Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1I)=[O:4].[CH2:15]([OH:18])[C:16]#[CH:17].C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:17]#[C:16][CH2:15][OH:18])=[O:4]
Reactant: C#CCO
Reactant: COC(=O)c1sc2c(c1I)CCCC2
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2c(c1C#CCO)CCCC2
Temperature: 85 °C
Yield: 72.9 %

Procedure:
To a solution of 3-Iodo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (15 g, 46.6 mmol) and prop-2-yn-1-ol (5.22 g, 93 mmol) in Acetonitrile (100 mL) was added Pd(PPh3)2Cl (3.27 g, 4.66 mmol), copper(I) iodide (0.89 g, 4.66 mmol) and triethylamine (14 g, 140 mmol). The mixture was heated at 85° C. reflux under N2 for 3 hrs. The reaction was cooled to room temperature, and concentrated to dryness, which was diluted with H2O (50 mL), extracted with ethyl acetate (200 mL×3), The organic phase was washed with saturated aqueous NaHCO3 150 mL, dried over Na2SO4, After concentration, the crude product was purified by silica gel chromatography eluted with PE:EtOAc=10:1-4:1 to give afford title product (8.5 g, 73% yield) as yellow oil. LCMS (m/z) ES+=233 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:51]6[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 60.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (24 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.6 mg (60%)]. LC-MS m/z 760 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[N+:14]([O-:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:20])([F:1])[F:21])[S:10]([C:13]1[N+:14]([O-:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH:25]=[CH2:24]
Reactant: O=S(=O)(Nc1ccccc1C(F)(F)F)c1cccc[n+]1[O-]
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1ccccc1C(F)(F)F)S(=O)(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To N-(2-trifluoromethylphenyl)-2-pyridinesulfonamide 1-oxide (compound 129, Table A) (1.0 g, 3.0 mmol) in 10 ml of DMF is added NaH (0.30 g, 6.2 mmol) under N2, and the mixture is stirred at RT for 30 minutes. Allyl bromide (0.82 g, 0.59 ml, 6.8 mmol) is added dropwise, and the mixture is stirred at RT for 48 hours. It is then worked up and purified to give the title compound (compound 37, Table A). (DMF is dimethylformamide; RT is room temperature.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Cl-].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1)=[O:18]
Reactant: O=C(O)c1cccs1
Reactant: COc1c(C)cccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2cccs2)cc1C
Temperature: 10 °C

Procedure:
Into a solution of 60 g of 2,6-dimethyl anisole and 62.7 g of the chloride of 2-thiophene carboxylic acid in 250 ml of anhydrous methylene chloride there was introduced over 30 minutes 58.5 g of aluminium chloride while maintaining the temperature at about 10° C. The reaction medium was brought to the reflux temperature of the solvent for 21/2 hours, then poured onto one kg of crushed ice mixed with 150 ml of concentrated hydrochloric acid. The organic phase was decanted, the aqueous phase extracted with methylene chloride, and the organic phase washed with an aqueous solution of sodium hydroxide, then with water. After drying and evaporation of the solvent, 110 g of an oil was isolated which was distilled under reduced pressure to give 89 g of ketone. Boiling point (14 mm Hg)=225° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])([CH2:12][CH:13]=[O:14])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1.[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:15][S@@:16]([C:18]([CH3:19])([CH3:21])[CH3:20])=[O:17])([CH2:12][C@@H:13]([OH:14])[C:24]([F:26])([F:25])[F:23])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)N[C@](CC=O)(c1nc(Br)ccc1F)C(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C[C@@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
To a solution of (R)-N-((R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (0.12 g, 0.299 mmol) in THF (3 ml) at −78° C. was added (trifluoromethyl)trimethylsilane (0.475 ml, 2.99 mmol) dropwise. After 25 min, tetrabutylammonium fluoride, 1.0m in tetrahydrofuran (0.299 ml, 0.299 mmol) was added. The reaction mixture was stirred at −78° C. for 6 h (warmed up to −20° C.). Aqueous 1N HCl (0.8 mL) was added at −78° C. and the reaction was warmed up to rt, diluted with water, extracted with EtOAc (2×), washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane in 20 min to give (R)-N-((2S,4R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1,5,5,5-pentafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (30 mg, 0.064 mmol, 21.29% yield) as white solid. MS m/z=471, 473 M+, Calculated for C14H17BrF6N2O2S: 471.26.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:19](Cl)=[N:20][C:21]([NH2:25])=[N:22][C:23]=2[CH3:24])[CH:12]=1)[CH3:8]>CN1C(=O)CCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:23]([CH3:24])=[N:22][C:21]([NH2:25])=[N:20][C:19]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=1)[CH3:8]
Reactant: CCCCCN
Reactant: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(C(=O)OCC)c1
Temperature: 150 °C

Procedure:
Pentylamine (2.5 mL) was added to a stirred solution of the product from step (ii) (1.65 g) in NMP (3 mL). The mixture was heated at 150° C. for 15 h and allowed to cool. The solution was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) added. The aqueous phase was separated and the organic phase washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography eluting with 2% to 5% MeOH in DCM to give the subtitle compound as an orange solid. 0.7 g.
Reaction SMILES: [NH2:1][NH2:2].O.[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>CO>[CH3:4][O:6][C:7]([C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:2][N:1]=1)=[O:19]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 77.3 %

Procedure:
NH2—NH2—H2O (1.0 g, 20 mmol) was added to a solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.94 g, 8.81 mmol) in methanol (17 mL). The resulting reaction mixture was heated to reflux for two and half hours. The methanol was evaporated and the resulting solid was heated with 2.5% ethyl acetate in hexane to afford 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester as a solid in 77.3% yield. LC-MS purity: 93.345%.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.CI>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[C:8]=1[CH3:2]
Reactant: [Li]CCCC
Reactant: N#Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Br)ccc(C#N)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DIPA (12.1 g, 0.120 mmol) in 20 mL of dry THF was added 2.5M of n-BuLi (44 mL, 0.11 mmol) dropwise under Ar at −78° C., and then the reaction was allowed to warm to 0° C. After stirring for 1 hour, the solution was added to a solution of 4-bromo-2-fluorobenzonitrile (20 g, 0.1 mmol) in 200 mL of dry THF dropwise at −78° C. under Ar and the mixture was stirred for 3 hours, then MeI (15.6 g, 0.110 mmol) was added at one portion and the mixture was stirred for another 30 minutes. Then the reaction was quenched with aq. NH4Cl and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water, brine, dried and concentrated to brown oil, which was purified by silica gel column to give 4-bromo-2-fluoro-3-methylbenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (116 mg, 0.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41062 (160 mg, 0.47 mmol) at RT followed by a 2 N aq. solution of LiOH (0.47 mL, 0.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 30 mg of 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride SLA 41064 as a yellow solid (31 mg, 11% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][CH:12]=1.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[N:17]1([CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:12][N:11]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Brc1ccc(OCCCN2CCCC2)nc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OCCCN3CCCC3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
n-Butyllithium (5.68 mL, 14.20 mmol) was added dropwise to a mixture of 5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine (2.7 g, 9.47 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 14.20 mmol) in THF (20 mL) at −78° C. over a period of 10 minutes under an inert atmosphere. The resulting mixture was allowed to warm to ambient temperature and stirred for 12 h. The reaction mixture was quenched by the addition of a sat. aqueous solution of ammonium chloride, extracted with EtOAc (2×50 mL) and the organic layer dried over Na2SO4, filtered and evaporated to afford the desired material (3.10 g, 99%) as a yellow oil. The product was used in the next step directly without further purification, NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.26-1.41 (12H, m), 1.77-1.80 (4H, m), 1.95-2.04 (2H, m), 2.50-2.58 (4H, m), 2.62 (2H, t), 4.37 (2H, t), 6.69 (1H, d), 7.91 (1H, d), 8.52 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=251.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+].O>CS(C)=O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C@H:11]([CH2:21][C:27]#[N:28])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
The mixture of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (13.95 g, 32.6 mmol, J. Med. Chem. 1988, 31, 1598-611) and sodium cyanide (3.20 g, 65.2 mmol) in dimethylsulfoxide (100 mL) was stirred at 80° C. for 20 h. After cooling to room temperature, water (200 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (400 mL×2). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (5:1) to give 7.81 g (70%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34]>>[F:41][C:39]1[CH:38]=[CH:37][C:32]([C:33](=[O:34])[NH:35][CH3:36])=[C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)[CH:40]=1
Reactant: CNC(=O)c1ccc(F)cc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)ccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-Amino-4-fluoro-N-methylbenzamide. 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.77 (d, J=4.55 Hz, 3H), 3.16-3.24 (m, 2H), 3.78 (s, 3H), 3.92-4.01 (m, 4H), 6.83 (d, J=7.83 Hz, 1H), 6.93 (br. s., 1H), 6.99 (s, 1H), 7.53 (br. s., 1H), 7.78 (t, J=7.33 Hz, 1H), 8.25-8.48 (m, 2H), 8.62-9.04 (m, 2H), 11.86 (br. s., 1H). MS (ES+): m/z 586.18 [MH+] (TOF, polar).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: BrCCCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=374.4 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (5-bromo-pentyl)-benzene. (5-Bromo-pentyl)-benzene is a known compound and has been prepared as described in the following reference: J. Thomas; W. Marlow; J. Med. Chem.; 6; 1963; 107-111.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCCN1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 49 %

Procedure:
A mixture of isonipecotamide (10.6 g, 82.3 mmol), 1-bromo-3-(methyloxy)propane (C. A. Grob and A. Waldner, Helv. Chim. Acta, 1980, 63, 2152–2158., 12.6 g, 82.3 mmol), and potassium carbonate (22.8 g, 165 mmol) in ethanol (60 ml) was refluxed with stirring for 23 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in water (500 ml), and the aqueous layer was extracted with dichloromethane (300 ml×13). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo to give 8.04 g (49%) of the title compound as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([C:30]5[N:29]=[CH:28][N:27]([CH3:26])[CH:31]=5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: Cn1cnc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)c1

Procedure:
The title compound, white solid (19.5 mg, 45.3%), MS (ISP) m/z=475.1 [(M+H)+], was prepared in accordance with the general method of example 69 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine (intermediate A) (30 mg, 90.8 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36]Cl)[CH:31]=1>CN(C)C=O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:31]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.1 mg, 12%) as a trifluoro acetic acid salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C@@H:7]([NH:35]C(OCC1C=CC=CC=1)=O)[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6](=[O:46])[C@@H:7]([NH2:35])[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)N1CCCC(NC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](N)CC(=O)N1CCCC(NC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 6 h
Yield: 100.1 %

Procedure:
The solution of 4-(3-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionylamino}-1-piperidyl]-4-oxo-2(S)benzyloxycarbonylaminobutyric acid tert-butyl ester (1.35 g) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 10% Pd—C (0.27 g, 50% wet) was hydrogenated at atmospheric pressure for 6 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo to give 4-[3-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionylamino}-1-piperidyl]-4-oxo-2(S)-aminobutyric acid tert-butyl ester (1.07 g) as an oil.