Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]1[C:23]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:22][C:6]([O:7][C:8]2[C:9]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[C:5]([N+:37]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:37][C:5]1[CH:4]=[C:3]([F:2])[C:23]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:22][C:6]=1[O:7][C:8]1[C:9]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a mixture of an iron powder, acetic acid and water is added a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine in acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture is stirred for 2 hours, then, the reaction solution is filtrated through Celite, and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue is subjected to silica gel chromatography to obtain 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[Cl:22][C:23]1[C:28]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[Cl:22][C:23]1[C:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:2](=[O:1])[CH3:4])[CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nccnc1C1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To an ice cooled solution of 2-chloro-3-(piperidin-4-yl)pyrazine-3TFA (150 g, 0.278 mol) in anhydrous dichloromethane (1.5 L) kept under nitrogen was added triethylamine (194 mL, 1.39 mol, 5 eq.) over a period of 15 min., followed by acetic anhydride (53 mL, 0.556 mol, 2 eq.) over a period of 10 min. The resulting mixture was allowed to stir at room temperature for 2 h and quenched with 500 mL of water. After separation, the organic phase was further washed with water (500 mL) and brine (500 mL). The aqueous phases were combined and back extracted with dichloromethane (1 L). Organic extracts were combined, dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=2:3 to 100% ethyl acetate) to give 70 g 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone. Yield: 94% for two steps.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]O1)=[O:6]>>[OH:2][CH2:1][CH2:3][N:4]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:6]
Reactant: O=C1OCc2ccccc21
Reactant: NCCO
Product: O=C1c2ccccc2CN1CCO
Temperature: 150 °C

Procedure:
Ethanolamine (4.78 g, 78.3 mmol) and phthalide (10.0 g, 74.6 mmol) were placed in a round-bottom flask equipped with a Dean-stark trap. The reaction mixture was heated at 150° C. for 4 h then 18 h at 205° C. The product was solidified upon cooling. Pure 2-(2-hydroxyethyl)isoindolinone (10.8 g, 82% was isolated by recrystallization in CHCl3/hexanes as a white crystal. 1H NMR (CDCl3, 300 MHz) δ3.02-3.15 (br, 1H), 3.78 (t, 2H, J=5.0 Hz), 3.93 (t, 2H, J=4.4 Hz), 4.52 (s, 2H), 7.42-7.58 (m, 3H), 7.84 (d, 1H, J=7.4 Hz) ppm.
Reaction SMILES: C([O:3][C:4]([CH:6]([C:18](OCC)=[O:19])[CH2:7][CH2:8][C:9]1([CH2:15][O:16][CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:3][CH2:4][CH:6]([CH2:18][OH:19])[CH2:7][CH2:8][C:9]1([CH2:15][O:16][CH3:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]1
Reactant: CCOC(=O)C(CCC1(COC)C=CC=CC1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(CCC(CO)CO)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 29.6 g (0.096 mol) of 1-[3,3-di(ethoxycarbonyl)propyl]-1-methoxymethylbenzene (14, p=0) in 200 ml of THF is added slowly to a stirred suspension of 4.0 g of LAH in 300 ml of THF. The mixture is stirred 2 h at room temperature and then treated sequentially with 4 ml of water, 4 ml of 15% NaOH solution, and 12 ml of water. The mixture is filtered and the filtrate evaporated to a residue which is triturated with hexane to afford 1-[3,3-di(hydroxymethyl)propyl]-1-methoxymethylbenzene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C1(C)C=CC=CC=1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
To a solution of 3-(4-hydroxyphenyl)propionic acid (1.49 g, 8.96 mmol) in dimethylformamide (21.5 mL) were added potassium carbonate (1.30 g, 9.41 mmol) and benzyl bromide (1.69 g, 9.86 mmol), and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with toluene and water to separate the phases. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 5:1→3:1) to give 2.16 g of benzyl 3-(4-hydroxyphenyl)propionate as oil (yield: 94%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([O:20]CC)=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[OH-].[K+]>C(O)C.O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([OH:20])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CCOC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 2 g. of ethyl 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylate, 2 g. of potassium hydroxide and 50 ml. of ethanol:water (9:1) is refluxed for 4 hours. The mixture is concentrated, diluted with water and the solid 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid isolated. The preceding compound is heated neat at 190° C. to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1.O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)cn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Yield: 65.5 %

Procedure:
In a solution of 3.86 g of 2-amino-5-chloropyrimidine in 100 mL of pyridine, 10.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 23 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.02 g of potassium hydroxide in 20 mL of water was added and stirred at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was diluted with 380 mL of water, precipitated crystal was filtered off, and washed with 150 mL of water. The resulting crude product was dissolved in 50 mL of ethyl acetate with heating, and 50 mL of 2N hydrochloric acid was added and stirred for 1 hour, and then 50 mL of toluene was added, and precipitated crystal was filtered off. Thereafter, the reaction mixture was washed with 50 mL of water, and then with 50 mL of toluene to obtain 7.95 g of the aimed product as white crystal.
Reaction SMILES: [C:1]1([S:7]([N:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[OH-].[Na+]>CO>[CH3:25][C:22]1[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[O:24][N:23]=1
Reactant: Cc1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
N-Benzenesulfonyl-N-(3-methyl-4-phenyl-5-isoxazolyl) benzenesulfonamide (300 mg, 0.66 mmol) was dissolved in methanol. Potassium hydroxide (300 mg, 5.5 mmol) was added and the solution was warmed to 45° C. to dissolve the sodium hydroxide. Stirring was continued for 20 min. Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl. The solid precipitate was extracted with ethyl acetate, dried and evaporated in vacuo to give 210 mg (100% yield) of N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide, which was further purified by recrystallization from ethyl acetate/hexanes, m.p. 124-126° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:20])[NH:5][CH2:6][CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=12.[CH:21]([NH2:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:21]([NH:24][CH2:2][C:3]1[C:4](=[O:20])[NH:5][CH2:6][CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=12)([CH3:23])[CH3:22]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CCl)=C21
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CNC(C)C)=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 4 g of 1-chloromethyl-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one in 80 ml of methylene chloride is added 8 ml of isopropylamine. The mixture is stirred at room temperature overnight, 80 ml of saturated aqueous sodium carbonate are added, the organic layer is separated, washed with water, dried and evaporated. The residue is crystallized from diethyl ether and recrystallized from ethyl acetate, to give the 1-isopropylaminomethyl-3,4,5,5a, 6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 212°-214°.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])=[CH:3][C:4](=[O:6])[CH3:5].C([O-])([O-])=O.[K+].[K+].C[O-].[Na+]>Cl[Cu]>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:2]([CH3:1])[C:3]=1[C:4](=[O:6])[CH3:5]
Reactant: CC(=O)C=C(C)Nc1ccccc1C#N
Agent: Cl[Cu]
Agent: C[O-]
Agent: O=C([O-])[O-]
Product: CC(=O)c1c(C)nc2ccccc2c1N

Procedure:
1-(4-Amino-2-methylquinolin-3-yl)ethanone was prepared by a known process, starting from 2-(1-methyl-3-oxobut-1-enylamino)benzonitrile, by cyclization with CuCl and K2CO3 (J. Med. Chem., 31:1278 (1988)) or by a NaOMe-promoted process (Eur. Pat. Appl., C07D 215/42); yielding a yellow solid; MS(Cl): M++H=201.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.Cl.[CH2:28]([N:30]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:28][NH:30][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N:14]2[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]3[N:26]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[C:15]2=[O:16])[CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(N2C[C@@H]3CCCN3c3nc(SC)ncc3C2=O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.6 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (364 mg, 0.982 mmol) obtained in Step 1 of Example 56 was dissolved in DMF (10 mL), and the mixture was stirred at room temperature for 3.5 hours after adding 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol), 1-hydroxybenzotriazole.monohydrate (166 mg, 1.08 mmol), methylamine hydrochloride (100 mg, 1.47 mmol), and triethylamine (0.204 mL, 1.47 mmol). The mixture was diluted by addition of ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)—N-methyl-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamide (390 mg, 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1>C1C(Cl)=CC=C(Cl)C=1.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:11]([F:17])[CH:10]=1
Reactant: COCCO
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Solvent: O
Product: COCCOCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DHF (200 ml) at room temperature and under a atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. A solution of 4-bromo-2-fluorobenzyl bromide (15 g) in dichlorobenzene (75 ml) was added over 15 minutes. The mixture stirred for 12 hours at room temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with 2M hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml) and dried (MgSO4). Evaporation of the solvents gave an oil which was distilled using a short path distillation apparatus to give 1-(4-bromo-2-fluorobenzyloxy)-2-methyoxyethane (11.6 g), furnace temperature 125° C./0.01 bar; NMR (CDCl3): 3.40(3H, s), 3.5-3.7(4H, m), 4.58(2H, s) and 7.2-7.4(3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[C:4]2[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([NH:18][C:6]2[N:5]3[N:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[C:4]3[N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:20]=1)[CH3:26]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: N#CCCCCc1cnn2c(Cl)cc(Cl)nc12
Solvent: CCO
Product: CCOC(=O)c1cccc(Nc2cc(Cl)nc3c(CCCCC#N)cnn23)c1
Temperature: 50 °C
Yield: 54.4 %

Procedure:
To a solution of compound (13a) (1.24 g, 4.62 mmol) in 10 mL of ethanol was added ethyl 3-aminobenzoate (764 mg. 4.62 mmol). The reaction mixture was heated at 50° C. for 2 h and then cooled to room temperature. Solvent was removed and the residue was dissolved in EtOAc (50 mL) and washed with saturated aq NaHCO3, 10% HCl, and brine and dried over anhydrous Na2 SO4. Removal of the solvent provided a residue that was purified by flash column with use of EtOAc/hexane (25% to 50%) to yield 3-[5-chloro-3-(4-cyano-butyl)-pyrazolo[1,5-a]pyrimidin-7-ylamino]-benzoic acid ethyl ester (14a) (1.0 g. 50%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][C:46]#[CH:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][C:46]#[CH:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCn1cncc1CSc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: C#CCn1cncc1CS(=O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-(2-propin-1-yl)imidazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (639 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (356 mg) in dichloromethane (15 ml) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-(2-propin-1-yl)imidazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (451 mg) (Compound 443) as yellow amorphous.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:15][C:16](N)=[O:17]>>[C:16](=[O:17])([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:13][CH:12]=1)[NH2:15]
Reactant: NC(N)=O
Reactant: CCCCCCCc1ccc(O)cc1
Product: CCCCCCCc1ccc(OC(N)=O)cc1
Yield: 90 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 8040 g of p-heptyl phenol instead of 4-phenyl phenol, using 378 g of urea and carrying out the reaction for 16 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (p-pentylphenyl) carbamate was confirmed. The yield was about 90% based on the charged amount of urea.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:41]1[C:49]2[N:48]=N[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:49]=3[NH2:48])=[O:26])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid (363 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (356 mg, 79% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.28 (m, 2H, CH2), 1.34 (m, 4H, 2×CH2), 1.51 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.30 (t, J=8.0 Hz, 2H, CH2CO), 3.24 (m, 2H, NCH2), 4.80 (s, 2H, benzene-NH2), 6.52 (t, J=8.0 Hz, 1H, Ar—H), 6.69 (d, J=8.0 Hz, 1H, Ar—H), 6.87 (t, J=8.0 Hz, 1H, Ar—H), 7.08 (s, 1H, ═CH—CO), 7.13 (d, J=8.0 Hz, 1H, Ar—H), 7.31 (m, 2H, Ar—H), 7.41 (t, J=8.0 Hz, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.52 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H), 9.09 (s, 1H, benzene-NH). LC-MS (m/z) 454 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](C)(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:46]OS(O)(=O)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:46])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a clear solution of 2-(3-chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl)-1H-imidazole (Example 16) (500 mg, 1.2 mmol) in tetrahydrofuran (10 mL) at 0° C., n-BuMgCl (2M solution in THF, 2.4 mL, 4.8 mmol) was added over 10 minutes. After stirring for additional 10 minutes, ice bath was removed and solution stirred for 1 hour. The reaction mixture was re-cooled to 0° C. and triethylborane (1M solution in THF, 6 mL, 6 mmol) was added. After stirring for 2 hours, the reaction was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with aqueous sodium acetate (1 g in 4 mL water). After stirring for 5 minutes, solid hydroxylamine-O-sulfonic acid (1 g) was added and the mixture stirred for 20 hours. The reaction mixture was diluted with water and extracted with ether (2×250). The ethereal layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (710 mg) was purified by chromatography (silica gel, ethyl acetate/toluene 3/7) to give pure 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (180 mg, 36%) as a white solid: mp(DSC) 222° C. Anal. Calc'd. for C17H13N3SO2F3Cl: C, 49.10, H, 3.15, N, 10.11. Found: C, 49.42, H, 3.19, N, 9.75.
Reaction SMILES: [C:1]12([O:18][CH2:17][CH2:16][O:15]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([C:11](OC)=[O:12])[CH2:2]2.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]12([O:15][CH2:16][CH2:17][O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[O:12])[CH2:2]2
Reactant: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-methyl 3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carboxylate (4.7 g, 18.93 mmol) in toluene (50 mL) and CH2Cl2 (12.50 mL) to these solution of DIBAL-H (Diisobutylaluminum hydride) (22.72 mL, 22.72 mmol) was added drop-wise at −78° C. under argon, and the mixture was stirred for 2 h at this temperature.