Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][N:21]1[C:26](=[O:27])[CH:25]=[CH:24][NH:23][C:22]1=[O:28]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:23]2[CH:24]=[CH:25][C:26](=[O:27])[N:21]([CH3:20])[C:22]2=[O:28])=[CH:14][CH:15]=1
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: Cn1c(=O)ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 3-methylpyrimidine-2,4(1H,3H)-dione. M/e+ 367 for C19H16ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=5.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.91 (t, J=6.6 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 5.56 (d, J=8.0 Hz, 1H), 5.45 (s, 2H), 5.26 (d, J=0.7 Hz, 1H), 3.34 (s, 3H) ppm.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14]>C1(C)C=CC=CC=1>[C:1]([O:5][C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: N#CC(=NOC(=O)Cl)c1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)ON=C(C#N)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
The mixture was stirred for 3 hours at the same temperature and allowed to stand overnight. A solution of tert-butyl alcohol (11.1 g.) and pyridine (12 ml.) in toluene (20 ml.) was added dropwise, under ice-cooling, to the resultant mixture containing 2-chlorocarbonyloxyimino-2-(1-naphthyl)-acetonitrile. The mixture was stirred for 6 hours at the same temperature and allowed to stand overnight. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and n-hexane and methanol were added to the residue. The mixture was allowed to stand in a refrigerator and the precipitated crystals were collected by filtration and recrystallized twice from methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile (3.3 g.), mp 90° to 92° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:30])[C:20]=2[CH:21]=1
Reactant: COCCOc1ccc2c(c1)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COCCOc1ccc2c(c1)C1(CO2)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (30%): 1H NMR (300 MHz, CDCl3) δ8.38 (s, 1H), 7.24-7.18 (m, 1H), 7.15-7.07 (m, 1H), 7.06-6.97 (m, 1H), 6.96-6.88 (m, 1H), 6.70-6.61 (m, 1H), 6.54 (s, 1H), 6.43-6.35 (m, 1H), 4.82 (ABq, 2H), 4.13-3.98 (m, 2H), 3.75-3.67 (m, 2H), 3.42 (s, 1H).
Reaction SMILES: [C:1]([O:11]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Cl-].[Cl-].[Cl-].[Al+3].ClCCl>C(N(CC)CC)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:11])=[O:7]
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
8.7 g (50 mmol) of dimethyl adipate, anhydrous aluminum trichloride (20 g) and 100 ml of dry dichloromethane were cooled to 0° C. under an ice bath. At 0° C., triethylamine (dried with sodium hydroxide, 45 ml) was added dropwise and slowly. After addition, the ice bath was removed and the reaction was carried out at room temperature for 4 hours, being monitored with TLC. After the reaction was completed, the reaction liquid was poured into an ice-water mixture slowly, which was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml×2). The organic layers were combined and washed with water and then with saturated NaCl, dried with anhydrous magnesium sulfate, and filtrated. The solvent was distilled off under reduced pressure to give 5.1 g of 2-oxocyclopentanecarboxylate methyl ester. The yield was 71.8%.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([S:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([S:25][CH:8]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:34][CH:33]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a mixture of 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (100 mg, 0.5 mmol) in methylene chloride (5 mL) are added triethyl amine (0.09 mL, 0.62 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (86.2 mg, 0.62 mmol) and EDCI (118.7 mg, 0.62 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-(4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoylamino)-propionic acid methyl ester (90 mg).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,2,2-trifluoroethyl trifluoromethanesulfonate and isolated as light-yellow gum (0.9 mg, 6%). MS (m/e): 365.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:33][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C(=O)c1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1-c1ccc(Cl)cc1
Yield: 91 %

Procedure:
12.0 grams 3,3-bis-(p-chlorobenzoyl)-propionic acid ethyl ester, 3.9 grams phenylhydrazine and 2.7 grams glacial acetic acid were mixed and the mixture was heated in a nitrogen atmosphere to the boiling temperature under reflux for 6 hours. To the reaction mixture were then added benzene, and the pH was adjusted to 2-3, followed by extraction with water. The benzene was evaporated from the benzene phase and the dry, crystalline residue was recrystallized from a mixture of cyclohexane and petroleum ether boiling in a range from 50°-70° C. 13.0 grams 1-phenyl-3,5-bis-(p-chlorophenyl)-pyrazol-4-acetic acid ethyl ester, melting at 120°-122° C., were obtained, representing a yield of 91%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][C:8]=1[C:31]([F:34])([F:33])[F:32])C>[OH-].[Na+].C(O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:15][CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([C:31]([F:34])([F:32])[F:33])[CH:9]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
A solution of {{4-[3,3-bis-(4-chloro-phenyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester (135 mg, 0.25 mmol) in 1N NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaxtion mixture was evaporated and the residue dissolved in water (5 ml) and 1 N HCl (1.2 ml). The aquous phase was extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated to give the title compound in 130 mg (100%) yield.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8]([C:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:14]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][CH2:11]1)=[O:9].[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1.[Cl-].[Na+].O>[CH3:6][O:7][C:8]([C:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:20][CH:19]=3)[C:14]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12]1)=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Imidazole (2.1 g) is added to a solution consisting of the 1-[3-(4-hydroxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (9.6 g) and tert-butyldimethylsilyl chloride (4.7 g) in THF (100 mL). The reaction mixture is stirred at room temperature overnight. Brine solution is added and the reaction mixture is twice extracted with ethyl acetate. The combined extracts are dried and concentrated. Repeated concentration from hexane and then pentane gave 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (12.8 g.)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:29]([NH:32][C:33]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34]1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1([CH3:38])[CH2:37][CH2:36][N:35]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]=2[F:16])[CH2:34]1)(=[O:31])[CH3:30]
Reactant: CC(=O)NC1(C)CCNC1
Reactant: CCOC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Product: CCOC(=O)Nc1c(F)c(N2CCC(C)(NC(C)=O)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1

Procedure:
In the same manner as described in Example 2 (1), ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro1,4-dihydro-4-oxoquinoline-3-carboxylate was allowed to react with 3-acetylamino-3-methylpyrrolidine to give ethyl 7-(3-acetylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl5-ethoxycarbonylamino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C:58](O)=[O:59]>CN(C=O)C>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:58](=[O:59])[CH2:57][NH:56][C:61]([O:63][C:64]([CH3:66])([CH3:65])[CH3:67])=[O:62])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of (3S)-1-Cbz-3-{cyclohexylamino}pyrrolidine (3.0 g, 10.0 mmol), prepared in Intermediate 2, in DMF (30 mL) were added DIPEA (3.50 mL, 20.0 mmol), HBTU (4.88 g, 13 mmol), BOC-Gly (1.92 g, 11 mmol). After the mixture was stirred at rt for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO3. The organic material was extracted with EtOAc, and the organic extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (4.63 g, 92.0%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.Cl[C:16]1([C:28]([F:31])([F:30])[F:29])[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:18](=[O:27])[O:17]1>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[NH:19][C:18](=[O:27])[O:17][C:16]([C:2]#[C:3][C:4]3[O:5][CH:6]=[CH:7][CH:8]=3)([C:28]([F:29])([F:30])[F:31])[C:21]=2[CH:22]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(Cl)(C(F)(F)F)O1
Reactant: BrC(Br)=Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccco2)(C(F)(F)F)O1
Temperature: 25 °C
Yield: 110.5 %

Procedure:
To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at -20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to -50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to -35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH2:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:23]
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(Cl)c1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2,3-Dichloroquinoxaline (1.00 g, 5.02 mmol), 2,3-dichlorobenzenesulfonamide (1.41 g, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol) were suspended in dimethyl sulfoxide (30 mL) and the mixture was stirred at 150° C. for 3 hours. The reaction mixture was slowly added to a mixture (300 ml) of a 1% aqueous acetic acid solution and ice, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration and washed with water. Then, slurry purification was performed using diisopropyl ether, to give 2,3-dichloro-N-{3-chloroquinoxalin-2-yl}benzenesulfonamide (Compound AA) (1.53 g, yield: 78%).
Reaction SMILES: [Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][C:15]#N.ClCCl.S([O-])([O-])(=O)=[O:22].[Na+].[Na+].Cl>C(OCC)(=O)C.CO>[Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][CH2:15][OH:22]
Reactant: C[C@H](CC#N)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CCO)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 84 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried dichloromethane was then added to dissolve the same. The solution was cooled by a −70° C. bath, then 660 μl of a 1.5M [(CH3)2CHCH2]2AlH/toluene solution was added dropwise. The solution was stirred at the same temperature for 1 hour, then 0.5 ml of a saturated aqueous solution of sodium sulfate, 0.3 ml of methanol, 0.5 ml of 2N hydrochloric acid, and 15 ml of ethyl acetate were added and the solution stirred for 30 minutes. The reaction solution was filtered by Celite, then was washed by a saturated solution of ammonium chloride and saturated saline, then was dried over anhydrous magnesium sulfate and the desiccant filtered out. The solvent was distilled off under reduced pressure to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanol in an amount of 85 mg.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[I-].[C-]#N.[Na+].[Cu](C#N)[C:26]#[N:27]>Cl.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:26]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)#[N:27]
Reactant: N#C[Cu]C#N
Reactant: Nc1cccc2cnccc12
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
To a cold (0° C.) solution of 10.0 g (61.4 mmol) of 5-aminoisoquinoline in 288 mL of 1.5N hydrochloric acid, was added 15 mL of 5.2M sodium nitrite in water. After approximately 5 minutes, a cool saturated solution of sodium bicarbonate was added to the reaction mixture until the reaction solution tested negative using the iodide and starch paper test. The resultant solution was poured into a cold (0°-5° C.) biphasic mixture containing 300 ml of toluene and 150 mL of an aqueous solution containing 8.4 g (177 mmol) of sodium cyanide and 7.6 g (85 mmol) of copper cyanide. The resultant reaction mixture was warmed to room temperature, reacted for approximately 1 hour, and then diluted with a mixture of ethyl acetate and water. The resulting layers were separated, and the organic phase was dried over sodium sulfate, filtered, and then reduced to dryness under reduced pressure to provide 5.9 g of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(C)=O>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:1][C:2]2[CH:14]=[CH:13][C:5]3[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=3[CH:3]=2)[CH2:19][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1cc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OCCN3CCOCC3)cc2o1
Temperature: 60 °C
Reaction time: 72 h
Yield: 73.4 %

Procedure:
To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 60° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH2:30])(=[O:29])=[O:28]>>[NH:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH:30][C:13]([NH:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:29])=[O:28]
Reactant: NS(=O)(=O)c1ccc[nH]1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc[nH]1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and pyrrole-2-sulfonamide were used and the same method was applied as in Example 36 to obtain N-(pyrrole-2-sulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 750 mg (2.16 mmol) of N-(pyrrole-2-sulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 550 mg of the above-identified compound (yield 77.3%). Properties: colorless crystal, Melting point: >280° C. (decomposition), PMR (δppm, DMSO-d6):7.10 (1H,s), 7.24 (1H,d), 7.73 (1H,t), 7.85 (1H,d), 8.50 (1H,d), 7.93 (1H,d), 9.23 (1H,s), 11.68 (1H,s).