Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].CO>[N+](C1C=CC=CC=1)([O-])=O.O>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)n1c(N)cc(=O)n1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(=O)n(-c2ccccc2)n1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.7 g (0.1 mole) of 1-phenyl-2-ethoxycarbonyl-3-amino-3-pyrazolin-5-one (compound 2) and 30.2 g (0.11 mole) of palmitoylchloride are dissolved consecutively in a solution of 13.3 g (0.1 mole) of anhydrous aluminium chloride in 100 ml of nitrobenzene. The mixture is stirred for 1 h at room temperature and poured out in 500 ml of water. The precipitate is stirred with methanol, filtered off, and recrystallized from ethanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN([C:46]([O:50][N:51]1N=NC2C=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.ClCCl.C(=O)([O-])O.[Na+]>[CH3:46][O:50][N:51]([CH3:52])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (0.2 g, 0.451 mmol) was dissolved in dimethylacetamide (5 ml). N—O-Dimethylhydroxylamine hydrochloride (53 mg, 0.541 mmol) and di-isopropylethylamine (0.19 ml, 1.08 mmol) were added followed by HBTU (0.21 g, 0.541 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and saturated aqueous sodium hydrogencarbonate was added. The product was extracted into dichloromethane (×2), and the combined organics washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.2 g, 91%. LCMS RT: 2.41 min, MI: 487 Method: 2.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:21])([CH3:3])[CH3:2].CC1C=C(CCCCCCCCC)C=C(C=[N:27][OH:28])C=1O>>[CH:1]([C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:6]([CH:7]=[N:27][OH:28])[C:5]=1[OH:21])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCc1cc(C=O)c(O)c(C(C)C)c1
Reactant: CCCCCCCCCc1cc(C)c(O)c(C=NO)c1
Product: CCCCCCCCCc1cc(C=NO)c(O)c(C(C)C)c1
Yield: 96.1 %

Procedure:
Oximation and workup of 3-isopropyl-5-nonylsalicylaldehyde (3b) (57.6 g, 0.2 mol) as described for 1c gave 3-isopropyl-5-nonylsalicylaldoxime (58.21 g) in 96.1% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:16][O:14][C:13]([C:6]1[C:7]2[CH:11]=[C:10]([CH3:12])[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c2cc(C)oc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC)c2oc(C)cc12
Temperature: 25 °C
Yield: 75 %

Procedure:
To a well stirred suspension of 7-methoxy-2-methylbenzo[b]furan-4-carboxylic acid (from step 4) (4.5 g, 24.21 mmol) and powdered potassium carbonate (7.5 g, 54.61 mmol) in acetone (740.0 mL) was added dimethyl sulfate (4.1 g, 32.76 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and water (500 mL) was added to it. The organic material separated was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water ((2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (4.0 g) as brown viscous oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].S(Cl)([Cl:15])=O>CN(C)C=O.CC1C=CC=CC=1>[Cl:15][CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CN(CCO)C(=O)N1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(CCCl)C(=O)N1CCCC1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4 parts of N-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide in 22.5 parts of methylbenzene were added 2.9 parts of thionyl chloride. After the addition of a few drops of N,N-dimethylformamide, the reaction mixture was heated slowly to reflux temperature. After stirring for 2 hours at this temperature, the mixture was cooled and the whole was evaporated, yielding 4.5 parts (100%) of N-(2-chloroethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 31).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11](CC(C)C)[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([NH2:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]#[N:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1[nH]c(=O)c2ccc(C#N)cc2c1-c1ccc(Cl)cc1
Yield: 90.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (Example 186 (4)) (0.48 g, 1 mmol) and cyanuric chloride (0.55 g, 3 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-(4-chlorophenyl)-6-cyano-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.37 g, 80.4%) as crystals.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1

Procedure:
Procedure F′: 5-Bromo-2-trifluoromethylpyridine (Eur J. Org Chem (2003), 1559) (0.85 g, 3.7 mmol), methoxycarbonylphenyl-4-boronic acid (0.44 g, 2.4 mmol) and sodium carbonate (1 g, 9.4 mmol) are suspended in dioxane/water (9:1) (25 ml). The mixture is degassed for 20 minutes with a nitrogen stream, tetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol) is added and the mixture is heated to reflux under nitrogen overnight. The mixture is concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted several times with ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated. The crude product is purified by silica-gel column chromatography (gradient 10% ethyl acetate in cyclohexane to 10% cyclohexane in ethyl acetate) to give 4-(6-trifluoromethyl-pyridin-3-yl)-benzoic acid methyl ester. MS (FIA) 282.0 (MH+). Procedure G′: 4-(6-Trifluoromethyl-pyridin-3-yl)-benzoic acid methyl ester (0.57 g, 2 mmol) is dissolved in tetrahydrofuran/water (9:1) (25 ml), lithium hydroxide monohydrate (0.9 g, 2.2 mmol) is added and the mixture is heated under reflux overnight. The mixture is concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is acidified and the resulting precipitate is collected by filtration to give the 4-(6-trifluoromethyl-pyridin-3-yl)-benzoic acid. MS (FIA) 267 (MH−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.N1C=CC=CC=1.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:43][C:44]1[S:45][C:46]([CH3:50])=[C:47]([CH3:49])[N:48]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:43][C:44]2[S:45][C:46]([CH3:50])=[C:47]([CH3:49])[N:48]=2)=[O:40])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1nc(N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (95 mg) was dissolved in chloroform (3 ml) and pyridine (0.2 ml) to prepare a solution. A solution of triphosgene (45 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (54 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The crystal was purified by chromatography (chloroform:acetone=2:1) to give 29 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>ClCCl>[F:10][C:8]([F:11])([F:9])[C:6]1[C:5]([Cl:12])=[CH:4][C:3]2[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:28](=[O:30])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-trifluoromethylphenyl)amino]-1-piperidinecarboxylate (D62, 2.2 g) was dissolved in 25 ml of dichloromethane at 0° C. and triphosgene (0.6 g) and diisopropylethylamine (1.0 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, then crystallised from diethyl ether to yield the subtitle compound, 1.0 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][C:12]2=[N:17][C:18]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[NH:27][CH2:28][CH3:29])=[CH:6][CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:42][N+:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[S:45][C:44]=1SC>>[C:24]([C:22]1[CH:21]=[CH:20][C:19]([NH:27][CH2:28][CH3:29])=[C:18]([N:17]=[C:12]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:5][CH:6]=3)[C:15](=[O:16])[C:14](=[C:44]3[N:43]([CH3:42])[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[S:45]3)[S:13]2)[CH:23]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccc(C(=O)OC)cc1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared from intermediate 4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoic acid methyl ester and 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate in a manner similar to Example 45. 1H-NMR (CDCl3): δ 8.03 (2H, d), 7.64–7.70 (2H, m), 7.49–7.55 (3H, m), 7.36 (1H, m), 7.20 (1H, m), 7.08 (1H, d), 6.51 (1H, d), 5.24 (2H, s), 4.15 (1H, br t), 3.91 (3H, s), 3.80 (3H, s), 3.04 (2H, m), 2.51 (3H, s), 1.01 (3H, s); MS(ESI): 573 (MH+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([NH:17][C:18]2[N:19]=[C:20]([OH:35])[C:21]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:18]([NH:17][C@@H:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[CH3:16])[N:19]=[C:20]([OH:35])[C:21]=3[N:27]=2)=[CH:33][CH:32]=1
Reactant: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of crude (R)—N-tert-butyl-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (670 mg), TFA (5 ml) and dichloromethane (1 ml) was stirred at room temperature overnight. Solvents were removed under vacuum. To the residue was added a mixture of acetonitrile (5 ml) and water (50 ml) with vigorous stirring whereupon some oily material was formed. The mixture was diluted by EtOAc, neutralized by adding sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated. The residue was dissolved in EtOAc (40 ml) and dichloromethane (20 ml) was added slowly, followed by hexanes (5 ml). The resulting solid was collected to give 328 mg (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide. The filtrate was concentrated and purified by reverse phase HPLC (eluting by ACN/H2O+0.1% TFA) to give 200 mg (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:32][CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Cc1cnc(Cl)nc1Nc1ccc(F)c(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Nc1ccc(F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-N-(3-chloro-4-fluorophenyl)-5-methylpyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 440.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:31][CH:32]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To 4-(benzyloxy)-1-chloro-2-nitrobenzene (526 mg, 2 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (670 mg, 2.1 mmol) in 12 mL dioxane was added 4 mL of a 1 M Na2CO3 (aq) solution and Tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol). The suspension was heated at reflux for 15 h under Ar atmosphere and cooled to rt. It was added EtOAc (100 mL) and washed with brine (80 mL), water (80 mL), and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford tert-butyl 4′-(benzyloxy)-2′-nitrobiphenyl-4-ylcarbamate as a yellow solid (740 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.34 (m, 8H), (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 3H), 6.50 (s, 1H), 5.12 (s, 2H), 1.51 (s, 9H); MS (ESI) m/z 443 (M+Na+).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]1[CH3:23].II>C(Cl)(Cl)Cl>[Br:1][C:7]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]([CH3:3])[C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(C)cc2)n(C)c1C
Agent: II
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(Br)c(C(=O)c2ccc(C)cc2)n(C)c1C
Temperature: 0 °C

Procedure:
A solution of 27.4 ml (0.538 mole) of bromine in 150 ml of chloroform is added to a refluxing solution of 152.6 g. (0.538 mole) of ethyl 1,2-dimethyl-5-(p-toluoyl)pyrrole-3-carboxylate in 1500 ml of chloroform containing a few iodine crystals over a period of 45 min. The solution is heated under reflux for 10 min. and is then poured into ice water. The organic layer is separated and washed with sodium bicarbonate solution, sodium bisulfate solution, and brine. It is then dried over sodium sulfate and the solvent is evaporated in vacuo. After recrystallization of the product from methanol, it is extracted in a Soxhlet extractor with about one liter of diethyl ether and then crystallized from the cooled ether to yield ethyl 4-bromo-1,2-dimethyl-5-(p-toluoyl)pyrrole-3-carboxylate; m.p. 122°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 117.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (prepared in Example 26, 60.0 mg, 0.14 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 4.5 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give 2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (61.3 mg, 100%) as a pale yellow oil: EI-HRMS m/e calcd for C19H23N3O3S (M+) 373.1460, found 373.1454.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:36])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[C:22]=1[CH:23](O)[CH3:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:48])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:36])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[C:22]=1[CH:23]([F:48])[CH3:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:20]1[N:19]=[CH:18][C:17]2[CH2:16][N:7]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=3)[C:6](=[O:37])[O:5][CH:23]([CH3:24])[C:22]=2[C:21]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C(C)O)c1OCc1cccc(C#N)c1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C(C)F)c1OCc1cccc(C#N)c1
Product: Cc1ncc2c(c1OCc1cccc(C#N)c1)C(C)OC(=O)N(c1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %
Yield: 22 %

Procedure:
To a solution of [5-(3-cyano-benzyloxy)-4-(1-hydroxy-ethyl)-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (112) (245 mg, 0.10 mol) in dry dichloromethane (7 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (350 mg, 1.6 mol) at 0° C. under nitrogen atmosphere. The reaction was slowly warmed to room temperature and stirred for 30 minutes. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:1) as an eluant to give [5-(3-cyano-benzyloxy)-4-(1-fluoro-ethyl)-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (113) (54 mg, 22% yield) and 4-[3,5-dimethyl-4-(3-cyano-benzyloxy)-7-oxo-5,9-dihydro-6-oxa-2,8-diaza-benzocyclohepten-8-yl]-benzonitrile (114) (90 mg, 43% yield).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Product: Oc1ccc2ncn(-c3cccc(C(F)(F)F)c3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluoro-3-(trifluoromethyl)phenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=298.1 [M+H]+.