Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2C(O)=O.C(=O)(O)[O-].[Na+].[I-:22].[Na+].II>ClC(Cl)C.O.ClCCl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:22]
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: [I-]
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: FC(F)Oc1ccc2[nH]nc(I)c2c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 84.2 %

Procedure:
To a mixture of 5-(difluoromethoxy)-1H-indazole-3-carboxylic acid (1 g, 4.38 mmol), and sodium bicarbonate (1.22 g, 563 μL, 14.5 mmol) in dichloroethane (10.0 mL) and water (10.0 mL) were added in one portion sodium iodide (1.71 g, 11.4 mmol) and iodine (1.45 g, 5.7 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 45 minutes. After cooling to 25° C. the mixture was diluted with dichloromethane then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to an off-white solid which was dissolved in dichloromethane, hexane added to promote solid formation and allowed to stand. The solid formed was separated by decanting the mother liquor and dried to give 5-(difluoromethoxy)-3-iodo-1H-indazole (1145 mg, 3.69 mmol, 84.3%) as a white fluffy solid. MS (M−H)−=308.9; 1H NMR (CDCl3) δ: 7.52 (d, J=9.1 Hz, 1H), 7.28-7.36 (m, 1H), 6.57 (t, J=73.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>CCCCCC>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:21]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:22])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)N=C=O
Solvent: CCCCCC
Product: CC(C)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 63 %

Procedure:
A mixture of 14 g (0.06 mole) of 2-amino-5-chlorobenzophenone and 40 ml of isopropyl isocyanate was refluxed for 3 hrs. The solid that formed was suspended in 25 ml of hexane, and then collected on a filter and recrystallized from ethanol to give 12.0 g (63%) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea as colorless needles: mp 190°-192°; 1H nmr (CDDl3) δ1.19 ppm (d, J=6 Hz, 6H), 3.98 ppm (m, 1H), 4.95 ppm (m, NH), 7.2-7.8 ppm (m, 7H), 8.5 ppm (d, J=10 Hz, 1H) and 10.1 ppm (NH); 13C nmr (DMSO-d6) δ195.4 ppm (C=O) and 153.9 ppm (NHCO).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][C@H:5]([NH2:10])[CH2:6][N:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[CH2:20]([O:22][C:23]([CH:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1)=[O:24])[CH3:21].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:10][C@H:5]([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:4][C:3]([CH3:12])([CH3:11])[CH3:2])[CH:34]=1)=[O:24])[CH3:21]
Reactant: CN(C)C[C@@H](N)CC(C)(C)C
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(C=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN[C@H](CN(C)C)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of (S)-4,4,N1,N1-tetramethyl-pentane-1,2-diamine hydrochloride salt (Intermediate 2, 0.921 g, 4.73 mmol) in methanol (10 mL) cooled in an ice bath (0° C.) was added triethylamine (2.19 mL, 15.7 mmol) and the solution was stirred at this temperature for 25 minutes. To this cooled solution was added 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (0.937 g, 3.15 mmol) in methanol (35 mL) after which the solution was allowed to warm to room temperature and stirred for 2 hours. The solution was cooled to 0° C. and sodium cyanoborohydride (0.461 g, 7.3 mmol) and acetic acid (4 mL) were added and the solution was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated under reduced pressure, partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 2-{3-[((S)-1-Dimethylaminomethyl-3,3-dimethyl-butylamino)-methyl]-benzyl}1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester, which was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:19][C:18]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([CH2:13][CH2:14][CH:15]=O)=[N:8][C:7]=3[CH:17]=2)[CH2:3]1.[N+]1([O-])C2C=C3C(=[CH:32][C:24]=2[N+:23]([O-])=[C:22](N)N=1)CCC3.CO.C[CH2:39][O:40]C(C)=O>>[CH3:1][CH:2]1[CH2:19][C:18]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([CH2:13][CH2:14][CH2:15][N:23]4[CH2:22][CH2:39][O:40][CH2:32][CH2:24]4)=[N:8][C:7]=3[CH:17]=2)[CH2:3]1
Reactant: CCOC(C)=O
Reactant: Nc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Reactant: CC1Cc2cc3nc(CCC=O)n[n+]([O-])c3cc2C1
Solvent: CO
Product: CC1Cc2cc3nc(CCCN4CCOCC4)n[n+]([O-])c3cc2C1

Procedure:
Morpholine (0.64 mL, 7.3 mmol) was added to a solution of aldehyde 101 (0.47 g, 1.8 mmol) in EtOH (20 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (0.35 g, 5.5 mmol) was added and the mixture stirred at 0° C. for 30 min, then HOAc (0.5 mL) was added and the mixture stirred at 20° C. for 30 min. The solvent was evaporated and the residue partitioned between DCM and water, the organic phase was dried, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give (i) starting material 101 (83 mg, 17%) and (ii) alcohol 103 (134 mg, 28%) as a white solid: mp (MeOH/EtOAc) 70-71° C.; 1H NMR δ 8.21 (s, 1H, H-9), 7.71 (s, 1H, H-5), 3.78 (t, J=6.1 Hz, 2H, CH2O), 3.20-3.28 (m, 2H, CH2), 3.15 (t, J=7.2 Hz, 2H, CH2), 2.64-2.78 (m, 3H, H-7, CH2), 2.35 (br s, 1H, OH), 2.12-2.19 (m, 2H, CH2), 1.19 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 165.7, 154.6, 148.7, 147.3, 132.3, 122.6, 114.4, 62.1, 41.2, 40.9, 35.0, 30.6, 24.7, 20.2. Anal. calcd for C14H17N3O2.¼H2O: C, 63.7; H, 6.7; N, 15.9. Found: C, 63.7; H, 6.6; N, 15.9%; and (iii) 1-oxide 102 (331 mg, 55%) as a yellow gum: 1H NMR δ 8.22 (s, 1H, H-9), 7.70 (s, 1H, H-5), 3.60 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.21-3.28 (m, 2H, CH2), 3.05 (br t, J=7.4 Hz, 2H, CH2), 2.65-2.77 (m, 3H, H-7, CH2), 2.47-2.54 (m, 6H, 3×CH2N), 2.11 (p, J=7.3 Hz, 2H, CH2), 1.19 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 165.7, 154.4, 148.5, 147.5, 132.3, 122.7, 114.4, 66.7 (2), 55.1, 53.5 (2), 41.2, 40.9, 35.2, 35.0, 24.7, 20.2; MS (FAB+) m/z 392 (MH+, 100%), 311 (20); HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1978, found 329.1978.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[CH2:23]=[C:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[F-].[K+].O>CS(C)=O>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][C:24](=[CH2:23])[CH2:25][CH2:26]3)=[C:3]([C:21]#[N:22])[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5]2)=[N:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C=C1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=C1CCC(COc2c(C#N)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)CC1
Reaction time: 48 h
Yield: 68.1 %

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (0.35 g, 1 mmol) and (4-methylene-cyclohexyl)-methanol (0.252 g, 2 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (5 ml) and potassium fluoride (0.116 g, 2 mmol) was added to the clear solution. The resulting mixture was stirred at 20° for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product (0.3 g, 68%) was isolated by chromatography on silica gel eluting with a solution of 15% of ethyl acetate and 15% of acetone in hexane. MS: 440, r.t.: 3.0.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[CH3:26][NH:25][CH2:24][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])(=[O:16])=[O:15])[CH:12]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)cc1-c1cccnc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-1-[(2-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (202 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol-water to give the title compound as a white solid (yield 157 mg, 90%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C(O)(=[O:23])C.OO.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:23])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Agent: OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 51.6 g (0.178 mol) of 2-propionyl-3-hydroxy-5-(4-(methylthio)phenyl)cyclohex-2-en-1-one (prepared as in U.S. Pat. No. 4,555,263) in 150 mL of methylene chloride and 150 mL of glacial acetic acid was added 20.15 g (0.178 mol) of 30 percent hydrogen peroxide dropwise over twenty minutes. The reaction temperature rose from 20° to 28° C. at which point, the reaction mixture was placed in a cold water bath. After 20 minutes, an additional 6.75 g (0.0595 mol) of 30 percent hydrogen peroxide was added dropwise and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with 150 mL of methylene chloride, washed thrice with 250 mL portions of water and then with 200 mL of aqueous sodium bicarbonate. The organic layer was separated and dried over Na2SO4 and the solvent removed in vacuo leaving 51.6 g (94.8 percent of theoretical) of the above named product melting at 111°-117° C. Recrystallization of the residue from 2-propanol gave the pure product in a yield of 46.1 g (84.7 percent of theoretical). The product melted at 116°-117° C.; Rf -0.07 (silica gel, 50:50 ethyl acetate-hexane and 1.0 percent acetic acid), 1H NMR (CDCl3): δ 1.1 (t, 3H, --CH2CH3), 2.70 (s, 3H, CH3SO--), 2.7-3.7 (m, 7H, ring protons and --CH2CH3), 7.25-7.70 (m, 4H, ArH), 18.1 (s, 1H, OH).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Pat. No. 4,665,171) and 1.3 equivalent of oxalyl chloride in 200 mL dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 μL/milliequivalent of acetic acid derivative) resulting in vigorous gas evolution. After 45 minutes all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h under vacuum.
Reaction SMILES: [C:1](/[N:3]=[C:4](\[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28](OC)=[O:29])[CH2:6]1)#[N:2].[NH2:38][OH:39]>CO>[C:1](/[N:3]=[C:4](\[N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:18]2)=[O:12])[C@@H:7]([C:28]([NH:38][OH:39])=[O:29])[CH2:6]1)#[N:2]
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Reactant: NO
Solvent: CO
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)[C@H]2CCN(/C(=N/C#N)N3CCCCC3)C[C@@H]2C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL). The reaction mixture was stirred at rt for 2 h. LCMS showed the reaction was done. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O to give the product. MS (ESI): (M+H)+=507.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C]=O>O1CCCC1>[C:1]([C:4]1[O:5][C:6]([CH:11]=[CH:10][C:9]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccco1
Reactant: C=CC(=O)OC
Agent: [C]=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(C)=O)o1
Reaction time: 7 h
Yield: 16 %

Procedure:
Charged in a stainless steel autoclave having an inner capacity of 200 ml were 5.5 g of 2-acetylfuran, 1.72 g of methyl acrylate, 0.038 g of Rh4 (CO)12 and 50 ml of tetrahydrofuran, followed by supply of carbon monoxide under 30 kg/cm2. Reaction was carried out at 220° C. for 7 hours. Tetrahydrofuran and unreacted 2-acetylfuran were removed from the obtained light brown solution by distillation under reduced pressure, and the residue was separated and purified by silica gel column chromatography. From a fraction eluted with methylene chloride was obtained 0.62 g of methyl β-(5-acetyl-2-furyl)acrylate (3) (the yield was 16%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH2:14][O:15][CH3:16])[CH:12]2[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]3)=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:16][O:15][CH2:14][CH:13]1[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:3][CH:4]=3)[CH:12]1[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]2
Reactant: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Br)cc1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2=O)cc1
Temperature: 120 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl 1-(4-bromophenyl)-6-(methoxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (Intermediate IX, 890 mg, 2.33 mmol) in 1,4-dioxane (15 mL), was added 2-pyrrolidinone (0.177 mL, 2.33 mmol), (±)-trans-1,2-diamine (0.139 mL, 1.16 mmol), CuI (221.3 mg, 1.16 mmol) and potassium carbonate (643 mg, 4.66 mmol) under nitrogen atmosphere. The reaction mixture was heated at 120° C. for 36 h. After completion of the reaction as confirmed by TLC, the solvent was removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford pure tert-butyl 6-(methoxymethyl)-1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (600 mg, 66%) as a viscous oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.[OH:34][C:35]1[C:39]([CH:40]=[O:41])=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:40]([C:39]1[C:35]([O:34][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=4)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=3[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=2)=[N:36][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=1)=[O:41]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
A mixture of methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-(methanesulfonyloxy)benzoate (1.50 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.56 g), potassium carbonate (0.41 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 2 hrs. The reaction mixture was acidified by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3 to 1:1, v/v) to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-(methanesulfonyloxy)benzoate as pale-yellow crystals (0.80 g, yield 41%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 136-137° C.
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[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1>C(O)C.O1CCCC1.CO.[Pd]>[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[CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 96 h
Yield: 97.2 %

Procedure:
5-Methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)indole (9.00 g, 37 mmol) was dissolved in 190 mL of ethanol/tetrahydrofuran/methanol (10:10:1). 10% palladium on carbon (2.2 g) was added, and the reaction mixture was hydrogenated at 40 p.s.i. in a Parr shaker for 96 hours. The mixture was filtered through celite, the catalyst was washed with ethanol, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (5-10% 2M ammonia-methanol/dichloromethane) to provide 8.79 g (97%) of the title compound. MS(m/e): 245 (M+). EA calculated for C14H19N3O: C, 68.54; H, 7.81; N, 17.13. Found: C, 68.40; H, 7.52; N, 16.90.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:11][C@@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:6][CH2:7]2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: O[C@H]1CCc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O[C@H]2CCc3ccc(Cl)cc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A solution of (S)-6-chloroindan-1-ol (0.45 g, 2.67 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (112 mg, 2.8 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (0.41 g, 2.94 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred, filtered, and dried. Purification by silica gel chromatography (dichloromethane) yielded 365 mg of 2-fluoro-5-((S)-6-chloroindan-1-yloxy)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12].[CH3:13][O-:14].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12]
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C)[n+]([O-])c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-Bromo-6-methyl-4-nitro-pyridine 1-oxide (4 g, 17 mmol) was dissolved in methanol (anhydrous, 100 ml), and sodium methoxide (1.8 g, 33 mmol) was added. The mixture was stirred at room temperature for 90 minutes, diluted with water (90 ml) and concentrated under reduced pressure to half of its volume. The mixture was extracted with DCM (5×), the combined organic phases were dried (sodium sulfate) and concentrated to dryness under reduced pressure to yield 3.3 g of yellow crystals, 15 mmol, 88%) MS(APCI) m/z=217.9 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C@@H:10](NC(=O)OCC1C=CC=CC=1)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.FC(F)(F)S([N:44]=[C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=O)=O.O>O1CCCC1.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C@@H:10]([NH:44][C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[N:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:11][NH:12][C:13]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of 2-benzyl 1-tert-butyl {(2S)-3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxo-1,2-propanediyl}biscarbamate (1.58 g) in tetrahydrofuran (28 ml) was treated with 10% palladium on carbon (0.75 g) under a hydrogen atmosphere for 2 hours at room temperature. After the catalyst was filtered off, the filtrate was concentrated in vacuo to give a crude oil, which was dissolved in tetrahydrofuran (28 ml). To the solution were added triethylamine (2.04 ml) and di-tert-butyl ({[(trifluoromethyl)sulfonyl]imino}methylene)biscarbamate (2.86 g) successively at room temperature. The mixture was stirred at room temperature overnight. To the reaction mixture was added water to quench the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give di-tert-butyl {[((1S)-2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}-2-oxoethyl)amino]methylylidene}biscarbamate (1.53 g) as an amorphous solid.