Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[C:22]1([S:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:22]1([S:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:34])=[CH:31][CH:30]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Sc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Sc2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of dry methylene chloride, under nitrogen, and cooled to 0° C. is added 5.0 ml of triethylamine followed by a solution of 2.16 g of 4-(phenylthio)benzoyl chloride (Reference Example 34) in 30 ml of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.92 g of the desired product as a solid. M+H 397.1 M+Na 419.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14](O)=[O:15])[CH:11]([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:9]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@H:10]([C:14]([NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CN
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 3.21 g of the H-Gly-OEt.HCl dissolved in 10 ml of DMF, under cooling at -5° C., 5.00 g of Boc-Val-OH, 3.10 g of HOBT and 4.79 g of WSC.HCl were added, and the mixture was stirred at -5° C. for one hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, successively washed three times with 1N hydrochloric acid, once with saturated aqueous sodium chloride, three times with 5% aqueous sodium hydrogen carbonate, three times with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 5.93 g (yield: 85.2%) of Boc-Val-Gly-OEt melting at 91.5° to 93° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[NH:4][N:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]2[N:4]([CH3:18])[N:3]=[C:2]([CH3:1])[C:6]=2[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15].[CH3:18][N:3]1[C:2]([CH3:1])=[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1c2c(nn1C)CCN(C(=O)OC(C)(C)C)C2
Product: Cc1nn(C)c2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 37.97 %
Yield: 44.3 %

Procedure:
To a solution of tert-butyl 3-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (7.50 g, 29.84 mmol, 1.0 eq) in acetone was added K2CO3 (13.00 g, 3.0 eq) and iodomethane (2.20 mL, 1.2 eq). The reaction mixture was heated to reflux for 1.5 h and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 90:1 (v/v) DCM/MeOH) to give the title compounds tert-butyl1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.0 g, 37.97%) and tert-butyl 2,3-dimethyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.5 g, 44.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 252.32 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20](O)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([O:41][C:42](=[O:65])[NH:43][C@@H:44]([C:54]1[S:55][C:56]([C@@H:59]([NH2:64])[C:60]([F:63])([F:62])[F:61])=[CH:57][CH:58]=1)[CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:39]=[CH2:40].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:38]([O:41][C:42](=[O:65])[NH:43][C@@H:44]([C:54]1[S:55][C:56]([C@@H:59]([NH:64][C:20](=[O:21])[C@H:6]([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])[C:60]([F:61])([F:62])[F:63])=[CH:57][CH:58]=1)[CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:39]=[CH2:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc([C@@H](N)C(F)(F)F)s1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc([C@@H](NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (3.2 g, 10.6 mmol) in dichloromethane (70 mL) was cooled to −15° C., and then was added N-methylmorpholine (1.17 mL, 10.6 mmol) and isobutyl chloroformate and the mixture was stirred for 30 minutes. A solution of prop-2-en-1-yl[(1R)-1-{5-[(1S)-1-amino-2,2,2-trifluoroethyl]thiophen-2-yl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]carbamate (3.1 g, 7.07 mmol) and Hunig's base (1.48 mL, 8.48 mmol) in dichloromethane (70 mL) cooled to −15° C. was added to the mixed anhydride solution. The mixture was allowed to warm up to room temperature by stirring overnight. Sodium bicarbonate was added and the phases were separated using a phase separator and concentrated under reduced pressure. The crude was purified on silica gel using 10% to 60% ethyl acetate in hexane to provide the title compound as an oil. MS: m/z=742.2 (MNa+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)CC(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol) in DMF (5 mL) at rt under nitrogen was added sodium hydride (80 mg, 2 mmol, 60%). After stirring at rt for 10 min, 4-chloro-3-nitropyridine hydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EtOAc (50 mL) and washed with water, 10% aqueous lithium chloride solution, and then brine (1×30 mL each). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc to give the title compound (150 mg, 60%) as a yellow-orange solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.63 (d, 1H, J=6 Hz), 7.09 (t, 1H, J=9.2 Hz), 6.92 (d, 1H, J=6 Hz), 6.55 (dd, 1H, J=13.2, 2.4 Hz), 6.45 (dd, 1H, J=9.2, 2.4 Hz), 5.61 (s, 2H); MS (ESI+) m/z 250.18 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[CH3:39]>CN(C)C=O>[Cl:38][C:34]1[C:33]([CH3:39])=[C:32]([CH2:31][N:13]2[C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=3[N:11]=[C:12]2[C:14]([F:17])([F:15])[F:16])[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)-3-chloro-2-methylbenzene (1.500 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). Purification on a silica gel column (10-50% EtOAc in hexane) failed to produce pure material. The fractions containing product were combined and the solvent was removed under reduced pressure to afford methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (2.03 g, 4.34 mmol, 95% yield) (only 87% pure). A portion of this material (165 mg) was purified by RP-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give pure desired product (92.3 mg, 0.193 mmol, 4.24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J=2.27 Hz, 1H), 7.28-7.43 (m, 2H), 7.04 (t, J=7.96 Hz, 1H), 5.97 (d, J=7.83 Hz, 1H), 5.71 (s, 2H), 3.93 (s, 3H), 3.66-3.80 (m, 4H), 3.06-3.25 (m, 4H), 2.46 (s, 3H). MS (ES+) m/e 468 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[NH:14][C:15]1[CH:16]=[C:17]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:19]3=[C:20](Cl)[NH:21][C:22]([CH:23]=1)=[C:18]23)([CH3:11])([CH3:10])[CH3:9].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O)CCC>CO>[C:8]([O:12][C:13](=[O:30])[NH:14][C:15]1[CH:16]=[C:17]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:19]3=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[NH:21][C:22]([CH:23]=1)=[C:18]23)([CH3:11])([CH3:10])[CH3:9]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc2c3c(c(Cl)[nH]c3c1)C=NNC2=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(N4CCOCC4)[nH]c3c1)C=NNC2=O
Yield: 22.9 %

Procedure:
Triethylamine (0.039 mL, 0.28 mmol), the title compound of Example 187 (46 mg, 0.14 mmol), morpholine (96 mg, 1.1 mmol) and n-butanol (5 mL) were stirred in a flask with a condenser at 120° C. overnight. The mixture was allowed to stand at room temperature for two more days. The volatile components were removed under vacuum and the resulting mixture was subjected to silica gel chromatography, eluting with 95:5 dichloromethane:methanol to afford the title compound (12.5 mg, 0.032 mmol) as a yellow solid in 23% yield.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[N+]1([O-])CC[O:27]CC1.[OH2:31]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:27])[CH2:20][OH:31])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1cccc(C2(C)CCN(CCCCCC)CC2C)c1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CCCCCCN1CCC(C)(c2cccc(C(O)CO)c2)C(C)C1

Procedure:
1-Hexyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Example 26, 200 mg, 0.67 mmol) was dissolved in a mixture of water (2 mL) and acetone (18 mL). 4-methylmorpholine N-oxide (172 mg, 1.47 mmol) was added with stirring followed by osmium tetroxide (200 μL, 2.5% w/w in tert-butanol). The reaction mixture was stirred at room temperature for 4 hours before the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 mL) and water (25 mL). The organic phase was separated and dried (Na2SO4). Concentration in vacuo gave a residue which was purified by column chromatography on silica gel (10 g) eluted with a gradient of ethyl acetate:hexane:ammonium hydroxide solution (50:49:1 to 60:33:1), followed by ethyl acetate:methanol:ammonium hydroxide solution (94:5:1). Combination of the appropriate fractions and evaporation to dryness in vacuo gave the product as a yellow oil (145 mg).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)C>ClCCl>[CH:7]1([CH2:15][CH:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCC1CCCCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCC1CCCCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (490 mg) in dichloromethane (3 mL) was added pyridine (0.25 mL). To the solution was added a solution of 2-cyclooctylethanol (120 mg) in dichlormethane (3 mL) under ice cooling. The reaction solution was stirred at room temperature for 3 hours. To the solution was added diethyl ether, and it was washed in turn with aqueous sodium thiosulfate, 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound. This product was subjected to the subsequent step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][NH:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>C1COCC1.CCOC(C)=O>[CH2:36]([O:35][C:33]([N:14]1[CH2:15][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][C@H:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 105.6 %

Procedure:
To a stirred and ice-cooled mixture of (2R*,3S*,5S*)-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (11.46 g, 31.52 mmol), NaHCO3 (3.97 g, 47.3 mmol), H2O (80.0 ml), and THF (10.0 ml) was added a solution of benzyl chloroformate (Cbz-Cl, 5.92 g, 34.67 mmol) in THF (15.0 ml). A precipitated gummy material was dispersed by adding AcOEt (40.0 ml). After the resultant milky suspension was stirred with ice-cooling for 2.5 hours, the organic layer was separated from the mixture, and the aqueous layer was extracted with AcOEt (40 ml×4). The combined organic layer and AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a yellow oil (16.56 g). This was flash chromatographed over Sir (Merck Kieselgel 60, 200 g). Elution with n-hexane-AcOEt (60:1/30:1/20:1) gave title compound (13.88 g, 88.5%) as a pale yellow oil. IRmax (film): 1735(s), 1700(s), 1498(m), 1290(s), 1253(s), 1100(s), 775(s), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.42-7.28(m, 6H), 7.28-7.16(m, 4H), 5.98-5.87(m, 1H), 5.31-5.10(m, 2H), 3.92(dm, J=13.6 Hz, 1H), 3.63(dd, J=10.1, 9.7 Hz, 1H), 3.60(s, 3H), 3.53(dd, J=10.1, 7.9 Hz, 1H), 3.09(ddd, J=11.2, 5.6, 5.6 Hz, 1H), 3.12-2.95(m, 1H), 2.24-2.06(m, 1H), 2.06-1.93(m, 1H), 0.87(s, 9H), 0.02(s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCN2CCOCC2)ccc1N
Reaction time: 24 h

Procedure:
4-amino-3-methoxybenzoic acid (Aldrich; 5 g, 29.9 mmol) was stirred and dissolved in DMF (100 mL) at ambient temperature. 4-(2-aminoethyl)morpholine (Aldrich; 4.7 mL, 35.8 mmol) was added followed by DIPEA (15.6 mL, 89.7 mmol) and HATU (13.7 g, 36.0 mmol) causing a slight exotherm. The brown solution was stirred for 24 h and the solvent evaporated to a brown gum.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([O:27]CCCC)(=[O:26])=[O:25])[CH2:21]1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S-])#N.[K+:35]>COCCOC.O>[CH2:13]([O:12][CH2:11][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([O-:27])(=[O:26])=[O:25])[CH2:21]1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+:35]
Reactant: CCCCOS(=O)(=O)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Agent: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=S(=O)([O-])C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Yield: 74.2 %

Procedure:
Using the same reaction conditions, procedure and work up as described Intermediate I-25b (below), butyl 3-(1,3-bis(benzyloxy)propan-2-yl)cyclobutane-1-sulfonate (0.1 g, 0.22 mmol) was reacted with KSCN (24 mg, 0.24 mmol) and DME-water mixture (2 mL) to afford 0.07 g of the product (83% yield).
Reaction SMILES: OS(O)(=O)=O.[NH:6]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9](=[O:11])[NH2:10].[C:25](O)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.O>[NH:6]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9](=[O:11])[NH:10][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Concentrated H2SO4 (0.2 ml) was added to a solution of Cbz-Asn-OH (10 g, 37.6 mmol), trityl alcohol (20 g, 75.2 mmol), and acetic anhydride (7.1 ml, 75.2 mmol) in acetic acid (114 ml) and the reaction was stirred for 1 hour at 50° C. The solution was cooled and slowly added to 1.0 L of cold H2O. The white precipitate was filtered, dissolved in EthOAc (250 ml), washed with H2O, dried over Na2SO4 and filtered. The resulting white solid was crystallized from EthOAc/hexane to give 13 g (68%) of a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:19])[C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1ccnc(Nc2ccc(I)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(N(C)c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 2 h

Procedure:
To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid (4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl chloride (2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide (30 μL) dropwise and the mixture was stirred for 2 hours during which cessation of evolution of gas was observed. The resulting solution was diluted with dichloromethane (50 mL) and the solvent was removed under reduced pressure to provide the title compound as an oil which became a solid upon storing in the refrigerator.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)(SC2C=CC=CC=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[CH:7][CH:8]=2)[CH2:3]1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1ccc2c(c1)CN(C)C(=O)C2(Sc1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CN(C)C(=O)C2c1cc(Cl)cc(Cl)c1

Procedure:
A solution of 2-methyl-4-(3,5-dichlorophenyl)-4-(phenylsulfanyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolone (1.0 g) and nickel chloride hexahydrate (3.8 g) in methanol-tetrahydrofuran (3:1, 50 ml) was cooled to 0° C. Sodium borohydride (0.66 g) was added in small portions during 30 minutes at a temperature not exceeding 5° C. The slurry was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (200 ml) and aqueous sodium hydroxide (2M, 200 ml). The organic phase was dried and concentrated to dryness leaving crude 2-methyl-4-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydro-3(2H)-isoquino-linone (0.7 g). The crude product was purified by chromatography on silica gel using a mixture of dichloromethane and ethyl acetate (8:2) as eluent. Crystallization from methanol afforded the pure title compound, m.p. 163-165° C.