Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[CH:4][CH:3]=1.COC(OC)[N:34]([CH3:36])C.Cl.N[OH:41]>CC(O)C>[OH:41][N:34]=[CH:36][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[CH:6][N:7]=1
Reactant: Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Reactant: COC(OC)N(C)C
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: O=C1N(Cc2ccc(NC=NO)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
To a solution of 1′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.40 g, 1.0 mmol) in 2-propanol was added N,N-dimethylformamide dimethyl acetal (0.17 mL, 1.3 mmol). The mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and further N,N-dimethylformamide dimethyl acetal (0.12 mL, 0.9 mmol) was added. The mixture was heated at reflux for 6 h and allowed to cool to 50° C. Hydroxylamine hydrochloride (0.15 g, 2.2 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to ambient temperature, during which time a precipitate was deposited. The solid was filtered, washed with 2-propanol and diethyl ether and dried to afford N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide (0.37 g, 82%) as a colorless solid: mp 231-232° C.; 1H NMR (300 MHz, DMSO-d6) δ10.07 (s, 1H), 9.41-9.35 (m, 1H), 8.23-8.19 (m, 1H), 7.84-7.78 (m, 1H), 7.59-7.53 (m, 1H), 7.32-7.24 (m, 1H), 7.19-7.13 (m, 1H), 7.13-7.07 (m, 1H), 7.07-6.99 (m, 2H), 6.52 (s, 1H), 6.05 (s, 1H), 4.86-4.83 (m, 2H), 4.73 (ABq, J=44.3, 9.4 Hz, 2H), 4.22-4.06 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.6, 152.0, 146.6, 144.1, 141.8, 137.7, 137.5, 135.4, 131.7, 128.7, 124.0, 123.6, 123.0, 121.1, 110.8, 110.4, 109.4, 98.8, 79.3, 64.1, 63.5, 57.2; MS (ES+) m/z 444.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:14]C>Br>[OH:14][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 2.6 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26 ml of constant-boiling hydrobromic acid is heated under reflux for 2 hours. After, cooling the solvent is distilled in a water-jet vacuum. The crystalline residue is recrystallized from 50 ml of water at boiling temperature. There is obtained 3,4-dihydroxy-5-nitrobenzoic acid in the form of yellow crystals of m.p. 224°-226°.
Reaction SMILES: F[O:2][C:3]([O:6]F)([F:5])[F:4].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>N#N>[F:4][C:3]1([F:5])[O:6][C:9]([F:13])([F:8])[C:10]([F:12])([F:11])[O:2]1
Reactant: FC(F)=C(F)F
Reactant: FOC(F)(F)OF
Agent: N#N
Product: FC1(F)OC(F)(F)C(F)(F)O1
Temperature: -80 °C

Procedure:
Into a multineck glass reactor equipped with: magnetic entrainment mechanical stirrer, reflux cooler, thermocouple, inner plunging pipes for introducing the reagents, and maintained at a temperature of -80° C., there were simultaneously fed-after having introduced 75 of FC 75-0.5 l of bis(fluoroxy)difluoromethane at a flowrate of 0.3 l/h diluted with N2 (0.5 l/h) and 5.0 g of tetrafluoroethylene (3.0 g/h).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:27])[C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:16]1[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)c(F)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)c(F)ccc2n1
Temperature: 100 °C
Yield: 42 %

Procedure:
N,N-Diisopropylethylamine (0.15 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-6-fluoro quinoline (0.075 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.08; 1.1 eq) in dimethylformamide (3.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 42% yield (0.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]([OH:39])[CH2:36][NH:37][CH3:38])=[CH:34][C:29]=2[O:28][CH2:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]([OH:39])[CH2:36][N:37]([CH2:20][C:18]3[S:19][C:12]4[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=5)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=4[C:17]=3[CH3:22])[CH3:38])=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc3c(c2)OCO3)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)ethanol (Journal of Organometallic Chemistry, 1998, 339, 267-75) (74 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (101 mg) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[CH3:25][N:26]1[C:30]([C:31]2[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=2)=[CH:29][C:28]([C:40]([F:43])([F:42])[F:41])=[N:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:36]([C:34]1[S:35][C:31]([C:30]2[N:26]([CH3:25])[N:27]=[C:28]([C:40]([F:41])([F:42])[F:43])[CH:29]=2)=[CH:32][CH:33]=1)(=[O:37])=[O:38])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Cl)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol), triethylamine (50 μL, 0.36 mmol) and DMAP (1 mg, 0.008 mmol) in anhydrous CH2Cl2 (1 mL) was added 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride (82 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was purified by preparatory HPLC. The residue was dissolved into CH2Cl2 (50 mL) and washed with 0.1 N NaOH (5 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (26 mg, 57%). MS ESI 531.2 [M+H]+, calcd for [C22H25F3N4O4S2+H]+ 531.13.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[H][H].[S:11](Cl)([Cl:14])(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:11]([Cl:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)Oc1ccccc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A solution of phenol (17 g, 181 mmol) in dry toluene (380 ml) was stirred with sodium pieces (4.15 g, 180 mmol) in a 100° C. oil bath for 2 hours. When hydrogen formation had finished, the oil bath temperature was increased to 130° C. for two more hours. The reaction mixture was cooled to 0° C. transferred to a pressure equalising funnel and added slowly (1 h) to a cold (0° C.) solution of sulfuryl chloride (15 ml, 181 mmol) in toluene (50 ml). The reaction mixture was stirred at room temperature for 16 h, washed with H2O (3×100 ml), dried over Na2SO4 and concentrated in vacuo leading to a brown oil which was distilled under reduced pressure through a Vigreux column (70°-72° C./100 μm Hg, lit(I3a) ; 61°-65° C./50 μm Hg) to give a fraction of colourless oil containing 13 and ~10% penol (23.3 g, 67%), and a small fraction of pure I3 (1.17 g, 3%): νmax (CDCl3) 1587 (C=C). 1201 (SO3); δH (200 MHz; CDCl3) 7.34-7.57 (m, Ph); δC (50 MHz, CDCl3) 121.69 (2 CH), 123.15 (C), 128.84 (CH), 130.28 and 130.42 (2 CH); m/z (EI) 194 (M+, 14%). 192 (M+, 38), 93[(M-SO2Cl)+, 33], 65 [(M-127)+, 100].
Reaction SMILES: C([S:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:24])[CH2:10][CH2:9]1)(=O)C.C[O-].[Na+]>CO>[O:24]=[C:11]1[CH2:10][CH2:9][C@H:8]([CH2:7][CH2:6][CH:5]([SH:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(S)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 606 mg. of ethyl 15-acetylthio-9-oxoprostanoate (Example 113) in 20 ml. of reagent methanol is treated, under nitrogen atmosphere, with 1.6 ml. of 1N methanolic sodium methoxide. After 10 minutes the reaction is quenched by the addition of 0.3 ml. of glacial acetic acid and taken to dryness. A solution of the residue in ether is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to afford 428 mg. (89%) of an oil; λ max. 4.0 (sulfhydryl) and 5.78 μ (carbonyls).
Reaction SMILES: I[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:12]=[N:11][C:5]3[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=3[CH:3]=2)=[CH:20][CH:19]=1)[CH3:14]
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)NC(=O)CN3)cc1
Yield: 79 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (520 mg) was reacted with 4-ethoxycarbonylphenyl boronic acid as in General Procedure 4B to give the title compound as a light yellow solid in 79% yield. M.p.>200° C., LCMS: m/z=298.14 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.33 (3H, t, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 7.26 (1H, d, J=2.0 Hz), 7.67 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=8.1 Hz), 8.04 (1H, d, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1Cl

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.116 g, 25% yield). MS: m/z 469.1 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:50])[CH2:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)=[S:40])=[CH:34][C:33]=5[F:51])=[N:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:52][CH3:53])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.[BrH:54]>CC(O)=O.CCOCC>[BrH:54].[BrH:54].[F:51][C:33]1[CH:34]=[C:35]([NH:38][C:39]([NH:41][C:42](=[O:50])[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[S:40])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:52][CH3:53])[CH:23]=2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.3 g, 4.5 mmol) was dissolved in AcOH (70 ml) to which was added 33% HBr in AcOH (12 ml). The reaction mixture was stirred at room temperature for 1 hr, diluted with Et2O (1000 ml) and the resulting solids filtered, washed with Et2O, and dried under high vacuum to give the 1-{3-fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea, dihydrobromide salt (3.4 g, 100%). 1H-NMR (400 MHz, DMSO): 12.42 (s, 1H), 11.80 (s, 1H), 8.84 (br s, 2H), 8.64 (s, 1H), 7.92 (m, 1H), 7.59 (s, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.33 (m, 4H), 7.27 (m, 1H), 4.17 (d, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.17 (m, 2H), 3.10 (m, 2H), 2.83 (m, 2H), 2.45 (m, 1H), 2.15 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 602.2, found 602.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([N:35]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=3[NH:1][C:17]2=[O:23])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(C3CC3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.8 g) and triethylamine (0.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added cyclopropylamine (1.88 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was dissolved in methanol (20 sodium methoxide (28% methanol solution, 0.64 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.28 g, 88%).
Reaction SMILES: [C:1]([O:5]C(N1CCC(=O)CC1)=O)([CH3:4])([CH3:3])[CH3:2].Cl.C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C.[OH-:23].[Na+]>ClCCCl>[C:1]([O:5][N:18]1[CH2:19][CH2:20][CH:19]([NH:18][CH3:21])[CH2:20][C:21]1=[C:22]=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CNC1CCN(OC(C)(C)C)C(=C=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of N-t-butoxycarbonylpiperidin-4-one (3 g; M. S. Ashwood et al., J. Chem. Soc. Perkin Trans. 1, 1995, 641-644) andmethylamine hydrochloride (1 g) were added triethylamine (2.1 ml) and 1,2-dichloroethane (50 ml). Under ice-cooling, to the mixture was added sodium triacetoxy boron hydride (4.5 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours. The mixture was neutralized with sodium hydroxide, concentrated and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-t-butoxy-carbonyl-4-methylaminopiperidine (3.1 g) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][N:42]([CH:40]=[O:41])[CH2:43][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: O=CN1CCNCC1
Product: Cc1ccccc1-c1nc(N2CCN(C=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 6.2 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-formylpiperazine(20.6 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-(4-formylpiperazine-1-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (5.6 mg, 6%).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=2)=[O:13])[CH:6]=1)C.O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:36])=[O:3])=[CH:16][CH:17]=2)=[C:24]([CH2:33][CH2:34][CH3:35])[C:25]=1[OH:32])(=[O:31])[CH3:30]
Reactant: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)OCC)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To 3-{3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ureido}-benzoic acid ethyl ester (200 mg, 0.40 mmol) in 1:1 tetrahydrofuran:methanol (10 mL) is added 2 N NaOH (5 mL). The reaction mixture is stirred vigorously at room temperature for 3 h. The reaction mixture is diluted with water (30 mL), acidified with 5N hydrochloric acid to pH=4, and extracted with ethyl acetate (3×70 mL). The combined organic extracts are washed with brine, dried over sodium sulfate, and concentrated to dryness. The resulting residue is purified by reverse phase HPLC using a gradient of 90:10 to 20:80 (H2O/0.1% TFA):CH3CN as eluent to give the title compound (24 mg, 12%). LC-MS (m/e): 461 (M−1); 1H NMR (DMSO-d6) δ 12.93 (1H, s), 12.85 (1 H, s), 8.93 (1 H, s), 8.77 (1 H, s), 8.15 (1H, s), 7.82 (1H, s), 7.30-7.60 (7 H, m), 6.75 (1H, d), 5.20 (2 H, s), 2.60 (5 H, m), 1.50 (2 H, m), 0.90 (3 H, t).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]([F:35])([F:34])[C:17]1[CH:18]=[C:19]([C:27]2[O:31][N:30]=[C:29]([CH2:32]Cl)[N:28]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>>[F:35][C:16]([F:15])([F:34])[C:17]1[CH:18]=[C:19]([C:27]2[O:31][N:30]=[C:29]([CH2:32][N:7]3[C:6]4[CH:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:10]=4[N:9]=[C:8]3[CH2:11][CH3:12])[N:28]=2)[CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI) m/z 500 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28]1>>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Product: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.2 g, 2.9 mmol) was slowly added to a solution of ethyl (3S)-piperidine-3-carboxylate (0.7 g, 4.4 mmol) and DIPLA (2.6 mL, 14 mmol) in DCL (50 mL) at 80° C. The reaction mixture was stirred for 1 h and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 1.5 g (96%); MS (ESI) (M+H)+=526.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCOCC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 1.4 g of morpholine, 3 g of ethyl 2-chlorothiazole-4-carboxylate. 3 g of triethylamine and 12 ml of dimethylformamide, giving the title compound as colorless needles.