Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]([C:13]([Cl:16])([F:15])[F:14])=[CH:10][C:11]=1[OH:12])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CC(C)=O>[Cl:16][C:13]([F:14])([F:15])[C:9]1[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([O:12][CH:28]([CH3:30])[CH3:29])[CH:10]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC(C)C)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.9 %

Procedure:
A mixture of 15.0 g (0.047 mol) of product of Example 3, 6.5 g (0.047 mol) of K2CO3 and 5.2 ml (0.052 mol) of 2-iodopropane in 100 of acetone was stirred at reflux for 64 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in ether, washed with H2O, dried (MgSO4), and concentrated in vacuo to a brown oil which was kugelrohr distilled at 68 Pa, pot temperature 90° C., affording 15.11 g (88.9%) of product as a clear oil, nD25 1.4405.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CN
Solvent: CC#N
Product: CNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), methanamine (1 ml, 40% in water) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on flash column chromatography (EtOAc/MeOH) gave the title compound. Yield: 0.2 g, 69%. The amine was converted to the hydrochloric acid salt and crystallized from EtOH/Et2O. M.p. 243° C. MS m/z (rel. intensity, 70 eV) 275 (M+, 81), 97 (48), 70 (bp), 69 (73), 63 (58).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)c1
Reactant: NNc1ccccc1
Solvent: CO
Product: Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 7.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-methylphenyl)pyridazin-4(1H)-one (crude, 650 mg, 2.29 mmol) in 20 mL of methanol was added phenylhydrazine (370 mg, 3.44 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-methylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (55 mg, 7% for two steps) as a brown solid.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[C:31]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O>C1COCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C=Cc1ccc2c(c1)OCO2)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
Potassium t-butylat (1 Min THF, 11 mL, 11.0 mmol, 1.1 equiv.) was added to a solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(4-tert-butylphenyl)-2-methylpropanal (2.04 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 70° C. for 1.5 h. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 19:1) to yield 2.83 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH:8](=O)[CH:9]([CH3:11])[CH3:10]>C1C=CC=CC=1.[Ni]>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][N:6]=[CH:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C=O
Reactant: CN(C)CCCN
Agent: [Ni]
Solvent: c1ccccc1
Product: CC(C)C=NCCCN(C)C

Procedure:
A solution of N,N-dimethyl-N'-isobutylidene-1,3-diaminopropane in benzene is prepared by reacting 92 g of 3-dimethylamino-1-propylamine with 65 g of isobutyraldehyde in 200 ml of benzene by separating off the water of reaction azeotropically. This solution is hydrogenated in an autoclave at 90° C. and 125 atmospheres in the presence of 14 g of Raney nickel. Working up by distillation yields 95.6 g of pure product with a boiling point of 75° C./14 mm Hg.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.CCCCCC>[C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:11]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCC1CC(ON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 1 b, but using ethyl acetate/hexane mixtures (1:3 and 1:1) in the flash chromatography, starting from 15.24 g (0.0757 mol) of 3-(N-BOC-aminomethyl)-cyclobutanol, 12.35 g (0.0757 mol) of N-hydroxyphthalimide, 19.85 g (0.0757 mol) of triphenylphosphine and 13.3 ml (0.0795 mol) of diethyl azodicarboxylate (93%), the title compound, which melts at 161°-162° C. after recrystallization from ethyl acetate, is obtained. Evaporation of the mother liquor and recrystallization of the residue from ethyl acetate/hexane gives a further batch of the title compound, m.p. 145°-150° C.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14]CC1C=CC=CC=1)(=[O:6])=[O:5])[CH3:3]>[Pd].C(O)C>[OH:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)NC1CCCCC1O
Yield: 83.7 %

Procedure:
[(Methylethyl)sulfonyl][2-(phenylmethoxy)cyclohexyl]amine (11.41 g, 36.6 mmol) and 10% palladium on carbon (1.40 g) were combined in ethanol (300 mL) and placed on the power shaker under a hydrogen atmosphere at 60 psi's overnight. The solution was then filtered over a Celite® mat and the resulting filtrate was concentrated under reduced vacuum to yield the intermediate title compound (6.78 g, 84%) as a white solid. Ion Spray M.S. 222.1 (M*+1). Calculated for C9H19NO3S: Theory: C 48.84, H 8.65, N 6.32. Found: C 49.10, H 8.84, N 6.42.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([N:24]([CH2:39][CH3:40])[S:25]([CH2:28][CH:29]1[CH2:33][CH:32]([C:34](O)=[O:35])[CH:31]([CH2:37][CH3:38])[CH2:30]1)(=[O:27])=[O:26])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:39]([N:24]([CH2:22][CH3:23])[S:25]([CH2:28][CH:29]1[CH2:33][CH:32]([C:34]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:35])[CH:31]([CH2:37][CH3:38])[CH2:30]1)(=[O:27])=[O:26])[CH3:40]
Reactant: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.390 g, 1.287 mmol, Example #1 Step D), 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid (0.375 g, 1.287 mmol), and HATU (0.538 g, 1.416 mmol) in DCM (6.4 mL) was added TEA (0.538 mL, 3.86 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined and concd under reduced pressure. The material was purified by silica gel (120 g) chromatography eluting with a gradient of 20-100% EtOAc in DCM to provide N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 98%) as a brown solid: LC/MS (Table 1, Method b) Rt=2.39 min; MS m/z: 577 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[N:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])C.[OH-].[Li+]>C1COCC1.O>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:19]1[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)=[CH:21][C:17]([C:15]([NH:14][C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][C:4]([OH:36])=[O:3])=[O:16])=[N:18]1
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(OCC2(C)COC2)n(-c2ccccc2F)n1)c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC2(C)COC2)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
100 mg (0.2 mmol) of (S)-3-{[1-(2-fluoro-phenyl)-5-(3-methyl-oxetan-3-ylmethoxy)-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid ethyl ester were dissolved in a mixture of THF, MOH and water (2 ml each), and 14.5 mg (0.61 mmol) of lithium hydroxide were added. The mixture was stirred overnight at room temperature and the solvent removed. The residue was subjected to column chromatography (silica gel, DCM/MOH 9:1) to give 75 mg (75%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15]>>[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure D above, and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound was prepared.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([Br:16])=[CH:12][C:13]=1[O:14]C)=[O:8].O>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([Br:16])=[CH:12][C:13]=1[OH:14])=[O:8]
Reactant: COC(=O)c1sc(Br)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1O
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
BBr3 (26 mL, 1.0 M in heptane, 25.9 mmol, 3.0 Eq.) was added dropwise to a stirred solution of 5-Bromo-3-methoxy-thiophene-2-carboxylic acid methyl ester (2.17 g, 8.62 mmol, 1.0 Eq.) in anhydrous DCM (100 mL) at −10° C. under nitrogen. After 1.5 hours, water (40 mL) was added and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% Petroleum ether/DCM) to give the sub-title compound as a white solid (1.67 g, 7.04 mmol, 81%); 1H NMR (400 MHz, CDCl3) δ 3.90 (3H, s), 6.80 (1H, s), 9.68 (1H, br s).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].[CH3:11][CH:12]([C:16](=O)[CH3:17])[C:13](=O)[CH3:14]>C(O)(=O)C>[CH3:14][C:13]1[C:12]([CH3:11])=[C:16]([CH3:17])[N:7]2[N:8]=[CH:9][C:5]([N+:2]([O-:4])=[O:3])=[C:6]2[N:10]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2c([N+](=O)[O-])cnn2c(C)c1C
Yield: 30.2 %

Procedure:
80 cc of acetic acid, 8.2 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared according to H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) and 7.2 g of 3-methylpentane-2,4-dione were introduced into a 100 ml three-necked round-bottomed flask fitted with a magnetic stirrer, a condenser and a thermometer. The medium was refluxed for 3 hours. The medium was filtered at room temperature and the solid was washed with diisopropyl ether. This yielded 9.4 g of crude product. 3.5 g of this product was recrystallized in 23 cc of absolute ethanol. Drying under vacuum and over phosphoric anhydride yielded 3.1 g of 5,6,7-trimethyl-3-nitropyrazolo[1,5-a]pyrimidine (yield=80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.Cl>N1C=CC=CC=1>[N:1]1([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)N1CCc2ccccc21
Yield: 84.3 %

Procedure:
The procedure was modified from the reported one. In a 20 mL microwave reaction tube equipped with a magnetic stirring bar, indoline (1.196 g, 10 mmol), succinic anhydride (1.004 g, 10 mmol) and pyridine (8 mL) was mixed at room temperature. The tube was capped and irradiated in the microwave reactor (Biotage Initiator I) at 90° C. for 20 minutes. The reaction mixture was acidified to pH=1 using 2 M HCl. The resulting precipitate was filtered, washed with water and dried under high vacuum to afford light pink solid product (1.849 g, 92%). 1H NMR (400 MHz, CDCl3) d 8.19 (d, 1H, J=8.5 Hz), 7.18 (m, 2H), 7.03 (t, 1H, J=7.4 Hz), 4.08 (t, 2H, J=8.4 Hz), 3.22 (t, 2H, J=8.4 Hz), 2.78 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(O)CCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)CCCC2CCCCC2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.51 g) synthesized in Example 7 and 4-cyclohexylbutanoic acid (0.85 g) were dissolved in N,N-dimethylformamide (10 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (1.05 g) and hydroxybenzotriazole (HOBT) monohydrate (0.85 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) and the reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give 2-({4-[2-(4-cyclohexylbutanoylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (2.2 g) as a colorless oil. The obtained compound (2.2 g) was dissolved in tetrahydrofuran (10 mL), 1 M-borane/tetrahydrofuran complex (19.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (30 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (30 mL) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc([N+](=O)[O-])ccc3nc21
Temperature: 0 °C
Yield: 65 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid (3.8 g, 13.77 mmol) and POCl3 (20 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water, neutralized with concentrated NH4OH and the resulting solid was collected by filtration, washed with water and dried to afford 2.5 g (65%) of 1-ethyl-4-chloro-6-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]([C@:3]1([OH:25])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)#[CH:2].[O:26]=[Si]=O.C([O-])(=O)C.[Na+]>O>[C:1]([C@:3]1([OH:25])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)(=[O:26])[CH3:2]
Reactant: O=[Si]=O
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 45 °C

Procedure:
9.0 Kg of 17α-ethynyl-17β-hydroxy-6,16-dimethyleneandrost-4-en-3-one is added to a reactor vessel, flushed with nitrogen until the oxygen content is less than 4%. 108 Liters (85.3 Kg) of acetone is added and the solution heated to 45° C. A catalyst solution (prepared by the addition of 0.72 liters conc. sulfuric acid to 10.8 liters of deionized water, followed by the addition of 576 grams of mercuric oxide, red powder to the dilute acid) is added to the reaction mixture and stirred at 45° C. until the reaction is complete, as monitored by TLC. The reaction mixture is cooled to less than 25° C. and 2.3 Kg Celite 545, 2.2 Kg sodium acetate and 20 liters of water added and mixture stirred for 15 min. The resulting crude product is filtered using a pot filter coated with Celite 545. The reactor is rinsed with 50 liters of acetone and filtered. The combined filtrate is concentrated under vacuum to about 50 liters, cooled to below 20° C. and stirred for 15 min. The slurry is filtered and the filter cake washed with 10 liters of acetone and 20 liters of water. The filter cake is dried in a vacuum oven at 50° C. to yield 17α-acetyl-17β-hydroxy-6,16-dimethyleneandrost-4-en-3-one (mercury content 10,500 ppm).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]C1C=CC=CC=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:31]>CO.O1CCOCC1>[ClH:31].[ClH:31].[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccccc1C(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the compound prepared in Example 303 (1.00 g) in methanol (10 mL) was treated with hydrogen chloride solution in 1,4-dioxane (4 mol/L; 7.52 mL) and stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure and azeotropped from methanol several times to furnish the title compound (0.76 g), which was used without further purification, possessing the following physical data.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br>>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH:29]3[O:31][CH2:30]3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: BrCC1CO1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(CC3CO3)CC2)c2ccccc2)cc1

Procedure:
Method as described for Example 4, using compound 6 and epibromohydrin (102 mg, 84%):
Reaction SMILES: C([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:10]=1[CH3:28])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:11]2[C:10]([CH3:28])=[C:9]([NH2:8])[C:14]([CH3:15])=[CH:13][C:12]=2[O:16][CH3:17])=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COc1cc(C)c(NCc2ccccc2)c(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C)c(N)c(C)c1Cc1ccc(C(C)C)cc1
Yield: 86 %

Procedure:
Using N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline obtained in Reference Example 267, the title compound was synthesized in the same manner as in Reference Example 30. Yield 86%. Melting point: 91-92° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:15])[CH3:14]>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Product: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Yield: 91 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-4 [D], (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) and acetic acid gave the title compound as off-white solid in 91% yield. MS: 269.0 (M+H+, 1Br).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[C:4]1([CH2:1][CH:2]=[N:18][C@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[C@H](N)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C[C@H](N=CCc1ccccc1)c1ccccc1
Yield: 100.8 %

Procedure:
At first, zinc chloride (0.14 g, 1 mmol) was added to a toluene solution (100 ml) containing 12.0 g (100 mmol) of acetophenone (1a) as a ketone and 13.3 g (110 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 20 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction. Then, the reaction liquid after the reaction was washed with a 1N NaOH, followed by washing with 1N ammonium chloride aqueous solution, then drying with sodium sulfate anhydride, then filtration, then concentration, and then drying under vacuum, thereby obtaining 22.5 g of (S)-N-(phenylethylidene)-1-phenylethylamine ((S)-3aa, purity: 99%, yield: 100%).