Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19](F)=[C:20]([NH2:22])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([NH:22][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])[CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (283 mg, 0.811 mmol) and cyclopropanesulfonyl chloride (114 mg, 0.811 mmol) the title compound was obtained as a white solid (247 mg, 67% yield). MS (ESI): 453.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(=O)(O)[O-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:12]1([S:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)NN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)NNS(=O)(=O)c1ccccc1

Procedure:
180 g. (0.2 mole) of methyl carbazate (from hydrazine and dimethyl carbonate) is placed in a liter flask. 20.0 g. (0.24 mole) of sodium bicarbonate and 100 ml. water are added. The mixture is stirred and dropped in 35.2 g. (0.2 mole) of benzene sulfonyl chloride. Then the mixture is stirred for 16 hours. The crystals that have formed are filtered off, washed with water, and dried in air. Yield=34.5 g.; m.p. 149°-154° C. Upon recrystallization from ethanol 26 g. of material is recovered which melts sharply at 155° C.
Reaction SMILES: N.[CH3:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.C[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[C:24]1C=CC=C[N:25]=1>>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:24]([C:21]1[CH:22]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:25]
Reactant: CN1CCCCC1
Reactant: Cc1ccccn1
Agent: CC1CCCNC1
Agent: N
Solvent: Cc1cccnc1
Product: N#Cc1cccnc1

Procedure:
2.0 cc of the 80% PV3MO12Ox.20% SiO2 catalyst of Example 2 was placed in the microreactor and equilibrated at 405° C., then a gaseous mixture containing 7.5 moles of NH3 and 19.9 moles of air for each mole of the mixed heterocyclic containing 0.82 mole of 3-methylpyridine and 0.18 mole of 3-methylpiperidine was fed through the reactor using a contact time of 6.4 seconds. Conversion of the methylpiperidine was 100 percent and conversion of the methylpyridine was 92 percent. For each mole of combined 3-methylpiperidine plus 3-methylpyridine fed was obtained 0.853 mole of 3-cyanopyridine. If it be assumed that all of the converted 3-methylpyridine formed 3-cyanopyridine, the minimum selectivity of 3-methylpiperidine to 3-cyanopyridine was 50 percent.
Reaction SMILES: [N:1]([CH:4]([C:9]1[C:14]2[N:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[Cl:30])[C:16]3=[N:17][C:13]=2[C:12]([Cl:31])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:31][C:12]1[C:13]2[N:17]=[C:16]3[N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[Cl:30])[CH2:19][CH2:20][CH2:21][N:15]3[C:14]=2[C:9]([CH:4]([NH2:1])[C:5]([F:6])([F:7])[F:8])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 60 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-(1-azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (286 mg, 0.560 mmol), triphenylphosphine (220 mg, 0.839 mmol) and water (0.560 mL) in tetrahydrofuran (5.6 mL) was stirred at 60° C. for 1 day. After the mixture was diluted with ethyl acetate, the resultant mixture was extracted with 1N hydrochloric acid. The extract was washed with diethyl ether and neutralized with aqueous saturated sodium hydrogen carbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless solid (257 mg, 0.532 mmol, 95%).
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1.NC1N=[C:25](C2C=CC(F)=CC=2)[C:26]2CNCCC=2N=1.Cl.Cl.ICC>>[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][N:13]([CH2:25][CH3:26])[CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Solvent: CCI
Solvent: O
Product: CCN1CCc2nc(N)nc(-c3ccc(F)cc3)c2C1
Yield: 60.8 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride hemihydrate (1.8 g, 5.5 mmol) and iodoethane (0.4 mL, 5.5 mmol) to produce 0.91 g (48%) of 2-amino-4-(4-fluorophenyl)-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 242°-243° C. MS: 273 (HM+). IR(KBr): 3301, 3132, 2575, 1626, 1604 cm-1. 1H NMR (DMSO-d6) ∂7.63 (m,2H), 7.19 (m,2H), 4.39-3.01 (m,8H), 1.25 (t,J=2.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([OH:33])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:32])[CH:20]=3)=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:32])[CH:20]=3)=[C:12]([O:33][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(CN2CCOCC2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)N(C)C)c1-c1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-2-ol (250 mg, 0.55 mmol) are [sic] suspended in 11 ml tetrahydrofuran, 0.5 g powdered molecular sieve are added and the mixture is stirred for 15 minutes at room temperature. Potassium tert-butylate (93 mg; 0.83 mmol) is added and the suspension is stirred again for 1 hour at room temperature. The beige suspension is then cooled to −20° C., and N,N-dimethylsulphamoyl chloride (158 mg; 1.1 mmol) is added. The reaction mixture is stirred for 4 hours at 0° C. and 2 hours at 10° C and then concentrated. The residue is chromatographed over silica gel with methylene chloride/MeOH (99:1). 151 mg (49%) dimethylsulphamic acid 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-2-yl ester are obtained as a light-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:30])[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:30])[C:17]3=[N:32][NH:33][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(O)(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg) in 85% hydrazine monohydrate (0.2 mL) and methanol (2 mL) was stirred at room temperature for 1 hr. Then the solvent was removed under reduced pressure. The residue was purified by prep-TLC (methanol:dichloromethane=1:20) to give the title compound (50 mg, yield 80%). LC-MS (ESI) m/z: 378 (M+1)+; 1H-NMR (400 MHz, DMSO-d6); 3.44 (s, 3H), 5.24 (s, 1H), 6.84 (s, 1H), 6.98-7.06 (m, 4H), 7.11-7.13 (d, J=8.0 Hz, 1H), 7.38-7.42 (m, 3H), 7.46 (s, 1H), 7.56-7.60 (t, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18]C2CCCCO2)[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][OH:18])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccnc(COC2CCCCO2)c1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OCc1ccnc(CO)c1)c1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of 1266 mg of {2-[(tetrahydro-2H-pyrane-2-yloxy)methyl]pyridin-4-yl}methyl benzoate and 25 ml of methanol was added 1166 mg of pyridinium p-toluenesulfonate, followed by stirring for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 941 mg of [2-(hydroxymethyl)pyridin-4-yl]methyl benzoate as an amorphous substance.
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]([CH:23]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:24](O)=[O:25])=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]2)=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]([CH:23]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:24][OH:25])=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: B
Solvent: C1CCOC1
Product: OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.3 %

Procedure:
Borane-tetrahydrofuran complex (680 ul, 680 umol; 1 M solution in THF) was added to an ice cold solution of [rac]-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid (100 mg, 270 umol; example 4.5) in THF (1 ml). The solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (56 mg, 160 umol; 58%) as colorless foam. MS: m/e=355.3 [M+H+].
Reaction SMILES: Br.C(O)(=O)C.CS(C)=O.[CH2:10]([S:13]([NH:16][CH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]3[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=2)[CH2:19]1)(=[O:15])=[O:14])[CH2:11][CH3:12].C(OC(C)C)(C)C>C(O)(=O)C>[CH2:10]([S:13]([NH:16][CH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=2)[CH2:19]1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: CCCS(=O)(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCS(=O)(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
25 ml of 30% hydrogen bromide-acetic acid and 1.3 ml of dimethyl sulfoxide were added to 5.24 g of 2-(propylsulfonylaminomethyl)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of acetic acid. The mixture was stirred at room temperature for 2 hours. 150 ml of isopropyl ether was added to the mixture, and crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 4.82 g of 2-(propylsulfonylaminomethyl)-5-[pyridazin-3(2H)-on-6-yl]indane. This compound had the same physical properties as those of the compound obtained in Example 2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[CH2:7][CH:8]3[CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>O1CCCC1>[OH:19][CH2:18][CH2:20][NH:21][CH2:13][CH:8]1[CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[NH:9]1
Reactant: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CN21
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1(=O)NC(CNCCO)Cc2ccc(C(F)(F)F)cc21
Yield: 147.1 %

Procedure:
A solution of 8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide (685 mg, 0.260 mmol), ethanolamine (0.785 mL, 13.0 mmol) and triethylamine (0.33 mL, 2.6 mmol) in tetrahydrofuran (25 mL) was heated in a sealed tube at 100° C. for 3 h. The cooled reaction was concentrated in vacuo. The residue was chromatographed (silica, 2%–20% methanol/dichloromethane gradient) to provide 3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine 1,1-dioxide as a white solid (124 mg) and additional impure material: LCMS (neg. ion spectrum) m/z 323.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1O
Yield: 45 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=324 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:36](F)(F)F)=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4CCN(C5C=C(C=CC=5)C(O)=O)CC4)=CC=3)=O)N=2)C=CC=CC=1.N1CCC(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3CC)=O)=CC=2)CC1.C(OC(=O)C1C=CC(Br)=CC=1)(C)(C)C>>[CH2:36]([C:9]1[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=[O:13])[CH3:40]
Reactant: O=C(O)c1cccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)c1
Reactant: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Agent: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
With the same method used for the preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid, 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid was prepared from 2-phenyl-5-ethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 4-bromobenzoic acid tert-butyl ester. LC-MS for C30H29N3O4 (m/e) calcd 495, obsd 496 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:34]4[CH2:35][CH2:36][C:31]([F:37])([F:30])[CH2:32][CH2:33]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: FC1(F)CCNCC1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1C=C(N2CCC(F)(F)CC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.65 mmol), 4,4-difluoropiperidine hydrochloride (0.800 g, 5.1 mmol) and K2CO3 (0.73 g, 5.3 mmol) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([O:25]C)=[O:24])[CH:13]=2)[CH2:3][CH2:2]1.CO.[OH-].[Li+]>O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC2CCOc3ccccc32)c2nc(C)n(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylate (1.0 g, 2.8 mmol, STEP 1) in methanol (20 mol) and tetrahydrofuran (30 mL) was added 4M lithium hydroxide aqueous solution (4 mL, 16 mmol) at room temperature. After stirring for 5 hours at 60° C., the reaction mixture was concentrated in vacuum. The residue was dissolved with water and acidified (pH=3) with 2M hydrochloric acid. The resulting precipitate was filtrated, and dried in vacuum to afford the title compound as a white solid (0.85 g, 89%):
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)=[C:13]([CH3:31])[CH:12]=1)[CH3:6].O.Cl>O1CCOCC1>[OH:3][C@H:4]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[C:13]([CH3:31])[CH:12]=1)[CH3:6]
Reactant: CCOC(=O)COc1ccc(-c2c(C)cc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc(C)c1-c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.81 mL) was added to a mixture of ethyl (4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-2′,6′-dimethyl biphenyl-4-yloxy)acetate (0.16 g), water (1 mL) and 1,4-dioxane (2 mL), and the mixture was stirred at room temperature overnight. 1 mol/L hydrochloric acid (0.81 mL) was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The precipitate was collected by filtration to afford the title compound (0.12 g) as a pale yellow amorphous. The structure and physical data were shown in table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[S:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CO.C(Cl)(Cl)Cl.[NH4+:44].[OH-]>C1(C)C=CC=CC=1>[NH2:44][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:27]1[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]2[C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: [NH4+]
Reactant: Cc1ccc(-c2cc(=O)n(C)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)s1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(=O)n(C)c3ccc(C(N)(c4ccc(Cl)cc4)c4cncn4C)cc23)s1
Yield: 49 %

Procedure:
To a solution of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(5-methyl-thiophen-2-yl)-1H-quinolin-2-one (63 mg, 0.132 mmol) in toluene (1 ml) was added thionyl chloride (SOCl2, 0.097 ml, 1.32 mmol). The reaction mixture was heated to reflux for 2 hours. Thiony chloride was removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (5 mL) and to this solution was bubbled ammonia gas (NH3) for 10 minutes at −78° C. The excess NH3 was removed via bubble N2 at −30° C. After removal of THF, the product mixture was partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with CHCl3 then MeOH—CHCl3—NH4OH (1:99:0.1) as eluents to afford the titled compound as an off-white solid (31 mg, 0.065 mmol, 49% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[O:10])=[CH:5][CH:4]=1>Br.CC([O-])=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:10])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: Br
Agent: CC(=O)[O-]
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Yield: 105.9 %

Procedure:
4,4′-dimethoxybenzil (2.0 g, 7.41 mmol) was dissolved in 30 mL of hydrogen bromide and 10 mL of acetic acid glacial. The reaction was stirred at reflux temperature overnight. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulphate. Concentration under vaccum gave the title compound as a yellow solid (1.9 g, quantitative).
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:22])=[C:11]([C:13]2[C:14]([C:20]#[N:21])=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)(=[O:6])[CH3:5]>O1CCOCC1.O.O1CCOCC1>[F:19][C:16]1[CH:15]=[C:14]([C:20]#[N:21])[C:13]([C:11]2[CH:12]=[C:7]([C:4](=[O:6])[CH:5]=[O:2])[CH:8]=[CH:9][C:10]=2[F:22])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(F)c(-c2ccc(F)cc2C#N)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(F)ccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C

Procedure:
Selenium dioxide (0.556 g, 5.00 mmol) dissolved in 1,4dioxane:water (4:1, 5 ml) was added in one portion to 5′-acetyl-4,2′-difluorobiphenyl-2-carbonitrile (0.92 g, 3.58 mmol) in 1,4-dioxane (10 ml) and the mixture heated at reflux for 18 h. The reaction was allowed to cool to room temperature, filtered and the filtrate evaporated to give an orange-coloured glassy solid which was used without further purification (0.97 g).