Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NC[CH2:8][CH2:9]N(C)C)C.O.[OH:14]N1C2C=CC=CC=2N=N1.[NH2:24][C:25]1[C:26]([O:37][CH3:38])=[CH:27][CH:28]=[C:29]2[C:33]=1[CH:32]([CH2:34][CH2:35][NH2:36])[CH2:31][CH2:30]2.[OH-].[Na+]>CN(C)C=O.O.C(O)(=O)C>[NH2:24][C:25]1[C:26]([O:37][CH3:38])=[CH:27][CH:28]=[C:29]2[C:33]=1[CH:32]([CH2:34][CH2:35][NH:36][C:8](=[O:14])[CH3:9])[CH2:31][CH2:30]2
Reactant: On1nnc2ccccc21
Reactant: COc1ccc2c(c1N)C(CCN)CC2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1N)C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
In substantially the same manner as in Reference Example 38, 2-(7-amino-6-methoxyindan-1-yl)ethylamine was produced from (E)-(7-amino-6-methoxyindan-1-ylidene) acetonitrile. The crude product thus obtained was used, without further purification, for the reaction described below. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.3 g, 17.2 mmol.) and 1-hydroxybenzotriazole monohydrate (2.2 g, 14.4 mmol.) were suspended in N,N-dimethylformamide (30 mL). To the suspension was added, under ice-cooling, acetic acid (0.65 mL). This reaction mixture was stirred for one hour at room temperature, which was again cooled with ice. To the mixture was added dropwise a solution of the above-mentioned crude 2-(7-amino-6-methoxyindan-1-yl) ethylamine in N,N-dimethylformamide (10 mL). The mixture was stirred for 30 minutes, which was poured into water. The mixture was subjected to extraction with ethyl acetate. From the organic layer was extracted the hydrochloride with 2N hydrochloric acid. Then, the aqueous layer thus obtained was adjusted to pH 10 with a 4N aqueous solution of sodium hydroxide. From the aqueous layer, the organic matter was extracted with ethyl acetate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:ethanol=10:1) to afford the title compound (yield 1.6 g, 66%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[C:30]1([C:36]2[N:37]=[CH:38][NH:39][C:40]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:37]1[C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:39]=[CH:38]1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(-n4cnc(-c5ccccc5)c4-c4ccccc4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 84 %

Procedure:
A solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (0.45 g, 1.0 mmol) and 4,5-diphenylimidazole (2.21 g, 10 mmol) in DMF (15 mL) was stirred at 65° C. under N2 for 67 h (reaction almost complete, TLC). Volatiles were evaporated in vacuo, and the residue was chromatographed (MeOH/CH2Cl2, 1:90) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (0.53 g, 83%) and a mixture of 4,5-diphenylimidazole (19 mg) and the title compound (52 mg, 91% total). Recrystallization (iPrOH) gave 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(4,5-diphenylimidazol-1-yl)purine: mp 146-146.5° C.; UV (MeOH) max 279 nm (∈ 18 300), min 267 nm (∈ 16 800); 1H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 8.22 (s, 1H), 7.55-7.57 (m, 2H), 7.35-7.40 (m, 4H), 7.21-7.27 (m, 4H), 6.21 (d, J=5.5 Hz, 1H), 5.80 (“t”, J=5.6 Hz, 1H), 5.58 (“t”, J=5.1 Hz, 1H), 4.41-4.48 (m, 3H), 2.16 (s, 31), 2.15 (s, 3H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.2, 169.5, 169.4, 154.3, 153.5, 147.4, 142.9, 140.5, 139.2, 133.5, 131.1, 131.0, 128.33, 128.28, 128.17, 127.5, 127.2, 124.1, 86.4, 80.7, 73.2, 70.5, 62.9, 20.8, 20.5, 20.4; HRMS m/z 631.1694 (MNa+[C31H28ClN6O7Na]=631.1708). Anal. Calcd for C31H28ClN6O7: C, 59.00; H, 4.31; N, 13.32. Found: C, 58.89; H, 4.45; N, 13.24.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C>O>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:24]([OH:26])=[O:25])=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CSc1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(C=C(C(=O)O)c2cccs2)cc1
Temperature: 85 °C
Yield: 37.3 %

Procedure:
A mixture of acetic anhydride (90 mL), 4-(methylthio)benzaldehyde (13.17 g, 82.2 mmol), 2-(2-thienyl)acetic acid (12.09 g, 83.3 mmol), and triethylamine (8.60 g, 85 mmol) was heated to reflux for 4 hours. The reaction was cooled to 85° C., and water (80 mL) was added through an addition funnel. A brown solid was isolated by filtration and air dried to afford the propenoic acid (8.48 g, 37%): mp 201°-206° C. 1H NMR (DMSO-d6) 300 MHz 12.80 (br s, 1H), 7.77 (s,1H), 7.60 (d, J=5.2 Hz, 1H), 7.09 (m, 5H), 6.92 (d, J=3.3 Hz, 1H), 2.42 (s, 3H). 13C NMR (DMSO-d6) 168.24, 141.60, 141.30, 136.84, 131.08, 130.86, 128.46, 127.86, 125.51, 125.28, 14.52. Mass spectrum: M+H=277.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>O1CCOCC1.C(Cl)Cl>[CH:10]([NH:13][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)([CH3:12])[CH3:11]
Reactant: OCc1ccnc(Br)c1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)Nc1cc(CO)ccn1
Temperature: 110 °C

Procedure:
A mixture of (2-bromo-pyridin-4-yl)-methanol (500 mg, 2.66 mmol), isopropylamine (0.45 mL, 5.32 mmol), NatOBu (790 mg, 7.98 mmol) and Pd(tBu3P)2 (136 mg, 0.26 mmol) in 1,4-dioxane (5 mL) is heated in a microwave reactor at 110° C. for 45 min. The reaction is diluted with DCM (50 mL) and washed with saturated aqueous NH4Cl. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound that is used without further purification. MS (ESI) m/z 167.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:21])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88 %

Procedure:
To a mixture of (2E)-3-(4-methoxy-2-nitrophenyl)acrylic acid (16 g, 0.067 mol) in dry MeOH (150 mL) under nitrogen is added dropwise thionyl chloride (12.3 mL, 0.169 mol) at 0° C. The reaction mixture is refluxed for 3 h then cooled to room temperature. The solvent is removed under reduced pressure and the residue is taken up in EtOAc. The organic layer is washed with 10% aqueous NaHCO3, water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 14 g (88%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.03-8.07 (m, 1H), 7.58-7.60 (m, 1H) 7.51 (s, 1H), 7.16-7.18 (m, 1H), 6.29-6.33 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:35][C:36](=[O:40])OCC)(=[O:34])=[O:33])=[CH:27][C:26]=3[F:41])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:42][CH3:43].[NH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:41])=[CH:27][C:28]([S:32]([NH:35][C:36](=[O:40])[NH:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)(=[O:34])=[O:33])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:42][CH3:43]
Reactant: CCOC(=O)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Reactant: NN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NC(=O)NN4CCOCC4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Ethyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonylcarbamate (76 mg, 0.12 mmol, 1.0 eq) and 4-aminomorpholine (0.045 mL, 0.46 mmol, 4.0 eq) in toluene (2.5 mL, anhyd) were heated at reflux for 2.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water, followed by brine. After drying (MgSO4), the organics were concentrated and purified by chromatography (silica, 0 to 80% EtOAc/Hex, then 10% MeOH/DCM) to provide the title compound (40 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.41-7.16 (m, 4H), 7.03-6.90 (m, 3H), 6.57-6.43 (m, 4H), 4.02-3.98 (m, 2H), 3.71-3.65 (m, 3H), 3.57-3.50 (m, 3H), 3.48-3.38 (m, 1H), 3.31-3.25 (m, 1H), 2.69-2.58 (m, 3H), 1.46 (s, 6H); MS (EI) m/z 710.1 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(CC)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(CC)cc3)cc12

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-chloro-5-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and the mixture is then allowed to return to room temperature and 75 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 75 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 20 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×10 cm3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 440 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)butanamide are obtained in the form of white crystals melting at 240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C.ClC(O)CCCCC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14]
Reactant: OCCCCCCCl
Reactant: COc1cc(N)c2nccc(C)c2c1
Agent: CCCCCC(O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(NCCCCCCO)c2nccc(C)c2c1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred mixture of 1.9 g (0.01 mole) of 6-methoxy-4-methyl-8-quinolinamine and 1.4 g (0.01 mole) of 6-chlorohexanol at 150° was added portionwise over one hr 1.4 ml (0.01 mole) of triethylamine. The mixture was stirred for 1 hr at the same temperature, and then 0.8 g (0.0056 mole) of 1-chlorohexanol was added, followed by the portionwise addition of 0.8 (0.0056 mole) of triethylamine. The mixture was stirred for 1 hr and the procedure was repeated with 0.5 g (0.0037 mole) of 1-chlorohexanol and 0.5 ml of triethylamine. After the mixture was stirred an additional hr, the mixture was allowed to cool, diluted with acetone, filtered, and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane and chromatographed over 70 g of silica gel first with 500 ml of dichloromethane and then with the following solutions of ethyl acetate in dichloromethane: 5% (500 ml), 10% (1 liter), 15% (500 ml), and finally 20% (500 ml). Fractions of the 20% eluant containing the product, Rf(silica--ethyl acetate)=0.3, were combined and concentrated to dryness in vacuo. Recrystallization from 2-propanol afforded 1.6 g (55%) of the title compound, mp 97°-99°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=O)[CH3:7].C(OC(=O)C)(=O)C.OS(O)(=O)=O>O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[N:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:19][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)CCc1ccccc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(CCc2ccccc2)oc1C
Temperature: 90 °C
Yield: 34.8 %

Procedure:
In a 100 mL flask, 4-oxo-3-(3-phenyl-propionylamino)-pentanoic acid methyl ester (10 g, 36 mmol) and acetic anhydride (28 mL) were combined. Following addition of concentrated H2SO4 (1 mL), the solution was heated to 90° C. for 30 min and cooled to ambient temperature. The reaction was slowly diluted with DI water (30 mL, potential exotherm). The reaction mixture was partitioned between CH2Cl2 (150 mL) and water (150 mL). The organic phase was washed with DI water, 10% NaHCO3 (aq), brine (150 mL), and then was dried (MgSO4) and concentrated to a brown oil. The residue was purified by column chromatography (600 mL SiO2, 35% EtOAc/hexanes) to provide the desired product (3.25 g) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.72 (s, 3H), 3.47 (s, 2H), 3.08-2.96 (m, 4H), 2.24 (s, 3H); MS (EI+) 260 (M+H).
Reaction SMILES: O[C:2]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:13][C@@H:14]1[CH2:18]OS(=O)(=O)[N:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[CH3:13][C@@H:14]([NH:15][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:18][N:5]1[CH2:6][CH:7]=[C:2]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:4]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: OC1(c2cccs2)CCNCC1
Solvent: CN(C)C=O
Product: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of 4-hydroxy-4-thiophen-2-yl-piperidine (3.3 g, 18 mmol) and (R)-4-methyl-3-(pyrid-2-yl)-[1,2,3]-oxathiazolidine-2,2-dioxide (3.7 g, 17.5 mmol) was stirred in dimethylformamide (70 ml) at ambient temperature for 40 minutes, then evaporated to dryness in vacuo and the residue dissolved in tetrahydrofuran (30 m) and water (10 ml). Concentrated sulfuric acid (2.9 g) was dropwise added while maintaining room temperature. Thereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion and the resulting suspension stirred at ambient temperature overnight. Water (100 ml) and ethylacetate (100 ml) were added to the reaction mixture and the pH adjusted to 10 with the addition of 0.5N NaOH. The product was extracted with ethylacetate (3×100 ml) and the combined organic layer washed with brine (150 ml), dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained residue was dissolved in acetic acid (300 ml) and heated to 140° C. bath temperature for 3 hours. After cooling to room temperature the mixture was evaporated in vacuo and the residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated in vacuo. Column chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid gave 4.2 g of the title compound as the fumarate salt hemihydrate, m.p. 63°-8° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[N:24]1([C:30]2[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.C(OCC)(=O)C>[N:24]1([C:30]2[CH:31]=[C:32]([NH:42][C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: Nc1cc(-c2ccccc2)cc(N2CCOCC2)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(Nc2cc(-c3ccccc3)cc(N3CCOCC3)c2)n1
Temperature: 100 °C

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine (23 μL, 0.19 mmol) and TsOH—H2O (29.9 mg, 0.157 mmol) were added to a solution of 5-(morpholin-4-yl)biphenyl-3-amine (40 mg, 0.157 mmol) in dioxane (1.5 mL) and then the reaction mixture was heated to 100° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (aq) followed by brine. The aqueous layers were extracted with ethyl acetate, then the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided N-[5-(morpholin-4-yl)biphenyl-3-yl]-4-(trifluoromethyl)pyrimidin-2-amine as a light yellow solid. MS ESI calc'd. for C21H20F3N4O [M+H]+ 401, found 401. 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=4.9 Hz, 1H); 7.61 (d, J=7.6 Hz, 2H); 7.56 (s, 1H); 7.50-7.34 (m, 4H); 7.23 (s, 1H); 7.05 (d, J=4.9 Hz, 1H); 6.88 (s, 1H); 3.92 (t, J=4.5 Hz, 4H); 3.29 (t, J=4.5 Hz, 4H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCOC(C)=O>N1C=CC=CC=1>[C:21]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH2:13][O:14][C:27](=[O:29])[CH3:28])[N:10]=[CH:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 48 h

Procedure:
Alcohol 2 (prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3×1 L), 5% aq. HCl soln. (2×1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The acetate 3 was isolated as a white powder which was sufficiently pure for use in the next step.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(C2CCCCC2)c1C

Procedure:
Cyclohexylamine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting residue was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, and the solids were separated and the solvents removed under vacuum. Purification of the oil yielded the named product, 1H-NMR (CDCl3, ppm): 1.0 bm (2H), 1.23 t (3H), 1.6-1.7 bm (8H), 2.66 s (3H), 4.16 q (2H), 6.39 s (1H), and 7.25 bm (5H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NCCO
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 84 %

Procedure:
100 mg of 6-chloro-N-(3-methoxyphenyl)pyrimidin-4-amine, 27 mg of ethanolamine and 119 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and to the evaporation residue obtained 5 mL of water were added. The mixture obtained was extracted with EtOAc, the phases were separated and the organic phase obtained was dried and subjected to evaporation. 2-(6-(3-Methoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCCC>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=[CH:4][N:5]=2)[N:10]=1
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: C1CNCCN1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CCNCC3)c2n1
Yield: 96.2 %

Procedure:
A solution of 8-bromo-2-methoxy-[1,5]naphthyridine (4.78 g, 20 mmol, prepared as in WO 2006/032466) and piperazine (8.6 g, 100 mmol) in 1-pentanol (20 mL) was heated at 80° C. over night. The mixture was cooled and the precipitate filtered off. The filtrate was diluted with EA (100 mL) and washed with water (20 mL). The aq. phase contains some product, which was extracted with DCM/MeOH 9:1 (3×30 mL). The org. phases were combined, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (EA/MeOH 4:1 to MeOH) to give the desired intermediate (4.7 g, 96%) as yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][CH2:10]1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH2:10][CH2:11]1
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCNc2ccccc2C(=O)N(C)C)CC1
Yield: 62.4 %

Procedure:
A mixture of 3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl methanesulfonate (2 g, 6.06 mmol), 2-amino-N,N-dimethylbenzamide (1 g, 6.06 mmol), prepared as in Example 22, and potassium carbonate (2.1 g, 15 mmol) in 50 mL of acetonitrile was heated at reflux for 30 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (K2CO3) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-{3-[4-(2-methoxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylbenzamide (1.5 g, 3.78 mmol).