Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Se](=O)=[O:12].O>C(O)(=O)C>[CH:1]([C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:12]
Reactant: COC(=O)c1ccc(C)[se]1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C=O)[se]1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
To a solution of methyl 5-methylselenophene-2-carboxylate (5.0 g, 24.6 mmol) in acetic acid (30 mL) was added selenium dioxide (10.84 g, 98.4 mmol) at rt and the mixture was refluxed for 8 h. The cooled reaction mixture was poured into ice cooled water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (9:1) as eluents to give the product as pale yellow color solid (4.0 g, 75%), mp 63-65° C.; 1H NMR (400 MHz, CDCl3): δ 9.84 (1H, s, —CHO), 8.11 (1H, d, J=4.0 Hz, H-3), 7.99 (1H, d, J=4.0 Hz, H-4), 3.92 (3H, s, —COOCH3).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:7]=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=O.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:20])[C:13]=1[N:6]1[C:5]([CH2:3][OH:2])=[C:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=[N:7]1
Reactant: COC(=O)c1c(C(C)C)cnn1-c1c(Cl)cccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a 0° C. solution of 2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazole-3-carboxylic acid methyl ester (2.2 g, 6.8 mmol) in THF (30 mL) is added DIBAL-H (33.7 mL, 1M in toluene). The reaction mixture is stirred at ambient temperature overnight. The reaction is quenched by the addition of methanol and is concentrated under reduced pressure. The residue is partitioned between 5N NaOH and EtOAc. The layers are separated and the organic layer is filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure to give the title compound as a light yellow solid, (1.6 g, 80%). 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.44 (d, 2H), 7.34 (dd, 1H), 4.45 (s, 2H), 3.00 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:10]1[N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12][CH:11]=1>C1COCC1.CN1C(=O)CCC1.CCOCC>[CH2:1]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Mg]Br
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCCCCc1cccc(CCCCCC)n1
Yield: 73 %

Procedure:
A solution of n-hexylmagnesium bromide (2M in Et2O, 3.3 mL) is added to a solution of 6-chloro-2-(trifluoromethanesulfonyloxy)pyridine (435 mg, 1.66 mmol) in THF (7 mL) and NMP (0.5 mL) at 0° C. The reaction mixture turns black and GC inspection indicates quantitative conversion of the substrate after 5 min reacion time. For work-up, the mixture is diluted with Et2O (20 mL) and quenched with brine (20 mL), the aqueous phase is repeatedly extracted with Et2O, the combined organic layers are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexanes/ethyl acetate, 15/1) to afford 2,6-di(hexyl)pyridine as a colorless liquid (301 mg, 73%). 1H NMR (300 MHz, CDCl3): δ 7.47 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.7 Hz, 2H), 2.70 (t, J=7.8 Hz, 4H), 1.68 (m, 4H), 1.32 (m, 12H), 0.88 (t, J=6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 161.9, 136.2, 119.5, 38.5, 31.8, 30.0, 29.1, 22.7, 13.9. IR: 3060, 2955, 2926, 2871, 2856, 1590, 1577, 1456, 1378, 750 cm−1. MS m/z (rel. intensity) 247 (5, [M+]), 218 (7), 204 (22), 190 (23), 177 (100), 134 (12), 120 (44), 107 (15). HR-MS (C17H29N) calcd. 247.229999; found 247.229778.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([CH2:27][C:26](=[O:28])[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([C:29]6[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=6)[CH:24]=5)[O:19]4)[CH2:15][CH2:14]3)=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:35][O:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)=[O:38].COC(C1C=CC(B(O)O)=CC=1)=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]3[CH2:14][CH2:15][C:16]4([CH2:27][C:26](=[O:28])[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([C:29]6[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=6)[CH:24]=5)[O:19]4)[CH2:17][CH2:18]3)=[O:12])[CH:9]=2)[N:4]([C:43]2[CH:44]=[C:39]([CH:40]=[CH:41][CH:42]=2)[C:37]([O:36][CH3:35])=[O:38])[N:3]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1n[nH]c2ccc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc12
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(-n2nc(C)c3cc(C(=O)N4CCC5(CC4)CC(=O)c4cc(-c6cnn(C)c6)ccc4O5)ccc32)c1

Procedure:
The intended compound was produced according to the procedure described in Example 28-2 but using 1′-[(3-methyl-1H-indazol-5-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one and [3-(methoxycarbonyl)phenyl]boronic acid in place of 1′-[(3-methyl-1H-indazol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one and [4-(methoxycarbonyl)phenyl]boronic acid.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].N([O-])=O.[Na+].[ClH:21]>O.Cl[Cu]>[Cl:21][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2ccc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of sodium 7-aminonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 4.08 mmol) in water (6.0 mL) and conc. HCl (6.0 mL) was cooled to 0° C. A premixed solution of NaNO2 (295 mg, 4.28 mmol) in water (3.0 mL) was added slowly, maintaining the temperature close to 0° C. The resulting reaction mixture was stirred at room temperature for 30 min. A solution of CuCl (807 mg, 8.16 mmol) in water (1.0 mL) and conc. HCl (4.0 mL) was then added dropwise over 30 min, maintaining the temperature close to 0° C. The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo and dissolved in a small amount of water. The solids were filtered off and retained. The filtrate was concentrated in vacuo, purified by preparative HPLC and combined with the filtered solids to give the title compound (843 mg, 85%) as a dark grey solid. MS(ESI−) m/z 241.2 (M−H)−.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(Cl)cn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 45 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-(5-chloropyridin-2-yl)piperidin-4-amine dihydrochloride (0.196 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.124 g, 45%). 1H NMR (500 MHz, CDCl3): δ 8.06-8.02 (m, 1H), 7.55-7.49 (m, 2H), 7.47-7.41 (m, 3H), 7.39-7.33 (m, 1H), 6.52-6.45 (m, 1H), 5.24-5.14 (m, 1H), 4.02-3.93 (m, 1H), 3.18-3.06 (m, 1H), 2.49-2.39 (m, 2H), 1.78-1.66 (m, 2H), 1.72 (s, 9H), 1.39-1.28 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 157.4, 146.3, 137.5, 134.1, 131.9, 130.2, 128.9, 125.3, 120.5, 108.2, 107.3, 61.9, 50.5, 44.3, 32.0, 27.8; Mass Spectrum: M−H+ 475.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.I[CH2:32][CH2:33][OH:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:34][CH2:33][CH2:32][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:7][CH2:8]1)[CH3:1]
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CCO)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (125 mg) obtained in Example 221 is suspended in ethanol (5 ml), and thereto are added 2-iodo-ethanol (105 μl) and sodium carbonate (57 mg), and the mixture is stirred at 50° C. for 15 hours. To the mixture is further added 2-iodo-ethanol (53 μl), and the mixture is further stirred at 80° C. for 6 hours. Again, 2-iodo-ethanol (53 μl) is added thereto, and the mixture is stirred at 80° C. for 24 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water, a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2, then ethyl acetate) to give trans-3-[4-(N-(2-hydroxyethyl)-N-methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (53 mg). Subsequently, this product is dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure. The resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (55 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[CH3:24][Zn]Cl>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:24])=[C:3]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH:4]=[CH:5]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Reactant: C[Zn]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of methyl 4-(1-bromo-6-methoxynaphthalen-2-yl)benzoate (300 mg, 0.811 mmol) (see Example 12 step 1), MeZnCl (1.2 mL, 2.40 mmol, 2M in THF) and Pd(PPh3)4 (93.8 mg, 0.0811 mmol) in anhydrous THF (10 mL) was stirred at 60° C. under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous NH4Cl (20 mL), extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (PE/EtOAc=300/1 to 200/1) to give the product (210 mg, yield 85%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:30][C:31]1([CH3:41])[CH2:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:39]([NH2:40])[C:33]=2[O:32]1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:39]3[C:33]4[O:32][C:31]([CH3:41])([CH3:30])[CH2:35][C:34]=4[CH:36]=[CH:37][CH:38]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CCOC(=O)c1cnn2c(Nc3cccc4c3OC(C)(C)C4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-amine (0.088 g, 0.54 mmol), the title compound (0.194 g, 99%) was obtained.
Reaction SMILES: C([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])=[C:11]([C:28]([O:37][CH2:38][O:39][CH3:40])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:10]=1)CC=C)C=C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:29]([F:30])([F:31])[C:28]([C:11]1[CH:10]=[C:9]([CH2:8][NH2:4])[CH:14]=[CH:13][C:12]=1[Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])([O:37][CH2:38][O:39][CH3:40])[C:33]([F:36])([F:35])[F:34]
Reactant: C=CCN(CC=C)Cc1ccc([Sn](CCCC)(CCCC)CCCC)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 35 °C
Yield: 77 %

Procedure:
Compound 7 (622 mg, 906 μmol) was dissolved in dichloromethane (10 mL) and the solution was degassed by nitrogen bubbling over 15 min. The solution was then added to N,N-dimethylbarbituric acid (849 mg, 5.44 mmol) and Tetrakis(triphenylphosphine)palladium(0) (21 mg 18.1 μmol) placed in a two necked flask under nitrogen atmosphere and the resulting mixture was warmed 4 h at 35° C. The solvent was removed under vacuum, the residue dissolved in diethylether (20 mL), and washed with a 0.1M sodium carbonate solution (3×10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified over silica gel using dichloromethane/methanol (95/5) to give 423 mg (698 μmol, 77% yield) of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].C([O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])C.O>C1COCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:15])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a solution of (4-chlorophenyl)acetonitrile (15.1 g, 100 mmol) in THF (250 ml) was added NaH (60% dispersion in oil, 8.0 g, 200 mmol) in 3 portions over 5 minutes. To this was added a solution of 2-chlorobenzoic acid ethyl ester (18.3 g, 100 mmol) in THF (50 ml), dropwise over 10 minutes. The mixture was then heated at 60° C. overnight. After cooling to room temperature, water was added (2×10 ml, bubbling observed), and the reaction was concentrated, in vacuo, to ½ volume. The mixture was diluted with water (125 ml) and methylene chloride (125 ml), adjusted to pH=7 with 3 N aqueous HCl, and the aqueous layer separated and extracted with additional methylene chloride. The combined organics were dried (MgSO4) and concentrated, in vacuo, to give a brown oil (33 g) that began to solidify on standing. After stirring the residue overnight in diisopropyl ether (250 ml), the solid product was collected by vacuum filtration to afford, after drying, in vacuo, title product I-3A-1a (15.2 g, 52%) as a tan solid: −ESI MS (M−1) 288.0; 1H NMR (400 MHz, CD2Cl2) δ 7.74 (d, J=8.30 Hz, 1H), 7.60–7.25 (m, 7H), 5.65 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1F.OS(O)(=O)=O.O>CN(C=O)C>[C:7]([C:9]([C:22]1[C:21]([F:24])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[F:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)C(C)C#N
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C#N)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 150 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A stirred suspension of anhydrous K2CO3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150° C. and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled further (to ca. 12° C.) with a mild ice bath. The yellow reaction mixture is at this point treated with 3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over 20 min. The deep purple reaction mixture is stirred overnight at ambient temperature. The deep green reaction mixture is then poured into ice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/v H2SO4/H2O while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then chilled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et2O (1.2 L), taking care to dissolve the large clumps of green-black solid (which accounts for a significant amount of the product). The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:33][C:34]1[N:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][N:35]=1.[BH4-].[Na+]>ClCCCl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH:32][CH2:40][C:37]2[CH:36]=[N:35][C:34]([NH2:33])=[N:39][CH:38]=2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)cn1
Reaction time: 20 h
Yield: 24.9 %

Procedure:
Sodium triacetoxy borohydride (883 mg, 4.166 mmol) was added slowly at 0° C. to a solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine (Intermediate B, 500 mg, 2.083 mmol), 2-aminopyrimidine-5-carbaldehyde (256 mg, 2.083 mmol) in DCE (10 mL) and stirred for 20 h. After completion, the solvent was evaporated. The residue was dissolved in Methanol (15 mL), NaBH4 (237 mg, 6.249 mmol) was added slowly at 0° C. and stirred for 3 h. After completion, the solvent was evaporated, the residue was dissolved in ice water (20 mL) and extracted with EtOAc (2×20 mL) The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by prep HPLC to afford 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine (180 mg, 25%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.85 (q, 1H), 0.90 (quin, 1H), 1.73 (m, 1H), 2.07 (m, 1H), 2.75 (brs, 1H), 3.53 (s, 2H), 5.04 (s, 2H), 6.46 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.33 (m, 1H), 7.42 (m, 4H), 8.11 (s, 2H). Mass (M+H): 347.3
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:30][OH:31]>>[CH3:13][C:12]1[C:7]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:30][OH:31])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: N[C@H]1CCCC[C@H]1CO
Product: Cc1nc(NCc2ccccn2)nc(N[C@H]2CCCC[C@H]2CO)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using rac-[(1R,2S)-2-aminocyclohexyl]methanol instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, methanol-d6) δ ppm 1.35 (bs, 2H), 1.50 (bs, 6H), 1.89 (bs, 3H), 2.20 (bs, 3H), 3.40-3.48 (m, 1H), 3.60-3.68 (m, 1H), 4.10-4.18 (m, 1H), 4.64 (bs, 2H), 7.26 (t, J=5.64 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.75 (d, J=7.79 Hz, 1H), 8.46 (d, J=4.83, 1H); MS (ESI) m/z 342.8 (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[C:11](Cl)=[O:12].[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:14][N:15]([C: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)=[O:12])[C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CN(C(=O)c1ccc2ccccc2c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2-naphthoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 413.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:13]C)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].[OH-].[Na+]>CO.O.[Na]>[C:1]1([S:7][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C=C/C(=O)OC
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CC(=O)O)Sc1ccccc1
Temperature: 120 °C
Yield: 32.6 %

Procedure:
0.25 g of sodium in small pieces, in 50 ml (0.5 mol) of thiophenol, is heated to 90°-95° C whilst stirring, and 52.5 ml (0.55 mol) of methyl crotonate are added dropwise. The mixture is heated further for 1 hour at 120° C and 85 g (boiling point/5 mm Hg = 137°-138° C) of the resulting ester are distilled in vacuo. 53 g (0.25 mol) of this ester in solution in 200 ml of methanol are hydrolysed with 16 g (0.4 mol) of NaOH in 200 ml of water. The mixture is heated for 2 hours under reflux, the alcohol is evaporated in vacuo, the residue is taken up in water and the product is precipitated with concentrated HCl and extracted with ether. The extract is washed with water and dried, and 32 g (65%) of a white oil are obtained.