Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](Br)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nnc3n2-c2ccc(C(F)(F)F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-(trifluoromethyl)-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-(trifluoromethyl)-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[F:5][C:6]1[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:3][C:2]#[CH:1])[C:7]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)cccc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(F)c1CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 1.4 g (11.7 mmol) of propargyl bromide in 1 ml of dimethylformamide was added dropwise to a suspension of 1.3 g (8.4 mmol) of 3-fluoro-2-propyl-phenol and 1.7 g of potassium carbonate in 4 ml of dimethylformamide and the mixture was subsequently stirred at room temperature for one hour. The mixture was poured on to 30 ml of ice-water and extracted three times with 50 ml of dichloromethane each time. After drying concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). There were obtained 1.45 g (90%) of 1-fluoro-2-propyl-3-prop-2-ynyloxy-benzene as a pale yellow oil.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([O-])(=O)C.[Mg+2].C([O-])(=O)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 55 °C

Procedure:
21.72 parts of N-acetoacetyl-L-aspartic acid, 0.14 parts of magnesium acetate, and 9.5 parts by volume of acetic anhydride were mixed with 200 parts by volume of ethyl acetate and heated at 55±2° C. under argon for 24 hours.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13]C)[N:8]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].CC(=O)CC.Cl>O>[CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[N:8]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCOC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: O
Solvent: CCC(C)=O
Product: CCCCc1nc(CCO)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.0 g), 2-butanone (10 mL), water (6 mL) and concentrated hydrochloric acid (2 mL) was stirred at 100° C. for 1 hr. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.57 g, 59%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NCCCO
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)NCCCO)c(F)c1
Yield: 47 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in a mixture of anhydrous THF and anhydrous DMF and treated with 3-amino-1-propanol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) yielding 4-(2-fluoro-4-methylanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (47%) as a pale cream solid; m.p. (EtOAc/Hexane) 142-145° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.86 (br s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.21 (s, 1H), 7.30 (t, J=8.4 Hz, 1H), 7.16 (d, J=11.8 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 5.40 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.27 (dd, J=12.8, 6.8 Hz, 2H), 2.32 (s, 3H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 332 (100%). Anal. Calcd for C17H20FN3O3: C, 61.3; H, 6.1; N, 12.6. Found C, 61.0; H, 6.3; N, 12.7.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[O:9][CH2:8]1>O>[OH:9][CH2:8][CH2:7][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: C1CO1
Solvent: O
Product: CC(C)(CO)NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
2-(2-Hydroxy-ethylamino)-2-methyl-propan-1-ol was prepared from 2-amino-2-methyl-propan-1-ol following a modified procedure from Cottle et al. J. Chem. Soc. 1946, 289. To a solution of 2-amino-2-methyl-propan-1-ol (250 mL, 2.61 mol, 1.76 equiv.) in H2O (400 mL) at −5° C. (external temperature, NaCl/ice bath) was added ethylene oxide (65.25 g, 1.48 mol, condensed at −78° C.). The solution was stirred over 16 hours, during which time the temperature warmed to room temperature. The H2O was removed in vacuo and the remaining 2-amino-2-methyl-propan-1-ol was distilled. The crude residue was dissolved in boiling EtOAc and precipitated with the addition of hexanes to provide 2-(2-Hydroxy-ethylamino)-2-methyl-propan-1-ol (145.5 g, 74%) as colorless crystals. LC/MS found 134.03 (M++H, C6H16NO2 requires 134.12).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:11])[C:5]2=[N:10][CH:9]=1
Reactant: Cc1cc(C)c2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2ncc(Br)n2n1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 3.63 g (24.7 mmol) of 6,8-dimethylimidazo[1,2-b]pyridazine in 25 mL of chloroform was added 4.84 g (27.2 mmol) of N-bromosuccinimide. After 2 h, 1 mL of a saturated aqueous solution of sodium bicarbonate was added. The layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by flash chromatography to give 4.66 g of the title compound as a white solid, m.p. 137°-139° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14].C(=O)=O.C(O)C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14]
Reactant: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3)c2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CCO
Solvent: ClCCl
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a mixture of (Z)-2-(5-methoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (compound of example 4) (175 mg, 0.6 mmol, 1.0 eq.) in anhydrous dichloromethane (2 mL) cooled to −78° C. (dry ice/ethanol bath) was added, under an argon atmosphere, a 1M boron tribromide solution in dichloromethane (2 mL, 2.0 mmol, 3.2 eq.). The reaction mixture was stirred at ambient temperature for 18 hours and then quenched with ethanol. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/MeOH, 95:5 to 93:7) to afford (Z)-2-(5-hydroxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile as a yellow powder (150 mg, 91%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Si:22]([O:29][C:30]1[CH:35]=[C:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:33]=[CH:32][C:31]=1[C@H:44]1[CH2:49][CH2:48][C@H:47]([CH2:50][OH:51])[CH2:46][CH2:45]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[Si:22]([O:29][C:30]1[CH:35]=[C:34]([O:36][Si:37]([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:39])[CH3:38])[CH:33]=[CH:32][C:31]=1[C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([OH:2])=[O:51])[CH2:48][CH2:49]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](C(=O)O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
Pyridinium dichromate (146 mg) was added to a stirred solution of cis/trans-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol (50 mg) in N,N-dimethylformamide (1 ml) at room temperature under argon. After 24 hr, the reaction mixture was partitioned between water (20 ml) and diethyl ether (30 ml). The layers were separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:9 v/v) to give the title compound as a cream solid (23 mg, 44%); m/z (ES+) 465 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][N:4]=[N+]=[N-].[N-]=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[F:13][C:2]([F:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][NH2:4]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccn1

Procedure:
A stirred solution of 100 mg of 2,2-difluoro-2-(2-pyridyl)ethylazide I-1-6 was hydrogenated in 10 mL of ethyl acetate over 100 mg of 10% palladium on carbon using a balloon for 1 h. The catalyst was removed by filtration and the solvents removed at reduced pressure. A total of 1.8 g (9.7 mmol) of the azide was reduced using this procedure to give I-1-6 as a yellow oil: 1H NMR (CDCl3) δ8.66 (d, 1H, 4.2 Hz), 7.82 (td, 1H, 7.7, 1.7 Hz), 7.68 (d, 1H, 8.1 Hz), 7.37-7.40 (m, 1H), 3.44 (t, 2H, 14.3 Hz), 1.41 (br s, 2H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)CCc1ccc2c(c1)OCO2

Procedure:
3 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100 ml of chloroform. An equimolar amount of m-chloroperbenzoic acid was added to the solution under stirring under reflux with dry ice/alcohol to conduct the reaction for 1 h. 300 ml of chloroform and 300 ml of water were added thereto and then sodium carbonate was added to the mixture until the aqueous layer became alkaline. After separation of the layers, the chloroform layer was washed with water twice and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The oily product was purified according to silica gel column chromatography (chloroform: methanol=20:1) to obtain 1.6 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH2:1]([C:3]1[N:4]([CH2:15][C:16]2[CH:35]=[CH:34][C:19]3/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=4[O:23][CH2:24][C:18]=3[CH:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)c[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCc1nc(-c2ccccc2)cn1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 92.9 %

Procedure:
Using 2-ethyl-4-phenyl-1H-imidazole (Tetrahedron Letters, 1967, p 265, 47 mg, 0.273 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (90 mg, 0.273 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (114 mg, 92%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: OCC(F)(F)F
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(COCC(F)(F)F)[nH]c(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (1 g, 6.23 mmol), 2,2,2-trifluoroethanol (2.235 mL, 31.14 mmol) and cesium carbonate (6.09 g, 18.68 mmol) in dimethylformamide (10 mL) was heated in a microwave oven at 100° C. for 30 min. The mixture was filtered and the volatiles were removed in vacuum. The residue was treated with diluted HCl (pH 4.5) and cooled to 0° C. The resulting crystals were collected by filtration and dried in vacuum cabinet to yield the title compound, 0.92 g (66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7][C:6]2=[CH:13][C:14]=1[O:15][CH3:16].[CH3:17][N:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:30])[O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:29][O:28][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C@H:19]1[C@@H:7]([C:8]([OH:10])=[O:9])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:14]([O:15][CH3:16])[CH:13]=2)[C:11](=[O:12])[N:18]1[CH3:17])=[O:30]
Reactant: COc1cc2c(cc1OC)C(=O)OC(=O)C2
Reactant: CN=Cc1ccccc1NC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
4,5-Dimethoxyhomophthalic anhydride (9, 1.16 g, 5.2 mmol) was added to a solution of 8 (1 g, 5.2 mmol) in chloroform (10 mL) and the mixture was stirred for 2 h at room temperature. The precipitate was filtered, washed with chloroform (2×10 mL) and dried to yield acid cis 10 (750 mg, 35%): mp 212-213° C. (dec). IR (KBr) 1737, 1626, 1599, 1578 cm−1; 1H NMR (300 MHz, methanol-d4) δ 7.80 (s, 1 H), 7.51 (s, 1 H), 7.29 (m, 2 H), 7.11 (t, J=7.0 Hz, 1 H), 6.83 (m, 2 H), 5.33 (d, J=6.60 Hz, 1 H), 4.45 (d, J=6.60 Hz, 1 H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.65 (s, 3 H), 2.80 (s, 3 H); ESIMS m/z (rel intensity) 851 (35), 459 (13), 436 (100), 415 (6), 215 (15); ESIHRMS m/z MNa+ calcd. for C21H22N2O7, 437.1325; found, 437.1333.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(OC([NH:43][CH2:44][C:45](O)=[O:46])=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH2:43][CH2:44][C:45]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1)=[O:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCC(=O)N1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.026 g, 0.05 mmol) and tert-butoxycarbonylamino-acetic acid (0.0087 g, 0.05 mmol) in dichloromethane (3 mL) was treated with EDCI (0.0104 g, 0.055 mmol) and triethylamine (0.006 g, 0.06 mmol). Reaction mixture was stirred at room temperature for 18 hours and was then partitioned between dichloromethane and an aqueous saturated hydrogenocarbonate solution. The dichloromethane layer was then washed with aqueous 10% citric acid, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (26 mg, 77%).
Reaction SMILES: [CH3:1][SH:2].[OH-].[K+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1>CN(C)C=O.C(O)C>[CH3:1][S:2][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
28.3 g of methylmercaptan are dissolved in 500 ml of dimethylformamide at 0° C., under nitrogen. 37.4 g of potassium hydroxide, dissolved in 150 ml of ethanol, are then added dropwise at -10° C., after which 94.5 g of 4-chloronitrobenzene are added. The reaction mixture is warmed to 100° C. and stirred at this temperature for 8 hours. It is then stirred into 5 kg of ice water. The precipitate is filtered off with suction, washed, dried and recrystallised from methanol. Yield: 86.2 g of yellow crystals of melting point 71°-73.5° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O:14][C:15](=[O:29])[CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C>[CH2:23]([CH:16]([C:17]1[CH:18]=[CH:19][C:20]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[CH:21][CH:22]=1)[C:15]([OH:29])=[O:14])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCC(C(=O)OCC)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)O)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Yield: 18 %

Procedure:
The ethyl ester of the titled product was prepared in 18% yield by reacting phthalic anhydride and α-hexylbenzeneacetic acid ethyl ester in the presence of aluminum chloride in DMF according to the general procedure of Example 55. The title product was then prepared according to the procedure of Example 26 in yield from the intermediate ester, m.p. 118°-121° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:30]3[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH2:36])=[CH:32][CH:31]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
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: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc(C(N)=O)cc3)cn2)CC1

Procedure:
To a degassed solution of 4-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.80 mmol, 1.0 equiv; intermediate C13/step 1) in dimethoxyethane (15 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.38 g, 5.60 mmol, 2.0 equiv; commercially available from CSIRO Molecular Science, Australia), tetrakis(triphenylphosphine)palladium(0) (97.0 mg, 0.08 mmol, 0.03 equiv) and an aqueous solution of 2 M sodium carbonate (5.6 mL) and the reaction mixture heated by microwave irradiation under Ar to 130° C. for 30 min. The crude reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases washed with a sat. solution of sodium chloride (2×50 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol providing 0.31 g (28%) of the title compound. MS (ISP): 398.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: COc1cccc(Cl)c1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C=O)c(Cl)c1F
Temperature: -70 °C

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 20 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After one hour at −70° 3.93 ml DMF in 7 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 15 ml of a 1 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel to yield 0.25 g 2-chloro-3-fluoro-4-methoxybenzaldehyde. Analogously to example 9, the corresponding imine is produced starting from 411 mg (2.6 mmol) 5-amino-2-methylquinolin and 490 mg (2.6 mmol) 2-chloro-3-fluoro-4-methoxybenzaldehyde in toluene. 800 mg (2.4 mmol) [(2-chloro-3-fluoro-4-methoxyphenyl)methylene]-2-methylquinolin-5-amine in THF are added to 0.42 ml (4.8 mmol) of the lithiated 1,1,1-trifluoroepoxypropane at −100° C. analogously to example 9. Typical work up and chromatographic purification on silica gel (acetone in hexane 0% to 50° A)) yield 796 mg and 100 mg of two diastereomers of {[2-chloro-3-fluoro-4-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine.