Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:22][CH2:23][CH2:24][OH:25])[C:9]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27].[C:29](O)(=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:29]([N:1]([CH2:26][CH3:27])[C:2]1[C:7]2[N:8]([CH2:22][CH2:23][CH2:24][OH:25])[C:9]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:30]
Reactant: CC=O
Reactant: CC(=O)O
Reactant: COc1ncc(Nc2nc3cccc(N)c3n2CCCO)c(OC)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(Nc3cnc(OC)nc3OC)n(CCCO)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a mixture of 3-{7-amino-2-[(2,4-dimethoxypyrimidin-5-yl)amino]-1H-benzimidazol-1-yl}propan-1-ol (99 mg, 0.287 mmol), acetaldehyde (90%, 0.178 mL, 2.87 mmol) and acetic acid (0.066 mL, 1.15 mmol) in tetrahydrofuran (2.0 mL) was added sodium triacetoxyborohydride (384 mg, 1.72 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 14 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5.0-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (90 mg, 0.224 mmol, 78%) as a colorless amorphous.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)NCCCCCC(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(C(=O)NCCCCCC(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(5-carboxy-n-pentylaminocarbonyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.ICI>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 9-chloro-6-[1-(ethenyloxy)propyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (65.0 mg, 0.157 mmol) in dichloromethane (1.5 mL) were added diethyl zinc (1.0 M solution in n-hexane, 0.787 mL, 0.787 mmol) and diiodomethane (0.13 mL, 1.57 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained title compound. To the solution of residue in ethyl acetate/MeOH (1.0 mL/0.5 mL) was added 4N hydrochloric acid/ethyl acetate (25 μL). The reaction mixture was stirred at room temperature for 3 hrs. After the mixture was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (7.0 mg, 0.0184 mmol, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.O=P(Cl)(Cl)Cl.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:14][CH2:13][CH2:12][C:6]2=1
Reactant: COc1ccc2[nH]cc(CCNC(=O)CCc3ccc(C(F)(F)F)cc3)c2c1
Solvent: O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3c(c2c1)CCN=C3CCc1ccc(C(F)(F)F)cc1
Yield: 15.4 %

Procedure:
A mixture of 0.61 g (1.57 mmol) N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide and 1 mL POCl3 in 2.5 mL acetonitrile was heated to reflux for 16 h. Water was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to dryness to yield 0.09 g (15%) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH2:11])[CH2:3]1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:11][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:12])([CH3:1])[CH2:3]2)[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)C[C@H](N)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(Cl)nc(Cl)n2)c2ccccc21
Reaction time: 1.5 h
Yield: 59.4 %

Procedure:
To a solution of (1S)-3,3-dimethylindan-1-amine (0.67 g, 4.2 mmol) in THF (3 mL) cooled to 0° C. was added cyanuric chloride (0.874 g, 4.74 mmol) resulting in a white solid. DIPEA (0.724 mL, 4.16 mmol) was added and the yellow mixture was stirred for 1.5 hours. The reaction was quenched with H2O and extracted with DCM (3×). The combined organic layers were dried (Na2SO4), filtered and collected in vacuo to give a pale yellow oil. The residue was; purified by flash chromatography (0 to 25% EtOAc/hexanes) to afford the title compound (0.771 g, 60%) as a white solid. LC/MS: Rt=2.20 min, ES+ 310 (FA standard).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[N:22]=1>CC(O)C.CS(C)=O>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[CH2:32][CH2:33]2)[N:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3ccc(O)cc3)CC2)n1
Yield: 64 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 35 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 64% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 3:7:1.5) with 10% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:36](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[O:23][CH:36]=[N:25][N:24]=4)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4nnco4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 130 °C
Yield: 47.6 %

Procedure:
To a suspension of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (198 mg, 0.395 mmol) and triethyl orthoformate (1 mL, 6.01 mmol) in 1 mL xylenes was added a catalytic amount of p-toluenesulfonic acid. The reaction was heated at 130° C. for 12 h. The reaction was cooled and the mixture was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 2-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole (96 mgs, 48%) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.12 (s, 1H), 8.11-8.10 (m, 1H), 7.97-7.94 (m, 1H), 7.85-7.82 (m, 1H), 7.77-7.75 (m, 1H), 7.67 (t, J=7.83 Hz, 1H), 7.61-7.58 (m, 4H), 7.48-7.45 (m, 1H), 7.29-7.27 (m, 2H), 3.09 (s, 3H); MS (ES): 511.4 [M+H]+ and 533.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24](CC4C=CC(OC)=CC=4)[C:17]=23)[C:12]([CH3:34])=[CH:11][N:10]=1.FC1C=CC(F)=CC=1C1C=C(NC2C3C(=CN(CC4C=CC(OC)=CC=4)N=3)N=CC=2)C(C)=CN=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:34])=[CH:11][N:10]=1
Reactant: COc1ccc(Cn2ncc3nccc(Nc4cc(-c5cc(F)ccc5F)ncc4C)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4cc(-c5cc(F)ccc5F)ncc4C)c3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(2,5-difluorophenyl)-5-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and trifluoroacetic acid (35 mL) were combined and heated at 70° C. for 3 hours, then cooled to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo to give a residue which was dissolved in dichloromethane (75 mL) and was poured into a saturated solution of sodium bicarbonate (50 mL) to give a solid which was collected by filtration and dissolved in ethyl acetate (500 mL), washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give N-(2-(2,5-difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (3H, s) 7.09 (1H, d, J=4.80 Hz) 7.26-7.36 (2H, m) 7.50 (1H, s) 7.75 (1H, ddd, J=9.54, 6.13, 3.28 Hz) 8.24 (1H, d, J=1.26 Hz) 8.35 (1H, d, J=5.05 Hz) 8.43 (1H, s) 8.50 (1H, s) 13.03 (1H, s). MS [M+H] found 337.3.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=CC(OC(F)(F)F)=CC=2)=[O:19])[CH:5]=1)([O-:3])=[O:2].[C:32]([O:35][CH2:36][CH3:37])(=[O:34])C.CO>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18]([NH:20][CH2:21][CH2:26][C:32]([O:35][CH2:36][CH3:37])=[O:34])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCNC(=O)NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
1-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-3-(4-trifluoromethyloxyphenyl)-urea, FAB-MS: M+ =439; TLC: ethyl acetate/methanol (3:1) Rf =0.50.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C(#N)C>[O:30]=[C:29]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
A solution of tert-butyl 4-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate (10.0 mmol) in acetonitrile (30 mL) was added with 1,1′-carbonyldiimidazole (1.95 g, 12.0 mmol) and stirred at room temperature for 12 h. Concentrated in vacuo and was added with water (20 mL) and dichloromethane (100 mL), phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to provide the title compound as white solid (1.18 g, 28% over two steps). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.31-1.40 (m, 4H), 1.42 (s, 9H), 1.44-1.48 (m, 2H), 1.52-1.63 (m, 1H), 1.64-1.89 (m, 8H), 1.93-1.99 (m, 1H), 2.08-2.21 (m, 2H), 2.25-2.32 (m, 1H), 2.89-3.10 (m, 4H), 3.28-3.36 (m, 1H), 3.42-3.53 (m, 2H), 3.54-3.65 (m, 1H). MS (M+1): 421.3.
Reaction SMILES: [Na:1].C[C:3]1(C)[CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])[O:5][CH2:4]1.Cl[C:32]1C(C)=C[N+]([O-])=C(C)C=1C.[F:42][CH2:43]C1(CO)OCCCO1>>[Na:1].[F:42][CH2:43][C:6]1([CH2:9][O:10][C:11]2[C:16]([CH3:32])=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])[O:7][CH2:8][CH2:3][CH2:4][O:5]1
Reactant: OCC1(CF)OCCCO1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Agent: [Na]
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1(CF)OCCCO1
Yield: 12 %

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using 4-chloro-2,3,5-trimethylpyridine 1-oxide and (2-(fluoromethyl)-1,3-dioxan-2-yl)methanol to obtain the title compound (331 mg, 5 steps: 12%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[CH:16]1([C:14](=[O:15])[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:24])[C:4]([OH:25])=[O:3])=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Yield: 60.9 %

Procedure:
As in example 19, a stirred solution of 4-(2-cyclooctyl-2-oxoethoxy)-alpha-oxobenzeneacetic acid ethyl ester (0.318 g) in warm methanol (5 mL) was treated with 1N sodium hydroxide (2 mL). Within 5 minutes water (20 mL) was added, then after the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (2.5 mL) and extracted with dichloromethane (1×40 mL, 1×10 mL). The dried (MgSO4) extracts were evaporated and the resulting solid (0.255 g) was crystallized from diethyl ether-hexane to give 0.178 g of 4-[2-(cyclooctyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:15]2[CH2:16][CH:13]([OH:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.3 g, 14.8 mmol), 3-hydroxyazetidine hydrochloride (3.2 g, 29.5 mmol), and Et3N (4.3 mL, 31.0 mmol) in THF (50 mL) was stirred for 18 h at rt. 3-Hydroxyazetidine hydrochloride (1 g) was added. The reaction mixture was stirred for 24 h at rt and concentrated. The residue was diluted in CH2Cl2/water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (hexane/EtOAc, 1:1) to afford 3 g of the title compound. tR: 0.73 min (LC-MS 2); ESI-MS: 260.1/262.1 [M+H]+ (LC-MS 2); Rf=0.18 (hexane/EtOAc 1:1).
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].C1COCC1.C(Cl)Cl.O(C)S(C(F)(F)F)(=O)=O.[N:44]1C=CC=CC=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]([NH:1][NH2:44])=[S:26])=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: c1ccncc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: NNC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.75 h

Procedure:
To a suspension of the title compound of Example 52 (0.60 g) in 20 mL 1:1 THF:CH2Cl2 at room temperature is added methyl triflate (0.2 mL). The reaction is stirred for 45 minutes after which time everything goes into solution. Pyridine (0.38 mL) is added and then H2S is bubbled in for 1 hour. Nitrogen is then purged through the reaction for 30 minutes. Hydrazine monohydrate (0.28 mL) is added dropwise to the reaction mixture. The reaction is stirred for 1 hour after which time the solution turned from an orange to a pale yellow color and a precipitate is observed. The solid in the reaction is filtered and dried to give the desired product (0.26 g).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:39])[CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:40])[N:16]=2)[CH2:11][CH2:10]1>>[CH:1]1([C:4]([N:36]2[CH2:35][CH2:34][CH:33]([CH2:32][C:31]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:19]5[CH:20]=[C:15]([N:12]6[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]6)[N:16]=[C:17]([NH2:40])[N:18]=5)=[CH:22][CH:23]=4)[CH2:28]3)=[O:39])[CH2:38][CH2:37]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)C5CC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from cyclopropanecarbonyl chloride (Aldrich, Cat. #C116807) and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=518.3.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(=O)C>C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC=CN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 144 h

Procedure:
A futher batch of N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt was prepared substantially according to the previous method except that the following quantities and reaction conditions were used: N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one (racemate) (4.96 g); (-)-3BCS in acetonitrile (1.85M; 9.4 ml); trifluoroacetic acid (2.1 ml); and isopropyl acetate (55 ml). The mixture was stirred at 90° C. for 6 days and then cooled to 0-5° C. and aged for 1 hour. The solid N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt was collected and washed with isopropyl acetate (20 ml). Yield 9.40 g (90%); ee 99.6% (S) isomer. The chiral composition of the remaining liquors was determined as 88% (R), 12% (S).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1([CH3:23])[C:22]2[C:17](=[CH:18]C=C[CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1C=CC=CC=1.O>[CH3:12][C:13]1([CH3:23])[C:14]2[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1](=[O:4])[CH2:21][CH2:22]1
Reactant: CC(=O)O
Reactant: CC1(C)CCCc2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of 350 ml of glacial acetic acid and 170 ml of acetic anhydride was cooled to 0° C. and CrO3, 25.0 g (0.25 mol) carefully added in small portions. The resulting mixture was stirred for 30 minutes before 120 ml of benzene was added. 1,2,3,4-tetrahydro-1,1-dimethylnaphthalene was added slowly as a solution in 30 ml of benzene. Upon completing the addition the reaction was stirred for 4 hours at 0° C. The solution was diluted with H2O (200 ml) and extracted with Et2O (5×50 ml). The combined organic layers were washed with water, saturated aqueous NaCO3, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, and distillation afforded 16.0 g (74%) of the product as a pale-yellow oil, bp 93-96° C./0.3 mm Hg 1H NMR (CDCI3): δ 8.02 (1H, dd, J=1.3, 7.8 Hz), 7.53 (1H, m), 7.42 (1H, d, J=7.9 Hz), 7.29 (1H, m), 2.74 (2H, t, J=6.8 Hz), 2.02 (2H, t, J=6.8 Hz), 1.40 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 120 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 3-bromophenol (1.68 g, 9.77 mmol) in N,N′-dimethylformamide (32 mL), sodium hydride (purity 50%) (516 mg, 10.7 mmol) was added under ice-cold conditions, bromoacetaldehyde diethyl acetal (1.76 mL, 11.7 mmol) was added at 0° C., and the mixture was stirred at 120° C. overnight. The reaction solution was added water at room temperature, and extracted with diethylether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica-gel column chromatography (hexane). The title compound (2.69 g (yield >100%)) was obtained as a yellow oil.