Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[C:6]([Cl:23])[N:5]=[C:4]([CH3:24])[N:3]=1.Cl>O1CCOCC1>[ClH:23].[Cl:23][C:6]1[N:5]=[C:4]([CH3:24])[N:3]=[C:2]([NH2:1])[C:7]=1[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)c(CCC2CCNCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve tert-butyl 4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]piperidine-1-carboxylate (29.00 g, 81.72 mmol) in 1,4-dioxane (145 mL) and add 4M hydrogen chloride in 1,4-dioxane (204.2 mL, 817.1 mmol). Stir the solution for 18 h at RT. Concentrate the mixture under reduced pressure, slurry in diethyl ether (250 mL), filter, and dry the resultant solid under vacuum to give the title compound as a crude white solid (29 g). LC-ES/MS m/z (35Cl/37Cl) 255.2/257.2 (M+1).
Reaction SMILES: [Mg].C(I)C.[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7].[CH2:22]=[O:23].[NH4+].[Cl-]>C1COCC1>[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:22][OH:23])=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7]
Reactant: C=O
Reactant: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: C=CCc1c([SiH](C)C)cc(CO)c2ccccc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a vigorously stirred suspension of activated magnesium turning (480 mg, 20 mmol) in dry THF (70 mL) were added a piece of 12 and ethyl iodide (50 μL). The reaction mixture was heated to reflux until the red color disappeared. Heating (65° C.) of the suspension was continued while a solution of 1-allyldimethylsilyl-4-bromo-naphthalene (1 Scheme 26, 3.0 g, 10 mmol) in THF (20 mL) was added over a period of 15 min. Upon completion of the addition, the gray solution was heated further for 10 min and transferred to a separate flask containing. paraformaldehyde (700 mg) in THF (20 mL) via cannula. After stirring the reaction mixture at 50° C. for 30 min, concentrated NH4Cl (10 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (70 mL) and brine (30 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a colorless oil (1.8 g, 75%); 1H NMR (300 MHz, CDCl3) δ 0.58 (s, 6 H), 2.08 (d, J=7.50 Hz, 2 H), 3.21 (s, OH, 1 H), 4.93-5.03 (2 H), 5.04 (s, 2 H), 5.89 (m, 1 H), 7.47 (d, J=7.20 Hz, 2 H), 7.53-7.64 (2 H), 7.69 (d, J=6.90 Hz, 1 H), 8.11 (d, J=8.80 Hz, 1 H), 8.23 (d, J=8.80 Hz, 1 H), 13C NMR (75 MHz, CDCl3) −1.50 (2 C), 24.6, 63.5, 114.1, 124.5, 124.8, 125.9, 126.8, 129.1, 131.4, 133.7, 135.0, 137.3, 137.5, 138.3.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>>[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[CH:27][CH:28]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(I)c(Cl)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-Chloro-4-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(3-chloro-4-Iodo-phenyl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. HRMS m/z calcd for C25H24N4O3ClI [M+H]+: 591.0655. Found: 591.0657.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)=[N:21][C:22]=3[CH2:23][CH3:24])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[N:21][C:22]=3[CH2:23][CH3:24])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(CN2CC(C(=O)O)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Yield: 68.7 %

Procedure:
The title compound (0.10 g) was synthesized in a yield of 71% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-6-ethylpyridin-2-yl}methyl)azetidine-3-carboxylate (0.15 g, 0.32 mmol) that was obtained in Example 25 (25d) and a 1 N aqueous solution of sodium hydroxide (0.96 mL, 0.96 mmol).
Reaction SMILES: [CH2:1]=O.[CH:3]1([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]3[C@H:13]4[C@H:23]([CH2:24][CH2:25][C@:8]23[CH3:9])[C@:21]2([CH3:22])[C:16]([C:17]([F:28])([F:27])[C@@H:18]([OH:26])[CH2:19][CH2:20]2)=[CH:15][CH2:14]4)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)=O>[F:28][C:17]1([F:27])[C@@H:18]([OH:26])[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16]1=[CH:15][CH2:14][C@@H:13]1[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]1[CH2:11][CH2:12][C@@H:7]2[N:6]([CH:3]1[CH2:5][CH2:4]1)[CH3:1]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CC1)[C@H]1CC[C@H]2[C@@H]3CC=C4C(F)(F)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a mixture of 10 ml of formic acid and 5 ml of formaldehyde is added 1.4 g of 17β-(cyclopropylamino)-4,4-difluoroandrost-5-en-3β-ol. The mixture is heated at reflux for 5 hours, the volume is then reduced to 7.5 ml in vacuo, and 10 ml of 50% (w/w) aqueous sodium hydroxide is added. The aqueous layer is separated and extracted with ethyl acetate and the combined organic solutions are dried over magnesium sulfate. The solvent is then removed in vacuo and the residual product is purified by flash chromatography to give 4,4-difluoro-17β-[N-methyl(cyclopropylamino)]androst-5-en-3β-ol.
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:37])=[CH:21][N:22]4[S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.O.C(O)(=O)C>C1COCC1.C(OCC)(=O)C.C([O-])(O)=O.[Na+].[OH-].[OH-].[Pd+2].[C]>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:39][CH2:38][C:11]=2[N:12]=[C:13]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20]([CH3:37])=[CH:21][N:22]3[S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[N:14]=1
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2

Procedure:
To a solution of 6-benzyl-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.1 g, 2.0 mmol) in THF (15 mL) was added water (3.75 mL) and acetic acid (0.34 mL, 5.9 mmol), then 20 mol % Pd(OH)2/carbon (50% wet) (0.86 g, 0.61 mmol) was added. The reaction mixture was placed under an atmosphere of hydrogen gas via balloon. After 1.5 hours the mixture was diluted with ethyl acetate and neutralized with saturated aqueous NaHCO3. The mixture was then filtered through a pad of Celite®. The eluent was then further diluted with ethyl acetate and brine and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-20% MeOH/DCM) to provide 4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (d, J=1.0 Hz, 3 H) 2.32 (s, 3 H) 2.68 (t, J=5.6 Hz, 2 H) 3.00 (t, J=5.7 Hz, 2 H) 3.72 (s, 2H) 3.92 (s, 3 H) 7.30-7.48 (m, 4 H) 7.65 (d, J=1.0 Hz, 1 H) 7.85 (d, J=8.3 Hz, 2 H) 8.04 (dd, J=7.3, 2.0 Hz, 1 H). MS (ESI+) m/z 449.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH:12]=O)=[C:4]2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH2:12][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:4]2[CH:3]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2CC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2CCN2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)acetaldehyde (40 mg, 0.12 mmol) and piperidine (23 μl, 0.23 mmol) in 1,2-dichloroethane (3.5 ml) was added sodium triacetoxyborohydride (49 m, 0.23 mmol). The reaction mixture was stirred at 20° C. for 17 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with a 5% sodium bicarbonate solution (6 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue that was purified by automated ISCO chromatography (methanol/dichloromethane; 5/95). The title compound was obtained as a white solid (28 mg, 58%). LCMS m/z 414.1, 416.1 (M+H)+, ret. time=1.76 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][OH:10])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1
Reactant: Cn1nc(Cl)c(Cl)c1SCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(Cl)c(Cl)c1SCCOS(C)(=O)=O
Yield: 76 %

Procedure:
A solution of 5 g (0.022 moles) 1-methyl-3,4-dichloro-5-(2-hydroxyethylthio)pyrazole and 2.52 g (0.022 moles) methane sulfonyl chloride in 100 ml methylene chloride was stirred at room temperature for two days. To that mixture, 2.4 g (3.3 ml) triethylamine was added. The reaction mixture was then stirred over the weekend. The mixture was filtered and the filtrate was washed with water, then dried over magnesium sulfate, and then cooled with dry ice. Stripping of the solvent, followed by chromatography on silica gel, eluting with 5% ethyl acetate/methylene chloride gave 5.1 g of the product as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.[CH3:16][O-].[Na+].CI>CO>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:16])[N:7]=1
Reactant: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)cc(-c2ccco2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 150 mg (0.69 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile in 3 ml methanol were added 0.13 ml (0.69 mmol) sodium methylate solution (5.4M in ethanol) and 0.04 ml (0.69 mmol) methyl iodide and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 113 mg (71%) 6-amino-4-furan-2-yl-2-methylsulfanyl-nicotinonitrile as a brown crystalline solid. ES-MS m/e (%): 232 (M+H+, 100).
Reaction SMILES: [CH2:1]([Se:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH2:1]([Se:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1[Se]Cc1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2ccccc2)c1[Se]Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.37 g (0.0041 mol) 2-benzylseleno-3-methoxybenzoyl chloride (prepared from 2-benzylseleno-3-methoxybenzoic acid and α,α-dichloromethyl ether in dichloromethane at room temperature) in 10 ml pyridine at 0° C. is added with stirring a solution of 0.38 g (0.0041 mol-0.37 ml) aniline. After stirring at room temperature for 18 hours the contents of the flask are poured onto 150 g ice and 50 ml 25% HCl and extracted. The organic phase is washed with 50 ml 10% NaHCO3 and twice with 100 ml portions of dichloromethane and 200 ml water, dried over sodium sulfate and the solvent removed in vacuum.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25](O)=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:15][N:2]([CH3:1])[CH:3]([C:5]1([C:25](=[O:26])[CH2:24][C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:4]
Reactant: CC(C1NCCc2ccccc21)N(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(N(C)C)C1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2ccccc21

Procedure:
Prepared as Ex. No. 1, from 2.7 g (13.30 mmoles) of 1- dimethylamino-eth-1-yl-1,2,3,4-tetrahydroisoquinoline (diastereoisomeric mixture), 3.05 g (15.00 mmoles) of 3,4-dichlorophenylacetic acid and 4.2 g (20.39 mmoles) of dicyclohexylcarbodiimide, in 100 ml of dry methylene chloride.
Reaction SMILES: [Na+].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O-:13])=O)=[N:8][C:7]=2[CH:14]=1.[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([CH3:2])=[CH:14][C:7]=4[N:8]=3)=[O:13])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc2oc(C(=O)[O-])nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To 5-methyl-benzooxazole-2-carboxylic acid sodium salt (130 mg, 0.83 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (400 mg, 1.2 eq), BOP (430 mg, 1.2 eq), N,N-diisopropylethylamine (126 mg, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of solvent gave the crude product, which was purified by column chromatography on silica gel to give 60 mg of (S)-3-methyl-2-{4′-[(5-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester was obtained as a white solid.
Reaction SMILES: C(N1CCC([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)CC1)C1C=CC=CC=1.[CH:32]([OH:34])=O.CO>[Pd]>[CH:32]([N:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH:21]1[C:15]1[NH:14][C:18]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:17]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:16]=1)=[O:34]
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Reactant: O=CO
Agent: [Pd]
Solvent: CO
Product: O=CN1CCCCC1c1nc(-c2ccc(F)cc2)c(-c2ccncc2)[nH]1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg; prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CSc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(SC)ncn1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 0.41 g of sodium hydride (60% in oil), to which 2 ml of a tetrahydrofuran solution containing 0.58 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 2 ml of a tetrahydrofuran solution containing 1.1 g of 4-chloro-6-methylthiopyrimidine was slowly added dropwise, followed by further stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.3 g of 4-(2-butynyloxy)-6-methylthiopyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15](OC)=[O:16])[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=CCO)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Into a cooled (−78° C.) solution of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester (1.8 g, 6.4 mmol) in tetrahydrofuran (50 mL) obtained in the above 1) was slowly dropped, under an atmosphere of argon, 1 M diisobutylaluminum hydride in toluene (15.9 mL, 15.9 mmol). After dropping, the reaction mixture was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (10 mL) was added at 0° C. and allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (50 mL), and stirred for 30 minutes. After stirring, the reaction mixture was extracted with ether, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=2: 1) to obtain 0.95 g (yield 58.6%) of 4-(2-hydroxyethylidene)-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCOc1ccc(OC)cc1
Product: COc1ccc(OCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-methyl-2-(4-methoxyphenyloxy)-ethylamine analogously to Example 6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[C:26]#[N:27]>>[F:29][C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:19]=2)=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)ccc1F
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.27 (dd, J=5.6, 2.4 Hz, 1H), 8.06 (m, 1H), 7.68 (dd, J=8.8, 2.4 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.60 (t, J=9.3 Hz, 1H), 7.55 (dd, J=5.4, 1.5 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.98 (m, 1H), 6.89 (dd, J=3.9, 1.5 Hz, 1H), 4.16 (d, J=15.6 Hz, 1H), 4.05 (d, J=15.6 Hz, 1H), 2.10 (s, 3H); MS (ES) m/z 379 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)nc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.17 mmol) (from example 40, step 1) was dissolved in MeOH (1 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.051 mL, 0.17 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 10.66 μL, 0.17 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (0.896 mL, 5.38 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (60 mg, quant.) as a slightly yellow oil. MS m/z 372 (M+H)+