Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH:16]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
A mixture of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (124 mg, 0.299 mmol) produced in Example (70a), trifluoroacetic acid (1 mL, 12.9 mmol) and dichloromethane (2 mL) was stirred for 2 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 85 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]1(=[N:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][C:10]1[C:9]2[C:8]([N:7]=[C:1]3[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1N=C1CCCCC1
Solvent: ClCCl
Product: Clc1c2c(nc3ccccc13)CCCC2
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2-Cyclohexylideneamino-benzoic acid (1.5 g, 6.9 mmol) was added to phosphorus oxychloride (4 mL) at 0° C. and stirred for 5 minutes followed by heating to 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and slowly poured onto ice (˜100 g) and stirred for 30 minutes. CH2Cl2 (100 mL) was added and the mixture stirred for 5 minutes and the organic layer separated. The aq. layer was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 layers were washed with sat. aq. NaHCO3 (2×50 mL), sat. aq. NaCl (50 mL), dried over Na2SO4, decanted and concentrated to give 9-chloro-1,2,3,4-tetrahydro-acridine, which, was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][S:27][CH3:28])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.O>CN(C)C=O>[CH3:28][S:27]([CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:43]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CSC)ccc1-c1noc(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CS(C)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.7 %

Procedure:
To a solution of 32 mg of 3-{2-methoxy-4-[4-methylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one in 4 mL of dimethylformamide was added 15 mg of metachloroperbenzoic acid. The resulting mixture was stirred for 45 min at room temperature, then poured into water and extracted with dichloromethane. The organic extracts were washed with a saturated aqueous solution if sodium bicarbonate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of methanol in dichloromethane) to give 25 mg of 3-{4-[4-methanesulfinylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one as a white solid which was further purified by trituration with diisopropyl ether.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[CH2:7]([NH2:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>CN(C)C=O>[CH2:7]([NH:16][C:3](=[O:4])[CH2:2][Cl:1])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCl)NCC(=O)c1ccccc1
Reaction time: 4 h

Procedure:
Chloroacetyl chloride (25 g; 0.226 mole) was added slowly to a stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mole) in anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The internal temperature rose to ca. 40° C. The mixture was stirred for 4 hours after the addition and the bulk of the DMF evaporated under vacuum. The residue was treated with water (200 ml) and the crystalline precipitate collected, washed with water and dried. Yield 24.75 g (77%). m.p. 118°-119° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3].[CH3:14][I:15]>CO>[I-:15].[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:14])[CH3:3]
Reactant: CI
Reactant: CN(C)CCCCc1ccccc1
Solvent: CO
Product: C[N+](C)(C)CCCCc1ccccc1
Product: [I-]

Procedure:
To a solution of 287 mg of N,N-dimethyl-4-phenylbutylamine in 3 ml of absolute methanol, 505 μl of methyl iodide was added at a room temperature with stirring, and the mixture was stirred at a room temperature for 6.5 hours. The reaction mixture was concentrated under a reduced pressure, and after adding ethyl acetate allowed to stand for formation of crystal. The crystal was filtered, washed with ethyl acetate, and dried under a reduced pressure to obtain 439 mg of the title compound as a colorless crystal.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:25][C:24]=1[CH2:36][C:37](O)=[O:38].P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[CH:25][C:24]=1[CH2:36][C:37]([NH:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1)=[O:38]
Reactant: O=C(O)Cc1cc(-c2ccc(Cl)cc2)ccc1Cl
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2Cl)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). 3.07 ml of triethylamine were added dropwise at 20° C., the mixture was stirred for 5 min, and 2.81 g (10 mmol) of (4,4′-dichlorobiphenyl-3-yl)acetic acid (EP 1943218 A1 and US 2009/215624 A1) were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 3.3 g (59% of theory) of the title compound of melting point 146-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25].CN(C)C=O>O>[CH2:15]([CH:14]([CH2:17][CH3:18])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[O:19])[CH3:16]
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (5.58 g), dimethyl methoxymethylenepropanedioate (5.62 g) and N,N-dimethylformamide (22 ml) was stirred at 100° C. for 1.5 hours. After cooling to ambient temperature, water (90 ml) was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (4.85 g).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[K+]>O1CCOCC1>[OH2:5].[CH3:49][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Product: O
Temperature: 85 °C
Reaction time: 2 h
Yield: 184.2 %

Procedure:
A light brown solution of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methoxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (19.1 kg, 27.8 mol), a method for preparation of which is described in Step C above, was suspended in dioxane (191 L, 10 volumes) and treated with a 15% aqueous KOH solution (76.4 L, 4 volumes). The mixture was heated to reflux (approximately 85° C.). Once the suspension became homogeneous, the reaction mixture was kept at reflux for 2 hours. In-process monitoring after 2 h showed completion. The heat was discontinued and the suspension was concentrated to remove approximately 80 L of solvent. Water (141 L) was added and the suspension was stirred at ambient temperature for 1 h and filtered through centrifuge. The solid was washed with water till the filtrate ran clear to obtain 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide monohydrate as a light brown solid (14.1 kg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[N+:16]([CH2:19][C:20](=O)[CH2:21][CH2:22][CH3:23])([O-:18])=[O:17]>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:19]([N+:16]([O-:18])=[O:17])=[C:20]([CH2:21][CH2:22][CH3:23])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)C[N+](=O)[O-]
Reactant: O=Cc1ccccc1Cl
Solvent: CC#N
Product: CCCC1=C([N+](=O)[O-])C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Yield: 20 %

Procedure:
To an aqueous solution (50 mL) of nitromethane (50 g) was added an aqueous solution (50 mL) of n-butylaldehyde (59 g), and the mixture was stirred with heating at 60° C. for 6 hours. The reaction mixture was allowed to cool to ambient temperature, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give a brown oil (58 g). To a mixed solution of the obtained oil (50 g) in water (50 mL) and acetone (50 mL) was added sodium chromate (70 g). Under ice-cooling, concentrated sulfuric acid (46 mL) was added dropwise and the mixture was stirred for 5 hours. Ice-water (200 mL) was added and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-nitropentan-2-one (40 g) as a brown oil. A solution of 2-chlorobenzaldehyde (1.8 g), 3-aminopyrazole (1.0 g) and 1-nitropentan-2-one (1.4 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (680 mg) as yellow crystals.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH2:31][C:32](O)=[O:33].[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:44]=3[N:43]=[N:42]2)[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:33]=[C:32]([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:51])[F:52])=[CH:49][C:44]=3[N:43]=[N:42]2)[CH2:37][CH2:36]1)[CH2:31][N:14]1[CH2:15][CH2:16][CH2:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:12]
Reactant: FC(F)(F)c1ccc2c(c1)nnn2C1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(n2nnc3cc(C(F)(F)F)ccc32)CC1
Reaction time: 23 h

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.132 mL, 0.743 mmol) was added via syringe to a mixture of the product of Example 68E (230 mg, 0.743 mmol), 1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (201 mg, 0.743 mmol), and 4-(dimethylamino)pyridine (9.1 mg, 0.07 mmol) in CH2Cl2 (3 mL). The reaction was allowed to proceed at ambient temperature for 23 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50%-100% ethyl acetate/hexanes, 0-20 minutes, 30 mL/minute) to yield an amorphous solid which was triturated with 12 mL 1:1 ether/hexanes and 2 mL ether. The solid was collected by vacuum filtration and air-dried to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.37 (s, 1H), 7.73 (d, J=8.7, 1H), 7.51 (d, J=8.4, 1H), 7.39-7.14 (m, 10H), 5.10-4.95 (m, 1H), 4.82-4.66 (m, 1H), 4.34 (d, J=15.1, 1H), 4.27-4.06 (m, 2H), 3.71-3.50 (m, 2H), 3.46-3.29 (m, 1H), 3.14-2.94 (m, 1H), 2.73-2.63 (m, 2H), 2.64-2.47 (m, 1H), 2.44-2.14 (m, 3H), 1.96-1.82 (m, 2H). MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][O:48][CH3:49]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:9][CH:10]=1
Reactant: COCCOc1c(CCl)cccc1OC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.251 g of 1-chloromethyl-3-methoxy-2-(2-methoxyethoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (1:2 EtOAc-heptane); Rt=6.07.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([C:51]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:52])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(N(Cc2cnn(C(=O)C3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) in dimethylformamide (5 mL) were added triethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g). By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.23 g) was obtained.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([O:33]C1C=CC=CC=1)=O)(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:47][CH2:43][CH2:44][CH2:45][CH3:46])=[O:33])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCN
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sulfonyl]phenyl]benzamide produced in Example 45 and 0.09 ml (0.88 mmol) of butylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 130 mg (yield: 68.0%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)C>[CH3:24][C:22]1[CH2:21][C:20](=[O:25])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Yield: 42.8 %

Procedure:
4-Methoxy-phenylhydrazine hydrochloride (5.6 g, 32 mmol; product of Aldrich Chem. Co.), sodium acetate trihydrate (5.45 g, 40 mmol; product of Kishida Chemicals) and ethyl acetoacetate (4.16 g, 32 mmol; product of Kishida Chemicals) were dissolved in 40 ml ethanol, and the solution was heated under reflux for two hours to complete the reaction. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure, 40 ml ethanol was added to the residue, and the insoluble matters were removed by filtration. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in a small volume of a solvent mixture of benzene and ethyl acetate (4:1), and the solution was subjected to silica gel chromatography (150 g of Silica Gel 60; product of Merck) Elution was performed by using a solvent mixture of benzene and ethyl acetate (4:1), the eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized with methanol, giving 2.80 g (yield: 42.9%) of PMPMP. Its structure was confirmed by 1H NMR and 13C NMR. The spectra thus obtained are shown in Table 1 below.
Reaction SMILES: [NH3:1].C[CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH2:5][C:4]1=[O:10].O=O.[CH3:13]O>>[C:9]([CH2:6][CH:7]([CH3:13])[CH2:8][CH2:3][C:4](=[O:10])[CH3:5])#[N:1]
Reactant: CO
Reactant: CC1CCC(C)C(=O)C1
Reactant: N
Agent: O=O
Product: CC(=O)CCC(C)CC#N
Reaction time: 18 h

Procedure:
A solution of 2 ml of NH3 in 50 ml of methanol is charged into an airtight container fitted with a gas inlet tube and mechanical stirrer. To this solution is added with stirring 0.015 g of CuCl2 2H2O and 1.25 g of 2,5-dimethyl cyclohexanone. Stirring is continued until all solids had dissolved. The container is pressurized with oxygen, and allowed to sit at room temperature for 18 hours. The methanol solvent is removed by rotary evaporator and the product extracted in ether. The ether layer is concentrated. GLC analysis confirmed the presence of 1-cyano-2-methyl-5-ketohexane.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].CC(O)=[O:42]>>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33](=[O:42])[CH3:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 22 h

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AX) (10 g, 10.83 mmol) (prepared by methods analogous to those described in US20040138439) in AcOH (130 mL) at 120° C. was added K2CrO7 (6.3 g, 21.42 mmol) in one portion. The mixture was stirred for 22 h at the same temperature. Volatiles were removed under reduced pressure, AcOEt was added, and the solids were removed by filtration. The organic layer was washed with a saturated solution of NaHCO3 and brine prior to drying over Na2SO4. Concentration of the organic solution and purification of the resulting residue by silical gel column (PE:EA=3:1) provided intermediate AY (2.3 g).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:1]([CH2:2][C:3]([OH:5])=[O:4])[NH2:21])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(Cl)cc1

Procedure:
Malonic acid (7.29 g, 70.0 mmol), 4-chlorobenzaldehye (9.84 g, 70.0 mmol) and ammonium acetate (10.9 g, 140 mmol) were heated in ethanol (15 ml) at 55° C. for 15 hours. Upon cooling the solvent was removed under reduced pressure and the residue was suspended in water and basified to pH 8 using saturated sodium carbonate solution. The aqueous was extracted with dichloromethane (3×) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a cream solid, 3.48 g.