Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-:13].[Na+].[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O>CC(CC(C)C)C#N.C1CCCCC1>[CH:11](=[O:13])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C)cc1OC
Reactant: O=C([O-])[O-]
Agent: CC(C)CC(C)C#N
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1ccc(C=O)cc1OC
Temperature: 25 °C
Yield: 110.4 %

Procedure:
In a 5 L flask equipped with mechanical stirrer and reflux condenser were placed 100.0 g (0.657 mol) of 3.4-dimethoxytoluene, 2.64 L of cyclohexane (0.25 M), and 104.5 g (0.986 mol) of anhydrous sodium carbonate. The apparatus was flushed with argon. The mixture was stirred and heated to reflux while continuing to sweep argon gently over the solution. A mixture of 197.28 g of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 0.69 mol, 1.05 eq.) and 4.08 g 2,2'-azobis- 2,4-dimethylpentanenitrile (VAZO-52, 0.016 mol, 0.025 eq.) were gradually added through a funnel to the solution over a period of 120 minutes. After addition of the mixture was complete, the reaction mixture was allowed to stir for another thirty minutes at reflux. The solution was allowed to cool to room temperature and the solids was removed by vacuum filtration. The receiver flask contained 122.0 g of sodium carbonate monohydrate. The cyclohexane was removed in vacuo. To the residue was added 600 mL of water and 600 mL of tetrahydrofuran. The solution was mechanically stirred and heated to reflux for two hours. After cooling, the tetrahydrofuran was removed in vacuo. The aqueous solution was extracted three times with 200 mL of methyl tert-butyl ether. The organic extract was dried with anhydrous magnesium sulfate. After removing the magnesium sulfate by vacuum filtration through a fritted funnel, the methyl tert-butyl ether was removed in vacuo to provide 120.6 g of crude veratraldehyde (0.725 mol, 110.4% yield) that was shown to be 74.9% pure by GC and 77.4% pure by HPLC. The product was purified by bulb-to-bulb distillation to provide 72.2 g of veratraldehyde (0.434 mol, 66.1% yield, 94.1% pure by GC, 97.2% pure by HPLC). The distilled material was dissolved in 1.5 volumes (108 mL) of toluene and 1.5 volumes of cyclohexane and allowed to sit overnight in a freezer. The crystals were collected the following morning by vacuum filtration. The filter cake was washed liberally with cyclohexane. After drying in vacuo, 53.7 g (0.323 mol, 49.2% yield, 100.0% pure by HPLC, 99.2% pure by GC) of white crystalline veratraldehyde was collected.
Reaction SMILES: [C:1](OC(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[H][H]>[Cr].[Cu]>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C
Agent: [Cr]
Agent: [Cu]
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 275 °C
Reaction time: 7 h

Procedure:
Into a 20 liters autoclave were charged 4770 g of isopropyl isostearate [Emery 2310, isopropyl isostearate, available from the Emery Co., Ltd. of U.S.A.) and 239 g of a copper-chromium catalyst (Nikki Co., Ltd.). Thereafter, hydrogen gas was charged into the autoclave at a pressure of 150 kg/cm2, followed by heating the reaction mixture to 275° C. After the hydrogenation under conditions of 150 m kg/cm2 and 275° C. for about 7 hours, the resulting reaction product was cooled, from which the solid catalyst was removed thereby obtaining 3500 g of a crude product. The crude product was distilled under reduced pressure to obtain 3300 g of colorless, transparent isostearyl alcohol as a distillate of 80° to 167° C./0.6 mmHg. The thus obtained isostearyl alcohol (monomethyl-branched isostearyl alcohol) had an acid value of 0.05, a saponification value of 5.5, and a hydroxyl group value of 181.4. The alcohol had absorption peaks at 3340 and 1055 cm-1 in the IR analysis and at delta 3.50 (broad triplet, --CH2 --OH) in the NMR analysis (CCl4 solvent). It was found from the gas chromatography that the alcohol was a mixture of alcohols which had about 75% of an alkyl group containing 18 carbon atoms in total with the remainder having 14 to 16 carbon atoms in total and whose branched methyl groups were positioned almost at the central portion of the alkyl main chain.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:14](=[O:16])[CH:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:26])[F:25])[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:8]=2)=[O:11])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:31][CH2:30][CH2:29]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Reactant: C1CNC1
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CCC2)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and azetidine (CAN 503-29-7) as starting materials and isolated (23 mg, 41%); MS (ESI, m/z): 428.6 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CSC.B>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a suspension of 4-iodobenzoic acid (14.88 g) in dry tetrahydrofuran (75 ml) was added borane dimethyl sulphide (6.12 ml ) dropwise under a nitrogen atmosphere. The reaction mixture was heated under reflux for 1 hr, after which time the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dissolved indichloromethane (20 ml) and added to a suspension of the pyridinium chlorochromate (14.23 g) in dichloromethane (100 ml). The resulting mixture was heated under reflux for 1 hr and allowed to cool to room temperature. The resulting mixture was diluted with diethyl ether (250 ml) and filtered through a plug of arbocel. The filtrate was evaporated under reduced pressure, and the crude product was purified by column chromatography over silica gel eluting with dichloromethane to afford the title compound as a white solid (11.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccccc2)CC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichloro-phenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and benzoyl chloride (0.038 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-benzoylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (103 mg, 80%) as a white solid, mp 63-66° C. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.94 min, m/z 471.32 (65), 469.31 (M++H, 100). HPLC tr=2.35 min (98.01%) 1H NMR (270 MHz, CDCl3) δ 1.35 (2H, m, CH2), 1.55 (2H, m, CH2), 1.76 (6H, m, 3CH2), 2.00 (2H, m, CH2), 2.87 (2H, m, CH2), 3.17 (1H, m, ½CH2), 3.87 (1H, br t, ½CH2), 4.19 (1H, m, CH), 4.43 (1H, m, ½CH2) 6.79 (1H, d, J=8.6 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.25 (1H, m ArH), 7.35 (1H, br d, NH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 23.81, 29.36, 32.26, 33.17 (CH2), 39.60 (CH), 40.78 (CH2), 43.70 (CH), 47.79 (CH2), 118.00, 120.65, 124.43, 124.88, 126.21, 128.57, 130.85, 130.87, 132.74, 133.06, 148.97, 153.09 (ArC), 163.63 and 174.71 (C═O).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]([Mg]Br)[CH3:9].C(Br)C.[Mg].[Cl-].[NH4+]>C(OCC)C>[NH:2]=[C:1]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC[Mg]Br
Reactant: COC(=O)CC#N
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCC(=N)CC(=O)OC

Procedure:
Methyl cyanoacetate (99 g.) was added to a stirred solution of ethyl magnesium bromide [prepared by the method well known in the art, from ethyl bromide (328 g.) and magnesium (71 g.)] in diethyl ether, at such a rate that vigorous reflux was maintained. The mixture was then heated at reflux for 40 hours and then treated with a saturated aqueous solution of ammonium chloride (3000 ml.). The ethereal layer was separated off and the aqueous layer was extracted with diethyl ether. The combined ethereal layers were dried over sodium sulphate, the solvent was removed in vacuo, and the residue distilled under reduced pressure to give methyl 3-iminovalerate (33 g.), b.p. 100°-120° C./20 mm Hg.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(O)(=O)C.O>[Br:10][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C1NCc2ccsc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1NCc2cc(Br)sc21
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A solution of 4H-thieno[2,3-c]pyrrol-6(5H)-one (1.0 g, 7.2 mmol) in acetic acid (9 mL) and water (7 mL) was cooled to 0° C. Bromine (407 μL, 7.92 mmol) was added and the reaction was maintained at 0° C. for 1.5 h. At completion, water (30 mL) was added and the mixture was and extracted with EtOAc (2×50 mL). The combined organics were washed with 5% aq. Na2SO3 (30 mL), sat. aq. NaHCO3 (30 mL) and brine (30 mL), then dried over Na2SO4, filtered, concentrated. The crude material was purified by flash chromatography over silica gel (5% MeOH/DCM) to yield 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.3 g, 83% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.28 (s, 1H), 4.39 (s, 3H); MS (EI) m/z=140.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11]C(=O)C(F)(F)F)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[NH2:11]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(Br)ccc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of N-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide (1.3 g, 3.97 mmol) in CH3OH (30 mL) was treated with potassium carbonate (1.099 g, 7.95 mmol), and the mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and poured into water, 1N aq HCl was added to adjust to pH 6, and the mixture was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4, and the drying agent was filtered off and solvent was removed in vacuo to give the title compound as a yellow solid (0.57 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][N:13]([CH2:15]N(C)C)[CH3:14]>O1CCOCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)CN(C)C
Reactant: Oc1ccc2ccccc2c1
Solvent: C1COCCO1
Product: CN(C)Cc1c(O)ccc2ccccc12

Procedure:
A mixture of 2-hydroxynaphthalene (20.18 g), N,N,N',N'-tetramethyldiaminomethane (19.10 ml) and 1,4-dioxane (200 ml) was heated on a steam bath for 24 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in 2M hydrochloric acid and washed with ethyl acetate, neutralised with concentrated sodium hydroxide solution and extracted with dichloromethane to give a solid which was recrystallised from petroleum ether, b.p. 60°-80° C. to give 2-hydroxy-1-(dimethylaminomethyl)naphthalene, m.p. 79°-80° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:14]([F:17])([F:16])[F:15])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2CC(O)(C(F)(F)F)ON=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:14]([F:16])([F:15])[F:17])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OC1(C(F)(F)F)CC(c2ccc(F)cc2)=NO1
Agent: OC1(C(F)(F)F)CC(c2ccccc2)=NO1
Product: Fc1ccc(-c2cc(C(F)(F)F)on2)cc1
Yield: 97.5 %

Procedure:
As described for Example 1b, 3-(4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol (35.6 g, 142.9 mmol), instead of 3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline, was converted to the title compound (32.2 g, 98%) which was obtained as a light brown solid. MS: m/e=298.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:37])=[O:36]
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccc(Cl)cc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,4-dichlorobenzenesulfonyl chloride (28 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,4-dichlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.2 mg). MS m/z 442 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1>[Si:21]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:10][OH:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: Cc1cccc(CO)c1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A solution of 3-methyl-1,2-benzenedimethanol (4.16 g, 27.3 mmol) obtained from Example 22-(1) in tetrahydrofuran (50 ml) was cooled to 0° C., and imidazole (1.86 g, 27.3 mmol) and tert-butylchlorodimethylsilane (4.12 g, 27.3 mmol) were added thereto. The mixture was stirred at room temperature for 3 hours, and then after adding water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, then the solvent was distilled off under reduced pressure, and the residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (4.93 g, 68% yield) as a colorless oil.
Reaction SMILES: Cl.N[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.N([O-])=[O:26].[Na+]>Cl.O1CCOCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:3](=[O:26])[NH:4][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[CH3:13]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc(N)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a mixture of 90 ml of 2% hydrochloric acid and 60 ml of dioxane was dissolved 3.50 g (10 mmol) of 2-amino-3,4-diethoxycarbonyl-6-phenylpyridine hydrochloride. A solution of 0.83 g (1.2 eq.) of sodium nitrite dissolved in 3 ml of water was added dropwise thereto. The mixture was stirred at room temperature for 4 hours and left standing overnight. The solvent was distilled off. The resulting crystals were collected by filtration with water. The crystals were recrystallized from ethanol, to give pale yellow prisms.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:7]=2[C:8](O)=[O:9])=O)[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>>[CH:1]1([C:4]2[C:6]3[C:7](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:8](=[O:9])[NH:19][N:18]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)C2CC2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(C3CC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-cyclopropanecarbonyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1.C(N(CC)CC)C>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[NH2:33][C:29]1[CH:28]=[C:27]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]3[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=3[C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])=[CH:3][C:2]=2[F:1])[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cnc(Nc2ccc(O)c(F)c2)c(C(=O)Nc2ccccc2)c1
Reactant: Nc1cc(Cl)ccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cnc(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
365 mg of a mixture of 2-(3-fluoro-4-hydroxyphenylamino)-5-methyl-N-phenylnicotinamide and the des-methyl analog and 4-chloropyridin-2-amine (264 mg, 2054 μmol) were dissolved in NMP (5.0 ml) and triethylamine (0.75 ml, 5381 μmol) was added. The flask was fitted with a reflux condenser, placed in a preheated oil bath (185° C.-190° C.), and stirred under argon. After about 22 hours, more 4-chloropyridin-2-amine (250 mg, 1.95 mmol), DMAP (171 mg, 1.40 mmol), triethylamine (0.30 ml, 4.1 mmol), and NMP (1 ml) were added, and stirring was continued at 190 C for another day. The reaction was then cooled to room temperature and quenched with water (20 ml). The water was decanted, and the residual solid was collected with DCM and MeOH, concentrated, and purified on silica gel (50:1→25:1 DCM/MeOH→15:1 DCM/2 N ammonia in MeOH) to afford the desired 2-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-5-methyl-N-phenylnicotinamide along with the des-methyl analog. This mixture was taken to the last step.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:22]([CH2:24][C:25]([NH2:27])=[S:26])#[N:23].CN1CCOCC1>C(O)C>[NH2:18][C:17]1[C:14]([C:15]#[N:16])=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]3)=[CH:20][CH:19]=2)[C:24]([C:22]#[N:23])=[C:25]([SH:26])[N:27]=1
Reactant: CC1(C)OCC(COc2ccc(C=C(C#N)C#N)cc2)O1
Reactant: N#CCC(N)=S
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1

Procedure:
0.43 g (1.51 mmol) of the compound from Example 2A, 0.38 g (3.78 mmol) of cyanothioacetamide and 0.38 g (3.78 mmol) of 4-methylmorpholine are dissolved in 15 ml of ethanol, and the mixture is stirred under reflux for 6 h. After cooling, the reaction solution is concentrated using a rotary evaporator, and the residue is chromatographed on silica gel 60. After removal of by-products (mobile phase gradient cyclohexane→cyclohexane/ethyl acetate 1:1), the product fractions are eluted (mobile phase gradient ethyl acetate→ethyl acetate/methanol 20:1). This is followed by fine purification via preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:26]1([C:29]([N:22]2[CH2:23][CH2:24][C@H:20]([O:19][C:17]3[CH:18]=[C:13]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]5)[CH:14]=[N:15][CH:16]=3)[CH2:21]2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)C5CC5)C4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60, 0.05 g, 0.139 mmol) in dry DCM (1.5 mL) was added cyclopropanecarbonyl chloride (0.015 g, 0.139 mmol) followed by TEA (0.035 g, 0.347 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.032 g, 59%) as a colorless foam. MS: 392.2 (M+H+).