Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([N:13](C1C=CC=CC=1)[C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH3:15])=[O:12].C=O.[C:34](O)(=O)[CH3:35]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][C:35]1[CH:34]=[CH:5][CH:4]=[CH:3][CH:11]=1)=[O:12]
Reactant: C[C@@H](C(=O)N[C@H](C=O)CC(=O)O)N(C(=O)c1cc2ccccc2n1C)c1ccccc1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@H](C=O)CC(=O)O)cc2ccccc21
Yield: 25 %

Procedure:
(3 S)-3-[(1-Methyl indole-2-carbonyl)phenyl-alaninyl]amino-4-oxobutanoic acid, semicarbazone (116 mg, 0.25 mmol) were dissolved in methanol (3 mL), formaldehyde (1 mL, 37% wt. aq) and acetic acid (1 mL) and the resulting solution was stirred for 9 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo diluted with water, and extracted twice with ethyl acetate. The ethyl acetate solution was washed with brine, dried over sodium sulfate and concentrated to give a crude product which was triturated with ether to afford the title product as a brown powder (26 mg, 25%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf0.33; MS(EI) for C23H21N3O5; M+H+=422; M−H+=420.
Reaction SMILES: C(O[C:4]([NH:6][NH:7][C:8]1[C:9](=[O:29])[N:10](O)[C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH3:23])=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=2)=[O:5])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH3:23][C:19]1[N:18]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:29])[C:8]4[N:17]3[C:4](=[O:5])[NH:6][N:7]=4)=[CH:12][C:13]=2[C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:21][N:20]=1
Reactant: CCOC(=O)NNc1nc2cc(-n3ccnc3C)c(C(F)(F)F)cc2n(O)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c1n[nH]c(=O)n12
Reaction time: 17 h
Yield: 82.4 %

Procedure:
To a solution of 1 g crude 3-(2-ethoxycarbonylhydrazino)-1-hydroxy-6-(2-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in 50 ml dry N,N-dimethylformamide was added 1.05 g (~4.0 mmol) triphenylphosphine. Stirring was continued at 130° C. for 17 h followed by evaporation in vacuo. Column chromatography (silica gel; eluent: dichloromethane containing 10% methanol) gave the title compound (0.7 g; 75%). M.p. 375° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:25])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([C:22]([CH3:24])=[CH2:23])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:25])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH:22]([CH3:23])[CH3:24])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
A suspension of cis-2-benzyl-6-chloro-3a-methyl-7-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.156 mmol, 55 mg) and 5% Pd—C (7.81 μmol, 16.63 mg) in MeOH (3 ml) was stirred under H2 atmosphere (1 bar, multiple hydrogenator) at ° C. for 1.5 h and then passed through Whatman membrane filter. The resulting filtrate was concentrated in vacuo a crude solid that was redissolved in MeOH (3 ml) and further 5% Pd—C (7.81 μmol, 16.63 mg) was added. The resulting suspension was stirred under H2 atmosphere (balloon) at 20° C. for 3 h and then passed through Whatman membrane. The filtrate was concentrated to give cis-2-benzyl-6-chloro-7-isopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (46.6 mg), m/z=354.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].N1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C(C)=CC=CC=1>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:16]1[CH2:17][CH2:18][CH2:15][CH2:14]1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: C1CCNC1
Product: O=C(O)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Yield: 96 %

Procedure:
4-Chloro-3-nitrobenzoic acid (5.0 g) is suspended in xylene (50 ml), and thereto are added triethylamine (2.5 g) and pyrrolidine (2.0 g), and the mixture is refluxed for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution, and the precipitated crystals are separated by filtration, washed with water and dried to give 3-nitro-4-(1-pyrrolidinyl)benzoic acid (5.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([OH:15])=O)[C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([N:19]([CH2:25][CH3:26])[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:22]3[CH2:23][CH2:24][CH:20]([N:19]([CH2:25][CH3:26])[CH2:17][CH3:18])[CH2:21]3)=[O:15])[C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C1CCNC1
Reactant: Cc1c(C(=O)O)n[nH]c1-c1cccc(Br)c1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(Br)c3)c2C)C1
Yield: 91 %

Procedure:
In analogy to the procedure described in example 12D], 5-(3-bromo-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 91% yield as off-white foam. MS: 405.2 (MH+, 1 Br).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) in a similar manner to that of Example 1 to give the captioned compound (2.3 g.), pale yellow powder, mp. 160° to 165° C. (dec.).
Reaction SMILES: CC(C(N=NC1C(C(O)=O)=CC=CC=1)C(N[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([NH:17][C:10]=2[CH:9]=1)=[O:16])=O)=O.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].[OH-].[Na+]>O>[N:14]1[C:15](=[O:16])[N:17]=[C:10]2[CH:9]=[CH:8][CH:13]=[CH:12][C:11]=12
Reactant: CC(=O)C(N=Nc1ccccc1C(=O)O)C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Reaction time: 5 h

Procedure:
20 g of C.I. pigment yellow 151 having an average primary particle diameter of 80 nm (in which the content of metal ions having a valence of at least 2 was 270 ppm), 4 g of a commercially available dye C.I. acid yellow 23 and 110 g of deionized water were mixed, a 1% sodium hydroxide aqueous solution was added so as to adjust the pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 5 hours, to obtain a water-based pigment dispersion. The obtained water-based pigment dispersion was diluted so as to have a concentration of 3% by weight, and the diluted water-based pigment dispersion was dropped to NO.2 filter paper, to show bleeding of the dye.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]([CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)=[C:17]([CH3:29])[N:18]2[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]([CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)=[C:17]([CH3:29])[N:18]2[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCn1c(C)c(Cn2ccnc2)c2c(CCNC(=O)OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCn1c(C)c(Cn2ccnc2)c2c(CCN)cccc21
Yield: 55.8 %

Procedure:
Hydrogenation of methyl 4-(2-benzyloxycarbonylaminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate (0.50 g) in tetrahydrofuran (20 ml) in the presence of 10% palladium on carbon (100 mg+a further 50 mg quantities after 24 and 48hours) for 72 hours, followed by work up as described for Preparation 32 gave the title compound as a gum (0.20 g), Rf. 0.15(SS3). δ(CDCl3): 1.70(2H,br), 2.47(3H,s), 2.81(2H,t), 2.88(4H,s), 3.70(3H,s), 4.48(2H,t), 5.37(2H,s), 6.86(1H,s), 6.95(1H,d), 7.04(1H,s), 7.17(1H,m), 7.24(1H,d), 7.42(1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH3:19])[C:13]([O:17]C)=[CH:14][CH2:15]O)=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH3:19])[C:13](=[O:17])[CH:14]=[CH2:15])=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1
Reactant: COC(=CCO)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
To a solution of 30 ml of 35% HClO4 and 15 ml CH2Cl2 at 0° C. was added 3.0 g (7.55 mmol) 4-(4-(4-bromo-2-fluorophenoxy)phenoxy)-3-methoxy-2-penten-1-ol in 15 ml CH2Cl2. The mixture was stirred at 0° C. for 45 min, then poured into water and extracted with ether. The combined ether extracts were washed with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC, eluting with 95:5 hexane:acetone, to give 1.9 g (69%) of the product as a clear, colorless oil. Structure was established on the basis of IR and NMR analysis. Calc: C, 55.91; H, 3.86. Found: C, 56.84, H, 4.00.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CC#N>[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1CN1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 2.00 g of 4-piperidone monohydrate hydrochloride and 5.40 g of potassium carbonate in 30 ml of CH3CN was added dropwise 1.57 ml of 2-methyl benzyl bromide at 0° C. After stirred at 0° C. or 3.5 h, the mixture was stirred at room temperature for an hour. At 0° C., the mixture was quenched with water and extracted with CHCl3. The organic layer was washed with water, aqueous NaOH, and brine, and dried over anhydrous Na2SO4. The organic solvent was evaporated to give the crude product of 2.52 g of N-(2-methylbenzyl)-4-piperidone as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH3:14])([O-:3])=[O:2].C(O)=O>[Pd].C(N(CC)CC)C.C(OCC)(=O)C>[CH3:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([CH3:10])[CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 2,6-dinitro-m-xylene (11.2 g) and 10% palladium on charcoal (620 mg) was stirred in triethylamine (36 mL) under an atmosphere of nitrogen and heated to reflux. Formic acid (9.25 mL) was added dropwise to the above mixture with vigorous stirring. After addition, the mixture was allowed to stir at reflux for an additional 15 min, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with brine and dried over magnesium sulfate. Evaporation afforded 9.51 g as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[C:24](=[O:27])([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:7][CH:6]3[CH2:5][CH2:13][CH2:12][CH2:24][O:27]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 12 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved in N,N-dimethylformamide (5 mL). 2-Brothomethyl-tetrahydro-pyran (0.34 g, 1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and the reaction mixture is stirred at 60° C. for 12 hours under N2. The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid residue is triturated with diethyl ether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellow filtrate (mixture of N1 and N3 regioisomers by NMR). The solids are collected and washed with diethyl ether to yield 0.12 g (37%) of the pure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+) m/z 496, 498 (M+, Br pattern) detected.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=1[CH3:8].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:21]([C:22]1[CH:30]=[CH:29][C:27]([O:28][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=2[CH3:8])=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:20]
Reactant: COC(=O)c1cc(-c2nc(CCl)c(C)o2)ccc1C
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of methyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-methylbenzoate (1.21 g), vanillin (0.65 g), anhydrous potassium carbonate (0.59 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.45 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reactant: C=CC(=O)NCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)NCCC1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (200 mg, 0.85 mmol) in DMF (30 mL) at room temperature, N-(2-(piperidin-4-yl)ethyl)acrylamide (222.8 mg, 1.02 mmol) was added followed by HOBt (172.9 mg, 1.28 mmol), EDCI.HCl (244.7 mg, 1.28 mmol) and Et3N (257.9 mg, 2.55 mmol). The reaction mixture was stirred at room temperature for 1 h and then partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-3% methanol/dichloroethane) to afford the desired product (120 mg, 29% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H), 8.07 (t, J=5.2 Hz, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.18 (dd, J=10.0, 17.2 Hz, 1H), 6.06 (dd, J=2.4, 17.2 Hz, 1H), 5.56 (dd, J=2.4, 10.4 Hz, 1H), 5.34 (t, J=4.0 Hz, 1H), 4.36 (d, J=12.8 Hz, 1H), 3.94-3.87 (m, 3H), 3.20-3.15 (m, 2H), 2.98-2.92 (m, 1H), 2.63-2.57 (m, 1H), 1.74-1.69 (m, 2H), 1.57-1.52 (m, 1H), 1.41-1.35 (m, 2H), 1.12-0.95 (m, 2H). ESI-MS m/z: 400.4[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:25]2([C:36]3[CH:41]=[CH:40][C:39](F)=CC=3)[CH2:30][CH2:29][CH2:28][N:27](CC(O)=O)[C:26]2=O)=CC=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:26]1[C:25]2[C:30](=[CH:39][CH:40]=[CH:41][CH:36]=2)[CH2:29][CH2:28][N:27]1[C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]1=[O:17]
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.35-6.96 (m, 8H), 4.68 (d, J=27.4, 2H), 4.34 (d, 1H), 4.19 (dd, J=7.4, 15.9, 1H), 3.84 (t, J=6.0, 1H), 3.78-3.52 (m, 4H), 3.02-2.81 (m, 2H), 2.68-2.45 (m, 1H), 2.25-2.06 (m, 1H); MS (DCI) m/z 353.1 (M+H)+.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[CH3:25][C:24]1[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Cc1cccnc1Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloro-3-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound. MW: 347.85; mp: 226.0-228.0° C.; 1H-NMR (DMSO-d6) δ: 8.66-8.62 (1H, m), 8.21-8.14 (2H, m), 7.91 (1H, d, J=8.1 Hz), 7.76 (1H, dd, J=7.7, 4.8 Hz), 7.68-7.60 (2H, m), 7.60-7.54 (1H, m), 7.50-7.43 (4H, m), 7.26 (1H, d, J=8.1 Hz), 6.89 (1H, d, J=16.5 Hz), 2.12 (3H,s).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.62 ml of 4-tert-butylbenzaldehyde (3.69 mmol), 600 mg of 2-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamine hydrochloride (2.46 mmol) and 340 mg of potassium carbonate (2.46 mmol) were suspended in 7 ml methanol at RT, and after stirring for 30 min at RT, were refluxed for 2 h. After cooling down to RT, 140 mg (3.69 mmol) of sodium borohydride were added and after stirring for 5 min at RT, the reaction mixture was then refluxed for 3 h. After cooling down to RT, the reaction mixture was treated with 0.5 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4 then 1:2) to give 784 mg light yellow oil (90%). MS (ISP) 354.3 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[Cl:41])=[O:29].O>CN(C=O)C>[Cl:41][C:32]1[CH:33]=[C:34]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:35]=[CH:36][C:31]=1[NH:30][C:28](=[O:29])[CH2:27][S:8][C:5]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:3]([CH2:2][F:1])=[N:7][N:6]=1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(CF)nnc2SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide (93 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered to give solid (126.8 mg, 74% yield). 1H NMR (DMSO, 300 MHz) δ 10.12 (broad s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (dd, J=4.8, 8.7 Hz), 7.87 (s, 1H), 7.76-7.52 (m, 5H), 7.46 (s, 2H), 7.11 (d, J=8.7 Hz, 1H), 5.35 (dd, J=12.3, 26.7 Hz, 1H), 5.19 (dd, J=11.7, 25.8 Hz, 1H), 4.26 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])=[CH:9][C:8]=2[C:33]([F:36])([F:35])[F:34])=[CH:4][CH:3]=1.CC[C:41]([C:43](Cl)=[O:44])=[O:42]>ClCCl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:41](=[O:42])[C:43](=[O:44])[N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]6[NH:30][N:31]=[CH:32][C:25]=56)=[CH:21][CH:22]=4)[C:14]3=[O:15])=[CH:9][C:8]=2[C:33]([F:35])([F:36])[F:34])=[CH:37][CH:38]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Reactant: CCC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C(=O)N(c2ccc(Oc3ccc(F)cc3)c(C(F)(F)F)c2)C(=O)N1c1ccc(Oc2ccnc3[nH]ncc23)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
1-[4-(4-Fluorophenoxy)-3-trifluoromethyl-phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) and THF (3 mL), and ethyloxalyl chloride (70 μL) was added thereto. The resulting mixture was stirred at 70° C. for 3 hours. The reaction solution was concentrated and then purified by reverse-phase HPLC (ODS column, 0.05% TFA-containing water/acetonitrile system, 5% to 95% linear gradient) to give the target compound (9 mg, 20%).