=CC1(O)CCCc2sccc21
Reactant: NC(N)=S
Solvent: CC(=O)O
Product: N=C(N)SCC=C1CCCc2sccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Vinyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (10.1 g, 56 mmol) was dissolved in acetic acid (70 mL) and thiourea (4.3 g, 56 mmol) was added in one portion. The reaction was stirred at 25° C. for 2 hours and then the majority of the acetic acid was removed in vacuo. The residue was diluted with diethyl ether to afford a white solid. This was filtered off and washed with additional ether before being dried in vacuo. The title compound was isolated as the acetate salt (13.8 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (330.06 mg, mmol) in 5% H2SO4 in TFA (2 mL) and water (1 mL) was stirred at 50° C. for overnight. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated slowly with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography (SiO2, 5% MeOH in EtOAc) to afford 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (15 mg) in 50% yield. ESMS m/z (relative intensity): 505.9 (M+H)+ (100), 527.9 (M+Na)+ (20).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]1([C:10]([C:12]2[CH:22]=[CH:21][C:15]([CH:16]([CH3:20])[C:17](Cl)=[O:18])=[CH:14][CH:13]=2)=[O:11])[S:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[OH:4][CH2:3][CH2:2][NH:1][C:17](=[O:18])[CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:5]2[S:9][CH:8]=[CH:7][CH:6]=2)=[CH:22][CH:21]=1)[CH3:20]
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: CC(C(=O)NCCO)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred solution of 2.44 parts of 2-aminoethanol in 15 parts of chloroform is added dropwise a solution of 5.6 parts of p-(2-thenoyl)hydratropoyl chloride in 15 parts of chloroform at room temperature (highly exothermic reaction). Upon completion, the whole is stirred and refluxed for 1 hour. The reaction mixture is cooled and washed with a 1N hydrochloric acid solution. The organic layer is separated, washed twice with water, dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from boiling ether, yielding N-(2-hydroxyethyl)-p-(2-thenoyl)hydratropamide; m.p. 87.1° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30]([NH2:34])([CH3:33])[C:31]#[CH:32]>>[NH2:34][C:30]([C:31]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])=[CH:14][C:13]=3[Cl:27])=[O:11])[CH:9]=2)[CH:32]=1)([CH3:33])[CH3:29]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CC(C)(C)N
Product: Cc1ccc(-n2cc(C(C)(C)N)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and 1,1-dimethyl-prop-2-ynylamine (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 5:95 as the eluent to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](#[N:18])[CH:16]=[CH2:17]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: C=CC#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CC(C)O
Product: N#CCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 98.5 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)piperazine (0.1 mol), 2-propenenitrile (0.15 mol), and N-methyl-N,N-dioctyl octanaminiumchloride (1 ml) in 2-propanol (150 ml) was stirred and refluxed for one hour. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in diisopropylether/acetonitrile 10/1. The solvent was evaporated, yielding 28 g (98.5%) of 4-(3,4-dichlorophenyl)-1-piperazinepropanenitrile (intern. 3).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>C1COCC1>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
Borane-tetrahydrofuran complex (1.0M, 130 ml) was added dropwise to a solution of 90 ml THF and 90 ml TFA (trifluoroacetic acid) at -5° C., and then 17.93 g 2-(2-amino-4-trifluoromethylphenyl)-1H-indole was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with water and basified with 50% NaOH. The solution was extracted with Et2O. This organic layer was washed with water and saturated NaCl solution, dried (MgSO4), and concentrated to yield 3.65 g solid. Purification by HPLC and recrystallization from MeOH/water yielded 1.93 g solid, m.p. 152°-154° C.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])C1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:25][C:24]([F:26])([F:27])[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:32]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:33]=3)[CH:30]=[CH:31][C:9]=2[OH:8])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2cn3ccccc3n2)ccc1O
Yield: 56 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give the title compound (130.3 mg, 45.9%) as a white solid. Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give the title compound (18.3 mg, 20.2%) as a white solid.
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>II.C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of I2 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2,1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:31]([CH3:30])(=[O:33])=[O:32])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-[4-(2-amino ethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (16.0 mg, 0.037 mmol) in DCM (1.0 mL) was added TEA (15 μL, 0.11 mmol) and methanesulfonyl chloride (4.2 μL, 0.055 mmol). The resulting mixture was stirred at rt for 1 h and then the solvent was removed under reduced pressure. The residue was dissolve in MeOH (1 mL) and 2.0 M sodium hydroxide in water (0.10 mL) was added. After stirring for 4 h, the reaction solution was diluted with MeOH and a few drop of acetic acid and then purified by preparative LCMS to give the desired product as a white solid (14.1 mg, 78.3%). MF=C12H13ClFN5O4S; LCMS calculated C12H14ClFN5O4S (M+H)+: m/z=377.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7](=[O:9])[CH3:8].[NH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:7]([C:6]1[S:5][C:4]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[N:3][C:2]=1[NH2:1])(=[O:9])[CH3:8]
Reactant: CC(=O)c1sc(S(C)(=O)=O)nc1N
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 120 °C

Procedure:
390 mg (1.77 mmol) of 1-[4-amino-2-(methylsulfonyl)-1,3-thiazol-5-yl]ethanone (Example 48A) were dissolved in 5 ml of DMSO, and 209.6 mg (0.89 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 0.585 ml (3.54 mmol) of N,N-diisopropylethylamine were added. The mixture was heated in a microwave at 120° C. for 45 min. This gave, after purification by preparative HPLC, 162 mg (52% of theory) of the product as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(C(C)C)CC)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: C=CC(O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(O)COc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
A mixture of 46.5 mg of 2-benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl trifluoromethane sulfonate, 22.7 mg of 3-ethynyl-3-quinuclidinol, 6.6 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 60.1 μl of diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 5% methanol/ethyl acetate, to give 10.7 mg of the target compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([NH:16][CH2:17][CH2:18][CH:19]=O)[N:12]=[CH:11][N:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:19][CH2:18][CH2:17][NH:16][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37]1
Reactant: O=CCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1cccc(N2CCN(CCCNc3ncnc4c3nc(-c3ccccc3)n4-c3ccccc3)CC2)c1Cl
Temperature: 45 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To the solution of 3-(8,9-diphenyl-9H-purin-6-ylamino)propanal obtained in step 2 (0.73 g, 2.13 mmol) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (0.6 g, 2.13 mmol) in 1.2-dichloroethane was added Na(OAc)3BH (0.72 g, 3.40 mmol) and acetic acid (0.24 mL, 4.25 mmol) at room temperature and stirred for 18 hours at 45° C. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by preparative HPLC (purification system, Gilson) to provide the title compound (460 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([N:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[N:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)cn2n1)C1CC1
Yield: 80 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy) [1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol), 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (90.4 mg, 0.440 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (126 μL, 0.733 mmol) and HATU (209 mg, 0.550 mmol) and in the same manner as in Example 24, the title compound (151 mg, 80%) was obtained as white crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]=[CH:43][O:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]=[CH:43][O:42][N:41]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncon4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncon4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.60 g) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (5 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→4:1), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 129) (534.9 mg) as yellow crystals.
Reaction SMILES: CN(C)CC(C)C([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.O.NN.[OH-].[Na+].ClC1C=CC([C:28]2[CH:32]([CH3:33])[CH2:31][NH:30][N:29]=2)=CC=1>C(O)CC>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([N:30]2[CH2:31][CH:32]([CH3:33])[CH:28]=[N:29]2)=[CH:12][CH:11]=1
Reactant: CC(CN(C)C)C(=O)c1ccc(Cl)cc1
Reactant: CC1CNN=C1c1ccc(Cl)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC1C=NN(c2ccc(Cl)cc2)C1

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was placed 100 g of 3-dimethylamino-2-methyl-4'-chloropropiophenone (0.47 mole), 200 ml of n-propanol, 48 g of hydrazine monohydrate (0.96 mole), and 5 g of 50% aqueous sodium hydroxide. The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the product was partitioned between methylene chloride and water. The organic layer was washed 3 times with water and dried over anyhdrous magnesium sulfate. The organic layer contains 82 g (0.42 mole) of 3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole an air sensitive solid. NMR data was consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In a large sealed tube is added 5-bromo-2,4-dichloropyrimidine (3 g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) and N,N′-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15% ethyl acetate/85% hexane) to give (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25 g, 89%). MS (ESI) m/z 278.4 (M+H)+