Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: C[C@@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (R)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (68 mg, 0.25 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (67 mg, 0.25 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.25 mmol), and NMP (280 μL, 3.0 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2R)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.68-8.76 (1H, m), 7.84-7.94 (2H, m), 7.75-7.84 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.28 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.82-3.97 (5H, m), 3.56-3.72 (2H, m), 3.22 (4H, m), 3.14 (1H, m), 2.97-3.10 (1H, m), 2.60-2.72 (1H, m), 2.29-2.42 (4H, m), 1.15 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH:23](/[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCCCC
Product: CCCC/C=C/c1nc(N)c2nc(NC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-methylaminoadenosine (7, 520 mg, 1.23 mmol) and (E)-1-borocatechol)-1-hexene (3.70 mmol). The mixture was purified by column chromatography (20% MeOH in CH2Cl2). Yield 42 mg (1.11 mmol, 9%), mp 161–166÷C; Rƒ 0.60 (20% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.91–6.83 (m, 1H, ═CHCH2), 6.29 (d, 1H, J=15.44 Hz, ═CH), 5.98 (d, 1H, J=7.55 Hz, H-1′), 4.81–4.74 (m, 1H, H-2′), 4.29 (t, 1H, J=5.49 Hz, H-3′), 4.13 (m, 1H, H-4′), 3.82–3.79 (m, 2H, H-5′), 2.97 (m, 3H, NHCH3), 2.29–2.22 (m, 2H, ═CHCH2), 1.52–1.36 (m, 4H, CH2CH2), 0.94 (t, 3H, J=6.52 Hz, CH3); MS m/z 379 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=6.15 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=18.67 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:28][CH:27]([O:29]CC3C=CC=CC=3)[CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:28][CH:27]([OH:29])[CH2:26]2)(=[O:23])=[O:24])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(O)C2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
3-Benzyloxy-cyclobutanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (180 mg, 0.288 mmol) in DCM (10 mL) was reacted with 1M BCl3 (0.86 mL, 0.864 mmol) at −78° C. The resulting mixture was stirred at room temperature for 1 hour. Purification by column chromatography on silica gel (4% MeOH in DCM), followed by preparative HPLC afforded 45 mg of the product (30% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26](=[O:27])[CH2:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)Cc1ccccc1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)Cc3ccccc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and phenacetyl chloride.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:19][C:32](=[O:33])[O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1)OCc1ccccc1
Yield: 97.1 %

Procedure:
Treatment of (±)-[7-(3-trifluoromethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.67 g, 5.06 mmol) with diisopropylethylamine (0.98 g, 7.59 mmol) and benzyl chloroformate (1.04 g, 6.07 mmol) generally according to the procedure described for Intermediate 12 provided 2.1 g (97%) of (±)-benzyl {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a colorless oil. Rf=0.51; Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.08; H, 5.05; N, 3.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=1.O>CC(N(C)C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)CCN2c1nc2ccccc2[nH]1
Temperature: 150 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
A mixture of 5-bromoindoline (1 g) and 2-chloro-1H-benzo[d]imidazole (0.770 g) in DMA/DMF (5 mL, 3/2) was stirred at 150° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (1.1 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.O[N:25]1[C:29]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:18]([NH:25][CH3:29])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
400 mg of 1-benzhydrylazetidin-3-carboxylic acid (synthesized according to the method described in WO2005/49602) was dissolved in 4 ml of dimethylformamide, and 683 mg of triethylamine, 122 mg of methylamine hydrochloride, 304 mg of 1-hydroxybenzotriazole and 431 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[NH:14][C:13](=[S:15])[NH:12][C:11](=[O:16])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH2:8][C:9]2[N:14]=[C:13]([S:15][CH3:19])[NH:12][C:11](=[O:16])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(COC2CCCCC2)[nH]c(=S)[nH]1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Product: CSc1nc(COC2CCCCC2)cc(=O)[nH]1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of 6-cyclohexyloxymethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.2 g), toluene (5.5 mL), iodomethane (0.48 g) and potassium carbonate (0.57 g) was heated at 90° C. in a sealed tube for 16 h. The mixture was partitioned in water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography (40% ethyl acetate in hexanes) to afford 6-cyclohexyloxymethyl-2-methylsulfanyl-3H-pyrimidin-4-one (90 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:31]([NH:39][C:40]([N:11]1[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:13][C:12]1([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of tert-butyl 3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (1.60 g, 3.69 mmol) in THF (37 mL) was added benzoyl isothiocyanate (0.595 mL, 4.43 mmol). After heating to reflux for 5 hours and to 60° C. for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.84 g, 84%) as an orange-yellow foam.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33](=[O:37])[NH:34]2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].N1CCCCC1>C(O)C.C(OCC)(=O)C>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=[C:32]2[C:31]3[C:35](=[CH:36][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[NH:34][C:33]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Reaction time: 6 h
Yield: 34.6 %

Procedure:
A mixture of 3-cyclohexyl-4-morpholinoethoxybenzaldehyde (3 g, 9.45 mmol), 6-acetamido-2-oxindole (3.5 g, 18.9 mmol) and piperidine (5 ml, 50 mmol) in ethanol (35 ml) was held in a sealed tube at 100° C. for 6 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 ml) and filtered to remove excess 6-acetamido-2-oxindole. The filtrate was extracted with 0.5N hydrochloric acid (200 ml) and brine (2×200 ml). The acid wash was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with brine (200 ml), dried over magnesium sulfate and concentrated. The combined solids were dissolved in dichloromethane (25 ml) and precipitated with diethyl ether (500 ml) to afford 1.6 g of a mustard yellow solid. The solid was dissolved in methanol (100 ml) and filtered, affording a yellow solid (which was set aside) and then precipitated with water (400 ml) and filtered. The solid residue was redissolved in methanol and concentrated to a solid. This process was repeated twice to afford ˜82% pure isomer 1 by HPLC. The filtered yellow solid was 77% isomer 2 by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl.Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Oc1ccccc1F
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccccc1OCc1ccc2ccccc2n1
Temperature: 8 °C
Yield: 52.5 %

Procedure:
To a solution of 2-fluorophenol (7.8 g, 70 mmol) in 20 mL ethanol is added 2-(chloromethyl)quinoline hydrochloride (15.0 g, 70 mmol) followed by a solution of potassium hydroxide (7.86 g, 140 mmol) in 50 mL ethanol. The reaction mixture is refluxed overnight. After filtering while still hot, the reaction mixture is cooled to 8° C. to afford 9.3 g (53%) of brown crystals, m.p. 84°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=2[N:34]=1.C(N(C(C)C)CC)(C)C>CCO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=3[N:34]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cc1ccc2oc(Cl)nc2c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)c2nc3cc(C)ccc3o2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.300 g, 0.76 mmol), chloro-5-methyl-benzooxazole (0.135 g, 0.81 mmol), and diisopropylethylamine (0.5 mL, 2.87 mmol) were combined in EtOH (2 mL) in a sealed tube, and the reaction was stirred at 80° C. for 8 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])[C:14]([N+:26]([O-])=O)=[C:13]([F:29])[CH:12]=2)[CH2:6][S@@:5](=[O:30])[CH2:4]1.[CH3:31][C:32]1([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH:38]=O)[CH2:34][CH2:33]1>>[NH2:26][C:14]1[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[CH:16][C:11]([CH2:10][C@H:7]2[C@H:8]([OH:9])[C@@H:3]([NH:2][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([C:32]4([CH3:31])[CH2:33][CH2:34]4)[CH:36]=3)[CH2:4][S@:5](=[O:30])[CH2:6]2)=[CH:12][C:13]=1[F:29]
Reactant: CC1(c2cccc(C=O)c2)CC1
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cccc(C4(C)CC4)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound can be prepared in an analogous manner as described for example 41 steps c) and d) from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol hydrochloride and 3-(1-methyl-cyclopropyl)benzaldehyde to yield the title compound as a yellowish foam: TLC (CH2Cl2-MeOH 9:1) Rf=0.48; HPLC RtG3=1.70 min; ESIMS [M+H]+=559.3; 1H NMR (400 MHz, DMSO-d6): δ 7.22-7.18 (m, 2H), 7.11 (d, 1H), 7.07 (d, 1H), 6.72 (s, 1H), 6.64 (d, 1H), 5.09 (m, 1H), 4.99 (d, 1H), 4.58 (s, 2H), 3.75 (m, 3H), 3.59 (d, 1H), 3.32 (s, 3H), 3.19-3.09 (m, 3H), 2.98 (m, 1H), 2.69 (m, 1H), 2.45-2.25 (m, 4H), 1.36 (s, 3H), 0.83 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[CH3:26]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 6.30 mmol) in CH2Cl2 (50 ml) was added TFA (20 ml) at room temperature. After 2 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetic acid (2.12 g, 95%) as a colorless powder. mp 274–283° C. (dec.); 1H-NMR (DMSO-d6) δ 2.24 (s, 3H), 3.46 (s, 2H), 7.00 (d, J=8.6 Hz, 1H), 7.06 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H1), 7.65 (d, J=8.2 Hz, 1H), 8.12 (s, 1H), 8.50 (s, 1H), 12.22 (br, 1H); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]3)=[N:13][C:14]([C:24]([F:27])([F:26])[F:25])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]3)=[N:13][C:14]([C:24]([F:27])([F:25])[F:26])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C1CCN(c2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(-c2c(-c3ccc(F)cc3)nc(C(F)(F)F)nc2N2CCC(C(=O)O)CC2)c1
Reaction time: 17 h

Procedure:
A solution of ethyl 1-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylate (0.4 g, 0.725 mmol) in tetrahydrofuran (4 ml) was treated with lithium hydroxide monohydrate (0.036 g, 0.87 mmol) in water (0.2 ml) and was stirred for 17 hours. Subsequently the reaction mixture was poured onto ice-cold water, acidified with dilute hydrochloric acid and extracted with dichloromethane (25 ml). Evaporation of organic layer furnished the required product. 1H-NMR (DMSO-d6) δ: 1.39 (m, 2H), 1.64 (m, 2H), 2.09 (m, 1H), 2.84-2.89 (m, 2H), 3.66 (m, 2H), 7.02-7.07 (m, 2H), 7.07-7.13 (m, 2H), 7.37-7.39 (m, 2H), 7.49-7.53 (m, 1H), 7.69 (s, 1H), 7.72-7.74 (d, 1H), 12.25 (br, 1H, D2O exchangeable); MS m/z: 525.0 (M++1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH:15]([CH2:17][CH3:18])[CH3:16].C1C=CC=CC=1.[OH-].[Na+]>CCOCC.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>[CH:15]([CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]#[N:13])([CH2:17][CH3:18])[CH3:16]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CCC(C)Br
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(C)C(C#N)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A mixture of 2-naphthaleneacetonitrile (30.00 g, 0.179 mole), dicyclohexyl-18-crown-6 [1.60 g, 0.0043 mole (2.4 mole %)], 2-bromobutane (50.20 g, 0.366 mole), benzene (80 ml) and sodium hydroxide solution (50%, 80 ml) is stirred at room temperature for 16 hours. The organic layer is diluted with ether (250 ml), separated, washed successively with water, dilute hydrochloric acid and water and dried over sodium sulfate. Evaporation and distillation under vacuum gives α-sec-butyl-2-naphthaleneacetonitrile (34.3 g, 86%); b.p. 130° C. (0.1 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:13][C:8]1[CH:9]=[C:10]([F:12])[CH:11]=[C:6]2[C:7]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]1)=[N:5]2
Reactant: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpiperazin-1-yl)quinoline (40.0 mg, 0.11 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-phenylpiperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.5 Hz), 7.72 (1H, d, J=2.2 Hz), 7.28-7.36 (3H, m), 7.01 (2H, dd, J=8.8, 1.0 Hz), 6.87-6.96 (2H, m), 6.81 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.61 (1H, t, J=2.3 Hz), 3.81-3.88 (4H, m), 3.48-3.57 (4H, m), 3.29-3.45 (4H, m), 3.18 (4H, dd, J=5.8, 4.0 Hz), 2.12 (3H, s). Mass Spectrum (ESI) m/e=517.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:30][NH:31][CH3:32].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:31]([CH3:32])[CH3:30])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)c1ccc(Cl)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 13.9 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Dimethylamine (2M in THF, 0.123 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (15 mg).