Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ncccc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ncccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
[4-{4-[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-Chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.25 g, 50%). MP=101-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, J=6.58 Hz, 1H), 8.25 (m, 1H), 8.05 (d, 1H), 7.75 (m, 1H), 7.55 (m, 2H), 7.02 (m, 4H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=501 (MH)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=1)=[O:39].N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=2)=[O:39])=[O:21])=[CH:17][CH:16]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{2-{[(tert-butyl)amino}sulfonyl}phenyl}benzoic acid (167 mg, 0.5 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.09 ml, 1 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). The compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.17 g, 0.6 mmol) and pyridine (0.122 ml, 1.5 mmol) were added to the solution. The mixture was stirred at r.t. overnight. The solvent was evaporated to give (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide. MS found for C29H26Cl2N4O4S M+=597, (M+2)+=599.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccnc1N
Reactant: Cc1nc2ccccc2c(=O)o1
Product: Cc1cccnc1-n1c(C)nc2ccccc2c1=O

Procedure:
Acetanthranil (4.5 g, 0.028 mole) was mixed with 2-amino-3-picoline (2.7 g, 0.025 mole) and the mixture was heated in an erlenmeyer flask, first at low heat and then at high heat over an open flame. The product was washed with ether and recrystallized from ethanol/water mixture. The yield was 3.7 g (58%), mp 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[C:26]([C:28]([F:31])([F:30])[F:29])=[CH2:27]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:26]([C:28]([F:31])([F:30])[F:29])=[CH2:27])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: Cc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
The mixture of 2-(3,5-dichloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (160 mg, 0.56 mmol), K2CO3 (232 mg, 1.68 mmol), compound 2-bromo-3,3,3-trifluoroprop-1-ene (146 mg, 0.84 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.1 mmol) in THF/H2O (2/1 mL) was stirred in a sealed tube at 80° C. for 3 h. It was partitioned between EA and H2O. The organic layer was washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by column chromatography to give the desired product (78 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1.[N+]([O-])([O-])=[O:12].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C.O.O>[Cl:1][C:2]1[S:3][C:4]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cc2c(s1)CCCC2
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 g (57.9 mmol) of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene are dissolved in acetic acid/water (247 ml/82 ml), 127 g (231 mmol) of ammonium cerium (IV) nitrate in water (50 ml) are added and the mixture is stirred at room temperature for 5 h. The reaction mixture is added to ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 5.60 g of 2-chloro-5,6-dihydro-1-benzothiophen-7(4H)-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.CCCCC.CON(C)[C:19](=[O:51])[C@@H:20]([NH:28][C:29]([CH2:31][N:32]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:36][N:35]([C:44](=[O:46])[CH3:45])[CH:34]([CH:47]([CH3:49])[CH3:48])[C:33]1=[O:50])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[C:44]([N:35]1[CH:36]=[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:32]([CH2:31][C:29]([NH:28][C@@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:2]2[O:1][CH2:5][CH2:4][CH:3]=2)=[O:51])=[O:30])[C:33](=[O:50])[CH:34]1[CH:47]([CH3:49])[CH3:48])(=[O:46])[CH3:45]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reactant: C1=COCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C2=CCCO2)C(=O)C1C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2,3-dihydrofuran (80 μl) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.55 N tert-butyllithium/pentane solution (660 g 1) is added thereto, and the mixture is stirred for one hour. The mixture is added to a solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (295 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (3 ml) cooled at −78° C., and the whole is stirred for two hours. The temperature is raised to 0° C., and the reaction mixture is stirred for 30 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (38.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1O.ClC[C:22]1[CH2:23][S:24][CH2:25][CH2:26][CH:27]=1.[C:28](=O)([O-])[O-:29].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[CH:23]1[C:22]([O:29][CH3:28])=[CH:27][CH2:26][CH2:25][S:24]1
Reactant: ClCC1=CCCSC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC1=CCCSC1c1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl

Procedure:
13.9 g of N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 8.2 9 of 3-chloromethyl-5,6-dihydro-2H-thiopyran and 8.3 g of potassium carbonate in 150 ml of acetonitrile are refluxed for hours. The mixture is cooled and filtered, the filtrate is evaporated down, the residue is taken up in 200 ml of methylene chloride and the solution is washed twice with 10% strength sodium hydroxide solution and 3 times with water, dried and evaporated out. 15.0 g of N-[4-chloro-3-(3-methoxy-5,6-dihydro-2H-thiopyranyl)-phenyl]-3,4,5,6-tetrahydrophthalimide (mp. 116-119° C.) are obtained. ##STR20##
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38.8 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mmol), 3-(trifluoromethyl)benzoic acid (38 mg, 0.20 mol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and Et3N (20 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%–5%–10% (NH4OH/MeOH)/CH2Cl2) to give 30 mg of the title product as a white solid. MS found: (M+H)+=484.25
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21](=[O:22])[N:20]=[C:19]([CH2:23][CH3:24])[NH:18]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:25]([CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21](=[O:22])[N:20]([CH2:35][CH2:34][CH2:33][CH2:32][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]([CH2:23][CH3:24])=[N:18]3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc(=O)n(CCCN2CCN(c3cccc(Cl)c3)CC2)[nH]1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCc1nn(CCCN2CCN(c3cccc(Cl)c3)CC2)c(=O)n1CCCCOc1ccccc1
Product: Cl

Procedure:
A mixture of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-1H-1,2,4-triazol-3-(2H)-one (3.86 g., 0.01 mole), 4-phenoxybutyl bromide (2.29 g., 0.01 mole), potassium carbonate (4.15 g., 0.01 mole) and a trace of potassium iodide in 50 ml. of acetonitrile is refluxed for a 65 hr. period. The reaction mixture is filtered, the filtrate concentrated under reduced pressure and residual material taken up in ether and filtered. Concentration of ethereal filtrate affords the free base. Conversion of the free base to the hydrochloride salt in ethanol with ethanolic hydrogen chloride and crystallization of the salt from ethanol affords analytically pure 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(4-phenoxybutyl)-3H-1,2,4-triazol-3-one hydrochloride, m.p. 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[C:34]([NH:37][CH2:38][CH2:39][NH2:40])(=[O:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[C:34]([NH:37][CH2:38][CH2:39][NH:40][C:23]([C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:10])[C@H:13]([O:31][CH2:32][CH3:33])[CH2:14]2)[S:19][C:20]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:25])(=[O:36])[CH3:35]
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCNC(C)=O
Yield: 57.4 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (200 mg, 0.40 mmol), N-acetylethylenediamine (0.08 mL, 0.80 mmol), WSC hydrochloride (230 mg, 1.20 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol), to obtain 134 mg of the title compound as a white solid (57%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[S:11])=[N:6][CH:7]=1.[CH3:25][C:26]([O-])=[O:27].[Na+].BrCC(OCC)=O>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[C:26](=[O:27])[CH2:25][S:11][C:10]2=[N:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(CNC(=S)Nc2ccc(N3CCOCC3)cc2)cn1
Reactant: CC(=O)[O-]
Agent: CCOC(=O)CBr
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(CN2C(=O)CSC2=Nc2ccc(N3CCOCC3)cc2)cn1
Temperature: 80 °C
Yield: 73 %

Procedure:
A suspension of 1-(5-Methylpyrazin-2-ylmethyl)-3-(4-morpholin-4-ylphenyl)-thiourea (1.7 g, 5.0 mmol, 1.0 equiv) and NaOAc (0.82 g, 10.0 mmol, 2.0 equiv) in 30 mL ethanol was treated with ethyl bromoacetate (0.55 ml, 5.0 mmol, 1.0 equiv) as a neat liquid via syringe. The heterogeneous mixture was heated to 80° C. overnight. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO3. After drying the organic layer with brine and Na2SO4, the product was purified by flash chromatography (40 to 90% EtOAc in hexanes) to afford 1.4 g (73%) of the title compound as a yellow-orange foam: 1H NMR (500 MHz, CDCl3) δ 8.53 (d, 1H, J=1.5 Hz), 8.39 (d, 1H, J=1.5 Hz), 6.85 (s, 4H), 5.15 (s, 2H), 3.90 (s, 2H), 3.85 (m, 4H), 3.12 (m, 4H), 2.54 (s, 3H); MS (ESI) m/z=384.2 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
Into a suspension of methyl 4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]4-oxobutanoate (250 mg, 0.48 mmol) in THF/H2O (2/1) (10 mL) was added NaOH (1.0 N, 2.4 mL). The resulting solution was stirred at rt for 1.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (2×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (83 mg, 34%) in 99.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:6]=O.[CH:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:17][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=1
Reactant: C=O
Reactant: c1ccsc1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Solvent: O=CO
Product: CC(C)c1ccc(C(=O)NCc2cccs2)cc1
Yield: 80 %

Procedure:
Thiophene (50 mmol), formaldehyde (10 mmol) and 4-isopropylbenzamide (10 mmol}were stirred in formic acid (10 ml) at 20° C. for four hours and treated in the same manner as in Example 2 to obtain N-(2-thienylmethyl)-4-isopropylbenzamide. Yield: 80%.
Reaction SMILES: C[Mg+].[Br-].[O:4]=[C:5]([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:17](Cl)Cl.CO>C1COCC1.O>[OH:4][C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCl
Reactant: CC(=O)Cc1cccc(C(=O)O)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(O)Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
CH3MgBr (3.0 M in THF, 11.2 mL, 33.7 mmol) was added slowly to a stirring solution of 3-(2-oxopropyl)benzoic acid (2 g, 11.2 mmol) in THF (100 mL) at 0° C. The resulting suspension was allowed to warm to rt then stirred overnight. The reaction mixture was diluted with H2O (50 mL) then quenched with 5 N HCl (pH<3). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give a yellow oil. Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (1.36 g, 62%) as a white solid. ES/MS calcd. for C11H14NaO3+ 217.1, found m/z=217.2 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]([F:34])([F:33])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH:29]([F:34])[F:33])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC(F)F)cc21
Yield: 32.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), sodium chlorodifluoroacetate (253 mg), K2CO3 (172 mg), DMF (3 ml), and water (0.60 ml) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (110 mg) as a pale yellow oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH2:25]([N:27]1[CH:32]=[C:31]([C:33]([OH:35])=O)[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26].C(N(CC)C(C)C)(C)C.[CH3:54][O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][C:65]=1[O:66][CH3:67])[N:62]=[CH:61][CH:60]=[C:59]2[O:68][C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][C:70]=1[F:76]>CN(C)C=O.CCOC(C)=O>[CH3:54][O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][C:65]=1[O:66][CH3:67])[N:62]=[CH:61][CH:60]=[C:59]2[O:68][C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:35])=[CH:71][C:70]=1[F:76]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) (0.072 g, 0.19 mmol) and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.053 g, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 min stirring at rt, 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.05 g, 0.2 mmol) was added. The reaction was stirred at rt for 12 h, diluted with EtOAc (25 mL), then washed with 1N Na2CO3, water and brine and then dried over MgSO4. The product was crystallized from MeOH to give 75 mg (68%) as a white solid. mp=151-4° C.; LCMS m/z=575 (M+1); 1H NMR (DMSO) δ: 11.04 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98, 8.01 (dd, 1H, J=2.3, 12.6 Hz), 7.52-7.56 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=5.4 Hz), 4.01 (q, 2H, J=7 Hz), 3.98 (d, 6H), 13.0 (t, 3H, J=7 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]([CH2:31][CH:32]([OH:48])[CH2:33][N:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]#[N:47])[CH2:36][CH2:35]3)[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=3)[C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:48][CH:32]([CH2:31][N:21]1[C:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]=2[C:23]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)=[N:22]1)[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]#[N:47])[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCNC3)CC1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.402 g, 0.601 mmol) in CH2Cl2 (3 mL) and the reaction mixture was stirred for 2 h. The mixture was concentrated, then diluted with EtOAc. The organic layer was washed with aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to afford the amine (0.342 g, 100%) as a yellowish foam. TLC (silica, 10% acetone/CH2Cl2): Rf=0.14. MS (electrospray): m/z 569.2 (569.1, calculated for C26H29IN6O, [M+H]+). 1H NMR (400 MHz, CDCl3:CD3OD(6:1)): 7.73 (d, J=8.6 Hz, 2H), 7.56 (dd, J=7.6, 1.8 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.02 (dd, J=8.4 Hz, 1H), 4.43-4.36 (m, 1H), 4.31 (s, 2H), 4.21 (dd, J=14.1, 4.5 Hz, 1H), 4.11 (dd, J=14.5, 6.3 Hz, 1H), 3.54-3.49 (m, 2H), 3.40-3.24 (m, 8H), 3.18-3.06 (m, 3H), 3.03-2.95 (m, 3H).