Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:16](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:16][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1Nc1ccccc1
Product: Brc1ccc2ncn(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a stirred mixture of 4-bromo-N2-phenyl-benzene-1,2-diamine (step A) (420 mg, 1.6 mmol) and trimethyl orthoformiate (4.8 g, 5 ml, 45.2 mmol), formic acid (1.2 g, 1 ml, 26.1 mmol) was added at room temperature, and afterwards the reaction mixture was allowed to stir at for 2 h under reflux conditions. The reaction mixture was cooled to room temperature, evaporated and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with sat. sodium bicarbonate solution (20 ml) and brine (20 ml), dried (MgSO4) and evaporated. The crude product (400 mg) was purified by flash chromatography on silica gel (heptane/ethyl acetate 3:2) to yield the title compound as an off-white solid (358 mg, 82%), MS (ISP) m/z=275.0 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.SC1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:12]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: O=C(Nc1ccc(S)cc1)C1CCCC1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (1.96 g, 8.69 mmol) and N-(4-mercaptophenyl)cyclopentanecarboxamide (2.06 g, 8.69 mmol) in acetonitrile (40 ml) was cooled to 0° C. Triethylamine (0.88 g, 8.69 mmol, 1.21 ml) was added dropwise and the solution stirred for 10 mins at 0° C. for 10 mins and then at room temperature for 2 hrs. Water (15 ml) was added and the suspension filtered, washing with water (30 ml), and then dried to give the title compound as a pale yellow solid (1.87 g, 49%). 1H NMR (DMSO-d6) 1.50-1.61 (2H, m), 1.65-1.78 (4H, m), 1.82-1.93 (2H, m), 2.76-1.82 (1H, m), 7.52 (2H, d), 1.70-1.75 (3H, m), 10.08 (1H, s). ES+ 368.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[F:10][C:11]([F:29])([F:28])[S:12]([O:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([Br:26])[CH:22]=[CH:21][C:20]=2[Cl:27])(=[O:14])=[O:13].FC(F)(F)S(OC1N=CC2C(C=1)=CC=CC=2Br)(=O)=O>>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([Cl:27])=[C:19]2[C:24]=1[CH:25]=[C:16]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[N:17]=[CH:18]2.[F:28][C:11]([F:10])([F:29])[S:12]([O:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([Br:26])[CH:22]=[CH:21][C:20]=2[Cl:27])(=[O:13])=[O:14]
Reactant: N#Cc1cnc(N)cn1
Agent: O=S(=O)(Oc1cc2c(Br)ccc(Cl)c2cn1)C(F)(F)F
Agent: O=S(=O)(Oc1cc2cccc(Br)c2cn1)C(F)(F)F
Product: N#Cc1cnc(Nc2cc3c(Br)ccc(Cl)c3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile, and using 5-bromo-8-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 5-Bromo-8-chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8-bromoisoquinolin-3-yl trifluoromethanesulfonate. 1H NMR (DMSO, 400 MHz) δ 11.3 (br s, 1H), 9.42 (s, 1H, J=0.8 Hz), 8.85 (d, 1H, J=1.3 Hz), 8.81 (d, 1H, J=1.3 Hz), 8.79 (d, 1H, J=0.8 Hz), 8.07 (d, 1H, J=8.1 Hz), 7.58 (d, 1H, J=8.1 Hz). LCMS (2) Rt=3.58 min; m/z (ESI+) 360 & 362 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]3)=[O:24])[C:17]=2[CH:32]=1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([NH:31][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:10])[CH2:29][CH2:30]3)=[O:24])[C:17]=2[CH:32]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 4-fluorophenyl isocyanate (273 mg) in dioxane (5 ml) was added dropwise to a mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (981 mg), triethylamine (273 mg), dioxane (40 ml) and water (2 ml) at room temperature. The resulting mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was filtered, washed with water and ethyl acetate, and recrystallized from N,N-dimethylformamide to give 5-chloro-3-{[4-[N'-(4-fluorophenyl)ureido]-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (0.82 g).
Reaction SMILES: C1(C)C=CC(C2C=CC=CN=2)=CC=1.O.C1(S(O)(=O)=O)C=CC=CC=1.[Br:25]Br.[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1>ClC1C=CC=CC=1.O>[Br:27][CH:28]([Br:25])[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: BrBr
Agent: Cc1ccc(-c2ccccn2)cc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: BrC(Br)c1ccc(-c2ccccn2)cc1
Yield: 68.89 %

Procedure:
In a 300 ml four neck flask equipped with a water separator were placed 2-(4-tolyl)pyridine (20.0 g, 0.118 mol), chlorobenzene (100 ml) and benzenesulfonic acid monohydrate (20.82 g, 0.118 mol), and the mixture was heated. At around 90° C., water was azeotropically distilled into the water separator. The mixture was further heated while distilling water until the temperature of the distillate reached 131° C. Bromine (26.4 g, 0.165 mol) was added dropwise to this reaction mass at 120-130° C. over 8 hours. The reaction mixture was stirred with heating at a temperature in the above-mentioned range for 4 hours and analyzed by HPLC. As a result, 2-(4-bromomethylphenyl)pyridine was confirmed to have been produced in a 68.89% yield and 2(4-dibromomethylphenyl)pyridine was confirmed to have been produced in a 19.49% yield. This reaction mass was used as it was in the next reaction. From the 1H-NMR analysis, production of 2-(4-bromomethylphenyl)pyridine benzenesulfonate and 2-(4-dibromomethylphenyl)pyridine benzenesulfonate was confirmed. 2-(4-bromomethylphenyl)pyridine benzenesulfonate 1H-NMR(CDCl3, ppm) δ: 4.575(s,2H), 7.03-7.05(m,1H), 7.35-7.42(m,3H), 7.63(d,J=8Hz,2H), 7.80-7.87(m,2H), 7.88-8.05(m,1H), 7.99(d,J=8Hz,2H), 8.21-8.24(m,1H), 8.50-8.56(m,1H) 2-(4-dibromomethylphenyl)pyridine benzenesulfonate 1H-NMR(CDCl3, ppm) δ: 6.886(s,1H), 7.03-7.05(m,1H), 7.35-7.42(m,3H), 7.63(d,J=8Hz,2H), 7.8-8.07(m,1H), 7.88-8.07(m,1H), 7.99(d,J=8Hz,2H), 8.21-8.24(m,1H), 8.49-8.6(m,1H)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.C1C[O:32]CC1>>[F:18][C:16]([F:19])([F:17])[C:13]1[N:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:32])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137 %

Procedure:
To the solution of 5-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)pyridine (1.83 g, 6.90 mmol) in dry THF (20 mL), was added 9-BBN (20.70 mL, 10.35 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3M, 9 mL), and 30% H2O2 (8 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.67 g, 9.43 mmol, 137% yield) as a colorless oil. LCMS: rt=2.97 min, [M+H+]=284
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@H:23]([CH2:28][C:29]3[CH:37]=[C:36]([CH3:38])[C:35]4[C:31](=[CH:32][N:33]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:34]=4)[CH:30]=3)[C:24]([O:26]C)=[O:25])=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1>O1CCOCC1>[CH3:38][C:36]1[C:35]2[C:31](=[CH:32][N:33]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:34]=2)[CH:30]=[C:29]([CH2:28][C@@H:23]([O:22][C:20]([N:17]2[CH2:16][CH2:15][CH:14]([C:13]3[C:4](=[O:3])[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:19][CH2:18]2)=[O:21])[C:24]([OH:26])=[O:25])[CH:37]=1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Aqueous lithium hydroxide (1M, 130 mL, 0.13 mmol) was added dropwise to a stirred solution of (R)-1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (40 mg, 0.0646 mmol) in dioxane (2 mL) at 0° C., and the mixture was stirred for 2 h. The reaction was quenched with 1N hydrochloric acid, poured into ethyl acetate (30 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated in vacuo to afford a tan foamy solid (32 mg, 82%), which was used without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.02 (s,1H), 7.60 (s,1H), 7.52-7.32 (m, 3H), 7.29-7.13 (m, 2H), 7.05 (s,1H), 5.71 (s,2H), 5.29 (dd, J=9.0, 3.8 Hz, 1H), 4.28 (br, 2H), 3.34 (br, 2H), 3.34 (dd, J=14.1, 3.9 Hz, 2H), 3.21 (dd, J=14.4, 9.2 Hz, 2H) 3.13-2.75 (m, 4H), 2.60 (s, 3H), 1.95-1.72 (m, 4H), 0.95-1.85 (m, 2H), 0.051 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Br)cccc2-3)no1
Yield: 94.1 %

Procedure:
1.3 g (3 mmol) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one were stirred at room temperature for 5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.41 g (94%) of (S)-8-bromo-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: COC([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:6]1=[O:22])=O.[OH-].[Li+]>C(O)C.O1CCCC1.O>[O:22]=[C:6]1[C:7]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:8][CH2:9][CH2:5]1
Reactant: COC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Temperature: 90 °C
Yield: 67.5 %

Procedure:
To a solution of tert-butyl 2-(methoxycarbonyl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (17.2 g, 0.055 mol) from Step F in a 2:2:1 mixture of ethanol/tetrahydrofuran/water (555 mL) was added pulverized lithium hydroxide (26 g, 1.10 mol). The reaction mixture was heated to 90° C. for 60 h. The reaction mixture was allowed to cool and was then concentrated, dissolved in water and dichloromethane, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 11.4 g. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (9.41 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[CH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=[O:7].[H][H]>CO>[CH3:1][O:2][C:3](=[O:16])[CH:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)C(=CC1CCCCC1)CC(=O)O
Solvent: CO
Product: COC(=O)C(CC(=O)O)CC1CCCCC1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
2-Cyclohexylmethylidenesuccinic acid 1-methyl ester (0.22 g, 1.0 mmol) and each metal complex catalyst (0.005 mmol) were weighed in a Pyrex (registered trade name) test tube for autoclaving and the tube was put into a 50 mL-autoclave together with a stirrer in the tube, and then the atmosphere in the autoclave was substituted with nitrogen. The mixture was added with 2 mL of deoxygenized methanol, and after the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 0.5 MPa of hydrogen, the mixture was stirred at 45° C. for 18 hours. After 18 hours, the atmosphere of the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to quantitatively obtain optically active cyclohexylmethylsuccinic acid 1-methyl ester.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.N1C=CC=N1.C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:44]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:45])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(=O)C1CCCCC1
Yield: 54 %

Procedure:
As a starting material, 4-methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide corresponding to pyrazole derivative (I-H) was used. 0.4 Gram (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.19 g (1.3 mmol) of cyclohexylcarbonyl chloride corresponding to compound B-A-Hal as a reaction reagent were added. The mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified by flush column chromatography (Wako Gel C-300; hexane/ethyl acetate=1:1) to give 0.28 g (yield 54%) of 4-methoxy-5-methyl-6-(5-cyclohexylcarbonyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7].[CH3:17][NH:18][CH3:19]>C(O)C.Cl>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CCCCCCCCNC(=O)CCCCBr
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCNC(=O)CCCCN(C)C
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Bromo-N-octylpentanamide (17.25 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in ethanol (20 ml) was added. The solution was allowed to stand at room temperature for 3 hours, more dimethylamine (10 ml) added and the solution allowed to stand at room temperature for 18 hours. The solution was evaporated to give an oil, which was dissolved in dilute HCl and the solution at pH 5.5 was washed with dichloromethane. The pH was then raised to 7.5 and extracted twice with dichloromethane at this pH. The combined latter organic extracts were dried over MgSO4 and evaporated to give 5-dimethylamino-N-octylpentanamide as an oil (10.6 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[C:5]2[CH:23]=[CH:24][NH:25][C:4]=2[C:3]1=[O:26].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2CCOCC2)C2C=CNC=2C1=O>>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([O:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([C:6]2[C:5]3[CH:23]=[CH:24][NH:25][C:4]=3[C:3](=[O:26])[N:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCOC2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OC2CCOC2)c2cc[nH]c2c1=O

Procedure:
Example 31b was prepared according to the procedure used for the preparation of Example 29b, substituting the product of Example 31a for the product of Example 29a, to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[C:13]3[N:18]([CH2:19][C:7]1=[CH:6]2)[C:17](=[O:20])[C:16]([CH3:21])=[C:15]([CH:22]([O:25][C:26](=[O:36])[CH2:27][NH:28]C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:14]=3)#[N:2].C(C(O)=O)(F)(F)F.O>>[NH2:28][CH2:27][C:26]([O:25][CH:22]([C:15]1[CH:14]=[C:13]2[N:18]([CH2:19][C:7]3[C:8]2=[N:9][C:10]2[C:5]([CH:6]=3)=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:17](=[O:20])[C:16]=1[CH3:21])[CH2:23][CH3:24])=[O:36]
Reactant: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3cc(C#N)ccc3nc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(OC(=O)CN)c1cc2n(c(=O)c1C)Cc1cc3cc(C#N)ccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-2-cyano-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (DMSO-d6) d 8.81 (d, J=1.5 Hz, 1H), 8.77 (s, 1H), 8.27 (d, J=8.9 Hz, 1H), 8.13 (dd, J=8.9, 1.8 Hz, 1H), 7.24 (s, 1H), 5.91 (apparent br t, J=6.7 Hz, 1H), 5.29 (s, 2H), 3.98 (br s, 2H), 2.26 (s, 3H), 2.05-1.81 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). Anal. Calcd for C22H20N4O3.3/2 CF3CO2H.H2O: C, 52.00; H, 4.10; N, 9.70. Found: C, 52.04; H, 4.32; N, 9.73.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.O>[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:7][C:21]1[N:22]=[C:17]([Cl:16])[N:18]=[C:19]([N:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:20]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCCCN(CCCCCC)c1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCN(CCCCCC)c1nc(Cl)nc(N[C@@H](Cc2ccccc2)C(=O)OCC)n1

Procedure:
L-phenylalanine ethyl ester hydrochloride (1.0 g, 4.4 mmol) was added to a mixture of 2,4-dichloro-6-dihexylamino-1,3,5-triazine (1.5 g, 4.5 mmol) and sodium carbonate (0.92 g, 8.7 mmol) in acetonitrile (40 mL). The reaction mixture was heated to reflux for 16 h and then allowed to col to ambient temperature. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography through silica gel (elution with chloroform) to afford N-{4-chloro-6-(N,N-dihexylamino)-1,3,5-triazin-2-yl}phenylalanine ethyl ester. Anal. Calcd. for C26H40ClN5O2: C, 63.72; H, 8.23; N 14.29. Found: C, 63.67; H, 8.06; N 14.24.
Reaction SMILES: C(OC(C1ON=C(C2C=CC(N)=CC=2)C=1)=O)C.C1(N=C=O)CCCCC1.[CH2:27]([O:29][C:30]([C:32]1[O:36][N:35]=[C:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:45])=[CH:39][CH:38]=2)[CH:33]=1)=[O:31])[CH3:28].[K+].[Br-]>>[CH2:27]([O:29][C:30]([C:32]1[O:36][N:35]=[C:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:45])=[CH:41][CH:42]=2)[CH:33]=1)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3)cc2)no1
Agent: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Agent: O=C=NC1CCCCC1
Agent: [Br-]
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1
Yield: 75 %

Procedure:
The title compound was prepared from 3-(4-amino-phenyl)-isoxazol-5-carboxylic acid ethyl ester and cyclohexyl isocyanate by same procedure as set forth for the preparation of 3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid ethyl ester and was obtained in 75% yield. Mass (ES+), 358 (M++1); IR (KBr): 3304, 2928, 2852, 1731, 1634, 1570 (br); 1H NMR (DMSO-d6) δ: 1.33 (t, 3H), 1.14-1.81 (4×m, 10H), 3.45 (br, 1H), 4.37 (q, 2H), 6.18 (d, 1H), 7.50 (d, 2H), 7.60 (s, 1H), 7.79 (s, 1H), 7.8.1 (d, 2H), 8.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[N:13]=1)[C:5](N(OC)C)=[O:6].O1CCC[CH2:16]1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:16])[CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
490 mg of 2,6-dichloro-N-methoxy-N-methyl isonicotinamide was dissolved in tetrahydrofuran, 2.1 ml of 3M methyl magnesium bromide tetrahydrofuran solution was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hour. To the reaction solution was added ammonium chloride aqueous solution, and the mixture was diluted with ethyl acetate. The mixture was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 325 mg of the objective compound.
Reaction SMILES: COC1C=CC(CC#N)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](C)(C)[CH:21]=[O:22])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(C)(C)C=O)cc1
Agent: COc1ccc(CC#N)cc1
Product: COc1ccc(CC=O)cc1

Procedure:
This compound was prepared from 4-methoxyphenylacetnitrile in the same manner of Compound 45.