Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(NCc4ccccc4)CCC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(N)CCC3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
A mixture of N-[(1-benzylamino-cyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (220 mg, 0.417 mmol), 10% of palladium hydroxide on carbon (30 mg), and trifluoroacetic acid (160 μL) in methanol (20 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was adjusted to pH 8-9 by the addition of a solution of ammonia in methanol (7 M), and concentrated in vacuo. The residue was purified by preparative HPLC to give 105 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.6 Hz, 1 H), 7.86 (d, J=7.6 Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J=7.6 Hz, 1 H), 7.47-7.32 (m, 3 H), 5.33 (s, 2 H), 4.58 (brs, 2 H), 3.84 (s, 2 H), 3.53 (t, J=4.8 Hz, 2 H), 2.41 (s, 3 H), 2.21 (m, 2 H), 2.04-1.97 (m, 2 H), 1.91-1.82 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:18][C@H:17]1[CH2:19]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[CH2:19]([O:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:14]=1[NH:13]2)[CH:17]1[O:18][CH2:16]1
Reactant: Oc1cccc2[nH]c3c(F)cccc3c12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Product: Fc1cccc2c1[nH]c1cccc(OCC3CO3)c12
Yield: 78.4 %

Procedure:
1-Fluoro-5-hydroxycarbazole (25 mg, 0.124 mmol) and (2R)-(−)-glycidyl 3-nitrobenzenesulfonate, (32 mg, 0.124 mmol) were converted to 25 mg of the title compound substantially in accordance with the procedure of Preparation 122. Yield: 65%. 1H NMR. MS(FD).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]([CH3:37])[C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])=[C:21]([O:38][CH3:39])[CH:20]=3)=[CH:17][S:18][C:14]=2[C:13]([N:40]=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:12][N:11]=1>CN(C)C=O>[CH3:3][N:4]([CH:6]=[N:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]([CH3:37])[C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])=[C:21]([O:38][CH3:39])[CH:20]=3)=[CH:17][S:18][C:14]=2[C:13]([N:40]=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:12][N:11]=1)[CH3:5]
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 95 °C
Reaction time: 9 h
Yield: 93.4 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.116 mL, 0.87 mmol) was added to a solution of N-(4-{4-amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.156 g, 0.257 mmol) in N,N-dimethylformamide (6 mL). The solution was stirred at 95° C. for 9 h, then was cooled to ambient temperature, and the mixture was concentrated. Partial purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using dichloromethane as the mobile phase afforded crude N-(4-{4-{[(dimethylamino)methylene]amino}-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide as a yellow foam (0.16 g, 0.24 mmol): MS: (MH)+ 663.
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:27][C:28]3[C:33]([C:34](=[O:36])[CH:35]=2)=[CH:32][C:31]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=3)[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.[Pd]>[P:1]([OH:11])([OH:3])([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:27][C:28]3[C:33]([C:34](=[O:36])[CH:35]=2)=[CH:32][C:31]([N:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:30][CH:29]=3)[CH:21]=1)=[O:2]
Reactant: O=c1cc(-c2cccc(OP(=O)(OCc3ccccc3)OCc3ccccc3)c2)[nH]c2ccc(N3CCCC3)cc12
Agent: [Pd]
Solvent: CO
Product: O=c1cc(-c2cccc(OP(=O)(O)O)c2)[nH]c2ccc(N3CCCC3)cc12
Yield: 69.4 %

Procedure:
A suspension of 146 (200 mg, 0.36 mmol) in anhydrous MeOH (10 mL) was hydrogenated in the presence of 10% Pd/C (100 mg) at 25° C. for 20 min. The catalyst and precipitate were collected and dissolved in 10% NaHCO3 solution and then filtered. The filtrate was acidified with dil aq HCl and the precipitate was then collected and washed with acetone to give 147 (97 mg, 0.25 mmol). Yellow solid; yield: 69.8%; mp>300° C.; MS (ESI): m/z 387.1 (M+H)+; 1H-NMR (D2O+NaOD, 200 MHz): δ 1.78 (m, 4H), 3.08 (m, 4H), 6.70 (s, 1H), 7.12-7.20 (m, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 7.61 (d, J=9.8 Hz, 1H); Anal. (C19H19N2O5P) C, H, N.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]([C:20]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:6][CH:7]([C:20]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(NS(C)(=O)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methanesulfonyl chloride (37 μl, 0.48 mmol) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (134.6 mg, 0.4 mmol) and triethylamine (67 μl, 0.48 mmol) in dichloromethane (2 ml) at 0°. Stirring continued overnight (14 hours) while the cooling both attained room temperature. The reaction mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 10% ethyl ether/hexane. Fractions with Rf of about 0.07 on evaporation gave the title sulfonamide as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][C:2]1([C:8](=[O:15])[CH:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A solution of 105.5 g (0.5 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 100 ml of dimethylformamide is added dropwise, at 20°-25° C., to a suspension, stirred under pure nitrogen, of 13.2 g (0.55 mole) of sodium hydride in 100 ml of dry dimethylformamide. The reaction mixture is then stirred for three hours at 25° C., after which a solution of 81 g (0.5 mole) of 4-chlorobenzyl chloride in 50 ml of dimethylformamide is added dropwise and stirring is then continued for 14 hours. 50 ml of ice water are then cautiously added dropwise and the mixture is concentrated under reduced pressure. The residue is partitioned between 400 ml of methylene chloride and 200 ml of water and the organic phase is washed with three times 200 ml of water, dried over Na2SO4 and evaporated down. 112 g (66.8%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-one are obtained as a pale yellow resin.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:4]([C:9]2[CH:18]=[N:17][C:16]3[C:15](=O)[NH:14][C:13]([CH2:20][O:21][CH3:22])=[N:12][C:11]=3[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[Cl:35][C:15]1[C:16]2[N:17]=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:24])([F:23])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][C:11]=2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2cc(-c3ncccc3C(F)(F)F)cnc2c(=O)[nH]1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c2ncc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Dissolve 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[3,2-d]pyrimidin-4-one (276 mg, 0.822 mmol) in CHCl3 (25 mL) and 2,6-lutidine (294 mg, 2.74 mmol). Add phosphorous oxycloride (0.255 mL, 2.74 mmol) dropwise and heat the resulting solution to reflux for 24 hours. Cool the solution and remove the solvent under reduced pressure. Partition the crude residue between EtOAc (50 mL) and saturated NaHCO3 (aq) (50 mL). Remove the organic phase and extract the aqueous phase with additional EtOAc (50 mL). Combine the two organic extracts, wash with brine (100 mL), and dry over Na2SO4. Remove the solvent to yield the title compound as a light brown solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][C:38]1[CH:39]=[C:40]([NH:45][C:46](=[O:48])[CH3:47])[CH:41]=[C:42]([CH3:44])[CH:43]=1>C(Cl)Cl.CO>[Br:1][C:43]1[C:42]([CH3:44])=[CH:41][C:40]([NH:45][C:46](=[O:48])[CH3:47])=[CH:39][C:38]=1[CH3:37]
Reactant: CC(=O)Nc1cc(C)cc(C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
Benzyltrimethylammonium tribromide (BTMA-Br3) (7.8 g, 20.21 mmol) was added to a solution of N-(3,5-dimethyl-phenyl)-acetamide (3.0 g, 18.38 mmol) in CH2Cl2/MeOH (90 ml/90 ml) at room temperature in an Ar atmosphere. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 was then added to the resulting residue. The organic layer was washed with H2O, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=1:1) to give N-(4-bromo-3,5-dimethyl-phenyl)-acetamide (4.0 g, yield 90%).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: O=C(O)CBr
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOCCOC(=O)CBr

Procedure:
A solution of 13.9 g (0.1 mmol) of bromoacetic acid in 40 ml of toluene was treated with 11.8 ml (0.1 mol) of diethylene glycol monomethyl ether and 0.8 g of p-toluenesulphonic acid monohydrate. The mixture was heated under reflux on a water separator until water no longer separated. The reaction mixture was washed in succession with water, saturated sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and concentrated. Flash chromatography of the residue on 500 g of silica gel (elution agent methylene chloride/ether 4:1) yielded 2-(2-methoxyethoxy)ethyl bromoacetate as a pale yellow oil.
Reaction SMILES: [F:1][C:2](S(C1C=CC=CC=1)(=O)=O)=[CH:3][C:4]([CH3:13])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>C1CCCCC1>[F:1][C:2]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)([CH3:5])[CH3:13]
Reactant: CC(C)(C=C(F)S(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)C(F)=CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirring solution of 22.7 grams (0.067 mole) of 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene, 42.0 grams (0.14 mole) of tributyltin hydride, and 0.5 gram (catalyst) of azobisisobutyronitrile in 700 mL of cyclohexane is heated at reflux for about three hours. After this time the reaction mixture is cooled to ambient temperature, and 125 mL of silica gel is added. The mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1.[Ni]>[CH3:13][CH:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]([CH3:16])[CH3:17])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccccc1
Agent: [Ni]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.37 h
Yield: 21 %

Procedure:
A solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]benzenepropanamide (1.0 g, 3.1 mmol) and benzaldehyde (0.33 g, 3.1 mmol) in toluene (100 mL) was heated under reflux for 1 hour with the azeotropic removal of water then cooled (25° C.). To the resulting solution was added one equivalent of Raney nickel, and the resulting slurry was shaken vigorously under hydrogen (53 psi, 82 min 25° C.). The resulting slurry was filtered, and the filtrate was concentrated. The resulting oil was triturated with ether/hexane (1:1), and the resulting precipitate was collected by filtration to yield 0.27 g (21%) of the title compound, mp 120°-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[C:13]([CH3:25])[C:12]([CH:26]=[CH2:27])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:25])[C:12]([CH2:26][CH3:27])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1C

Procedure:
A mixture of Example 145A (450 mg, 1.2 mmol), palladium hydroxide (540 mg), and methanol (150 mL) was heated to 50° C. in a Paar shaker under 65 psi hydrogen pressure for 72 hours. The mixture was filtered, concentrated, and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+; (ESI(−)) m/e 278 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.28 (br s, 1H), 8.35 (s, 1H), 7.32 (d, 1H), 7.17 (d, 1H), 2.58 (q, 2H), 2.24 (s, 3H), 1.43 (s, 9H), 1.12 (t, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([N:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][N:41]([CH3:43])[C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M198) (397 mg, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (248 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[C:16]([NH:18][NH:19][C:20](=O)[CH:21]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=2)[CH2:22][CH2:23][CH2:24][Cl:25])=[O:17])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1>P(Cl)(Cl)(Cl)=O>[Cl:25][CH2:24][CH2:23][CH2:22][CH:21]([C:20]1[O:17][C:16](/[CH:15]=[CH:14]/[C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:2]([F:1])[CH:3]=2)=[N:18][N:19]=1)[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1
Reactant: Cc1cn(-c2ccc(/C=C/C(=O)NNC(=O)C(CCCCl)c3cc(F)c(F)c(F)c3)cc2F)cn1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C/c3nnc(C(CCCCl)c4cc(F)c(F)c(F)c4)o3)cc2F)cn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid N′-{(E)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (103 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 99 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]2[CH:29]=[C:30]([CH2:33][O:34]S(C)(=O)=O)[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].[F:45][CH:46]([F:49])[CH2:47]O>>[F:45][CH:46]([F:49])[CH2:47][O:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8]4[N:12]=[C:11]([CH:13]5[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]5)[O:10][N:9]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])=[CH:25][N:26]=2)[CH:29]=1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(COS(C)(=O)=O)cn45)c3)no2)C1
Reactant: OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(COCC(F)F)cn45)c3)no2)C1

Procedure:
Methyl 3-(3-(4-methyl-3-(6-(((methylsulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (133) (15.0 mg, 0.028 mmol) and K2CO3 (8.3 mg, 0.06 mmol) in 2,2-difluoroethanol (0.5 mL) was heated at 120° C. for 5 minutes. The reaction mixture was purified by preparative HPLC to afford methyl 3-(3-(3-(6-((2,2-difluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F95). MS m/z 527.1 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:43]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:43]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH2:24]([O:23][CH2:22][C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1COCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A solution containing 115 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol, 54 mg of benzyl bromide and 38 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 2 hours. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified twice by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) then dichloromethane for the elution to give 35 mg of 4-benzyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (ES) m/z 455 [M+H]+, 496 [M+H+CH3CN]+. 1H NMR (DMSO-dr) 2.36 (s, 3H), 4.47 (s, 2H), 4.49 (s, 2H), 6.96 (d, 2H), 7.24–7.47 (m, 11H).
Reaction SMILES: C([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][CH:16]=2)[N:10]=1)CCCCCCC.[CH2:24](Cl)[CH2:25]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:22]([C:14]1[CH:13]=[N:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:21])=[CH:22][CH:23]=2)=[N:10][CH:9]=1)[CH2:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:24][CH3:25]
Reactant: CCCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.84 G. of 4-(4-n-octylpyrimid-2-yl)-benzoic acid amide are maintained at reflux for 80 minutes in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide and then with water until neutral. The organic phase is dried over sodium sulfate and evaporated to give 1.91 g. of 5-octyl-2-(4-cyanophenyl)-pyrimidine which are distilled in a high vacuum; melting point 66.1°-66.5° C; clearing point 47.5° C.