Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:22]([Cl:25])=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:25][C:22]1[C:4]([C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[CH:3][C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[N:24][CH:23]=1
Reactant: CC(NC(=O)c1cc(N)ncc1Cl)c1ccc(OCC(F)(F)F)nc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)c(Cl)cn1
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (10 mg) from 2-amino-5-chloro-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (20 mg, 0.053 mmol, single enantiomer, Step-1) and propionyl chloride (6 mg, 0.080 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (10 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was quenched with saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL×3) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][C:19]=3[F:32])=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:12]=[C:11]2[CH3:37])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.O>C(O)C>[CH2:33]([C:13]1[N:12]=[C:11]([CH3:37])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][C:19]=1[F:32])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 3 h

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.17 g) in ethanol (10 mL) was added sodium tetrahydroboron (0.11 g), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.97 g, 82%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1>C1CCCCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH:3]=[O:4])=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1
Reactant: Cn1c(-c2ccccc2)cc2ccc(Cl)cc2c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: Cn1c(-c2ccccc2)c(C=O)c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of dry N,N-dimethylformamide are cooled to 0° C., under an argon atmosphere, 12 ml (128 mmol) of phosphorus oxychloride are added dropwise and the mixture is stirred at room temperature for 1 h. 13.7 g (51 mmol) of 7-chloro-2-methyl-3-phenylisoquinol-1(2 H)-one are added and the mixture is gradually heated to 110° C. and is maintained at this temperature for 4 h. It is cooled to room temperature, the solvent is evaporated under reduced pressure, 200 ml of diethyl ether and ice are added to the residue, 1N sodium hydroxide is added, the organic phase is separated and the aqueous phase is extracted with 200 ml of dichloromethane. The two organic phases are combined, dried over sodium sulphate and filtered and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and dichloromethane ranging from 80/20 to 50/50 and then with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30. After recrystallizing from cyclohexane, 7.68 g (26 mmol) of white solid are obtained. Melting point: 172°-173° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.5 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.25 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (54 mg, 0.77 mmol, 3.00 equiv), piperidine (11 mg, 0.13 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 36 mg (27%) of the title compounds as a white solid. LC-MS: (ES, m/z): 524 [M+H]+. H-NMR: (300 MHz, CDCl3, ppm) 8.396 (1H, s), 7.721˜7.674 (2H, m), 7.393˜7.316 (1H, m), 7.237˜7.191 (2H, m), 6.923˜6.786 (3H, m), 6.607˜6.570 (1H, d, J=11.1), 5.795 (2H, s), 5.018˜4.919 (1H, m), 4.8˜3.1 (4H, m), 2.465˜2.269 (5H, m), 1.274 (2H, m), 0.887 (2H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C)cn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)CN2Cc1ccccc1
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of 1-benzyl-5-methoxy-3-methylindole (200 mg, 0.796 mmol) in a 1:1 solution (2.4 mL) of acetic acid and tetrahydrofuran was added sodium cyanoborohydride (150 mg, 2.38 mmol) at room temperature. After being stirred overnight, sodium cyanoborohydride (50 mg, 0.80 mmol) was added with additional stirring for 6 h. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the reaction mixture was diluted with ethyl acetate. The separated organic layer was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=100/0 to 90/10) to obtain the title compound (62.4 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.611 g, 1.59 mmol) (from example 124, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.59 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.552 g, 98%) as a yellow semi-solid. MS m/z 353 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:31])([F:30])[C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(Cl)Cl>[F:31][C:9]([F:8])([F:30])[C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (26.3 mL, 342 mmol) was added to a solution of tert-butyl 4-[2-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (29.5 g, 85 mmol) in CH2Cl2 (171 mL). The mixture was stirred at room temperature for 16 h. The solvent was removed by evaporation. The residue was diluted with EtOAc (200 mL), washed with 2 N NaOH (3×100 mL), brine, dried over Na2SO4, and evaporated to give the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(OCc1ccccc1)c1ccc(O)nc1
Temperature: 0 °C

Procedure:
30 g of 6-hydroxynicotinic acid were treated with 500 ml of benzyl alcohol and 1 ml of concentrated sulfuric acid. After boiling at reflux for 3 days, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated, firstly in a water-jet vacuum and then in a high vacuum. The semi-crystalline residue was filtered over silica gel (eluent hexane/ethyl acetate=2:1, then ethyl acetate) and recrystallized from ethyl acetate/hexane. There were obtained 19 g of benzyl 6-hydroxy-nicotinate in colourless crystals, m.p. 178°-179° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:32]([O:33]C(OC)=O)=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1.O.Cl>CO>[ClH:3].[Cl:3][C:4]1[C:32]([OH:33])=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCCc4ccncc4)c(OC)cc23)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
2M Aqueous sodium hydroxide (1.5 ml mmol) was added to a solution of 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline (1.28 g, 2.5 mmol) in methanol (13 ml) and the mixture stirred for 2 hours at ambient temperature. Water was added and the mixture was adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. This solid was dissolved in methylene chloride (30 ml) and methanol (5 ml) and a solution of 5M hydrogen chloride in isopropanol (2.5 ml) was added. The solution was diluted with isopropanol and concentrated under vacuum to a total volume of 10 ml. The resulting solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (924 mg, 70%). 1H NMR Spectrum: (DMSOd6) 2.3(t, 2H); 3.12(t, 2H); 4.0(s, 3H); 4.28(t, 2H); 7.18(d, 1H); 7.4(s, 1H); 7.52(d, 1H); 7.95(d, 2H); 8.32(s, 1H); 8.82(s, 1H); 8.84(d, 2H); 10.65(s, 1H); 11.65(br s, 1H) MS-ESI: 455 [MH]+
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([CH3:13])[N:6]=1>CN(C=O)C>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([CH3:13])[N:6]=1
Reactant: Cc1cc(CO)cc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO)cc(C)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Sodium methoxide (11.3 mL, 28% solution in methanol) was added to a solution of (2-chloro-6-methylpyridin-4-yl)methanol (1.75 g) in DMF (18 mL), and the mixture was stirred at 80° C. for 12 hours. Subsequently, the reaction mixture was stirred at 120° C. for seven hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 70%) to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C=CC(=C)C.C1(=O)OC(=O)C=C1>>[CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:5]2[CH2:11][CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: O=C1C=CC(=O)O1
Solvent: C=CC(=C)C
Product: CC1=CCC2C(=O)OC(=O)C2C1

Procedure:
In a preferred mode of the process of this invention, 4-methylphthalic anhydride (4-MPA) is prepared. This preparation comprises reacting isoprene and maleic anhydride to form 4-methyl-1,2,3,6-tetrahydrophthalic anhydride (4-MTPA), then reacting this product with sulfuryl chloride in the presence of pyridine to form 4-MPA.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 179. Product was isolated as a tan foam (42 mg, 70%). LCMS (m/e) 501 (M+H); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.58 (d, 1H, J=8.3 Hz), 8.20 (dd, 1H, J=5 Hz), 8.17 (s, 1H), 7.92 (d, 1H, J=7.8 Hz); 7.85 (s, 1H), 7.66 (dd, 1H, J=7.8, 8.6 Hz), 7.28 (m, 1H), 6.95 (m, 2H), 4.03 (t, 2H, J=5 Hz), 3.24 (m, 1H), 2.08 (m, 2H), 1.70 (m, 2H), 1.39 (s, 6H), 1.31 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:22])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([CH3:25])[CH:9]([CH:17]([CH3:18])[CH3:19])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:5]([F:22])[CH:4]=1)#[N:2]
Reactant: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OC(C)(C)C)N(C)Cc1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-[(4-cyano-2-fluorobenzyl)amino]-3-methylbutanoate (7.2 g, 0.023 mol) in DMF (20 mL) was added dropwise to a stirred suspension of sodium hydride (2.2 g, 0.047 mol) in dry DMF (10 mL) at 00° C. The resulting mixture was stirred for 20 min at RT. Methyl iodide (6 mL, 0.094 mol) was then added dropwise at 0° C. and the mixture was allowed to stir for 3 hr at RT. The reaction mixture was quenched in ice water and extracted with ethyl acetate (250 mL). The organic layer was washed with water (3×100 mL) and dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether and ethyl acetate as eluent, affording the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.80 (d, J=10 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 3.79 (d, J=15 Hz, 1H), 3.64 (d, J=15 Hz, 1H), 2.65 (d, J=10.7 Hz, 1H), 2.18 (s, 3H), 1.44 (s, 9H), 0.92-0.83 (m, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH3:32])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18ClN5O2, 407.9
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24])=[CH:20][CH:19]=1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Product: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Yield: 98 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) using N-dodecyl-4-nitrobenzamide and hydrogen at a pressure of 20 bar at 50° C. gave the title compound (98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (t, 1H, J=5.6 Hz), 7.53 (d, 2H, J=8.7 Hz), 6.50 (d, 2H, J=8.7 Hz), 8.30 (s, 2H), 3.16 (m, 2H), 1.36-1.52 (m, 2H), 1.12-1.33 (m, 18H), 0.83 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 4.87 min (HPLC purity 99.7%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8](/[CH:10]=[CH:11]\[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12](/[CH:11]=[CH:10]\[C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:25])[N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(/C=C\c2c(-c3ccc(F)cc3)noc2C)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)O)n(C)n1
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 5-{(Z)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (6.29 mmol) in THF (14 mL) was added lithium hydroxide monohydrate (37.79 mmol) in water (18 mL) and the resulting mixture stirred for 12 h. After evaporation the mixture was diluted with water (10 mL) and citric acid (10%) and extracted with ethyl acetate (2×80 mL). The combined extracts were then dried with sodium sulfate, filtered and evaporated to afford 5-{(Z)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid (mg, 85%) as a white solid. MS: m/e=328.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C:13]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:24](=[O:32])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:22][C:20]1([CH3:23])[CH2:19][C:18]2[C:13]([O:12][C:8]3[CH:9]=[C:10]([F:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:14][C:15]([C:24](=[O:32])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)=[CH:16][C:17]=2[O:21]1
Reactant: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 87.3 %

Procedure:
To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (949 mg, 2.15 mmol) in 12 mL THF was added 4 mL of 1.0 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (800 mg, 87% yield). LCMS for C21H19FN4O5 m/z 427.20 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1.[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:5]2[CH:4]=[CH:3][CH:2]=[C:7]3[C:6]=2[CH:11]=[C:10]([S:35][C:32]2[CH:33]=[CH:34][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=2)[CH:9]=[N:8]3)[CH2:13][CH2:14]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccnc3ccc(Br)cc23)CC1
Reactant: CC(C)c1ccc(S)cc1
Product: CC(C)c1ccc(Sc2cnc3cccc(N4CCCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1

Procedure:
The compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate (0.5 g, 1.23 mmol) and 4-isopropylbenzenethiol (0.19 g, 1.23 mmol). Yield: 0.27 g (46%) of the title compound that was used in the next step without further purification. HPLC 89%, RT: 3.67 min (5-99% MeCN containing 0.1% TFA over 3 min); MS (ESI+) for C28H35N3O2S m/z 478.2 (M+H)+.