Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:24]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[OH:25])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc([N+](=O)[O-])cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-nitrobenzoic acid
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1coc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-pyridyl)ethylmercaptan and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
Add 3-phenyl-2,3-dihydro-1H-indole (Yamamoto, Y et al. Bull Chem. Soc. Jpn 44, 1971, 541-545) (0.158, 0.81 mmol), 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.266 g, 0.81 mmol), Et3N (0.161 g, 0.23 mL, 1.5 mmol) and DMAP (0.011 g, 0.09 mmol) to CH2Cl2 (25 mL) and stir at ambient temperature under N2 overnight. Dilute the reaction to 150 mL with CH2Cl2 and pour into saturated NaHCO3 (50 mL). Separate the organic layer and extract with 1M HCl (2×75 mL). Wash with brine, separate dry (MgSO4) filter and evaporate the filtrate. Chromatograph the residue on the ISCO using a gradient EtOAc-hexane system (0-100%) to give 0.167 g of the title compound. Mass spectrum (m/e) (M+1) 487.1492; Found: 487.1479.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[N:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH2:5]([NH:4][C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:23][S:20]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:22])=[O:21])[CH3:6]
Reactant: NS(=O)(=O)N1CCCCC1
Reactant: CCN=C(SC)N1CC(CC)C=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)N1CCCCC1)N1CC(CC)C=N1
Yield: 0.4 %

Procedure:
0.70 g (1 mol equiv.) 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.61 g (1.05 mol equiv.) piperidine-1-sulfonic acid amide were added to 7 mL acetonitrile, and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 1.12 g (96%) piperidine-1-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.45-1.72 (m, 8H), 3.07-3.17 (m, 5H), 3.48-3.57 (m, 2H), 3.73 (dd, J=11.0, 7.7 Hz, 1H), 4.08-4.19 (m, 1H), 6.58 (br.s., 1H), 6.87 (d, J=1.3 Hz, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CCN1CCC(=O)CC1
Reactant: CC(C)Oc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2cccc(OC(C)C)c2)CC1
Temperature: -20 °C

Procedure:
To a stirred solution of 1-bromo-3-(1-methylethoxy)benzene (5.0 g, 23 mmol) in anhydrous tetrahydrofuran (50 ml) at −78° C. under an atmosphere of nitrogen was added n-butyllithium (1.6M in hexane, 13.7 ml, 22 mmol) dropwise. The reaction mixture was stirred for 1 h at −78° C., before N-ethyl-4-piperidone (2.95 ml, 22 mmol) was added dropwise at −78° C. over 15 minutes, and the reaction mixture was then warmed to −20° C. over 30 minutes. The solution was poured onto 2N aqueous hydrochloric acid (35 ml) and this was further acidified to pH 1 with concentrated hydrochloric acid. Hexane (50 ml) was added and the two layers were separated. The organic layer was discarded and the pH of the aqueous layer was adjusted to 14 using sodium hydroxide pellets. The basic aqueous layer was extracted with hexane:diethyl ether (1:1, 5×50 ml) and the combined extracts were dried (MgSO4) and concentrated to give the title compound as a crude oil (4.2 g, 73% crude yield) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:6][C:7]1[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2].[OH2:38]>CO.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=1)[CH2:6][C:7]1[C:8]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2]
Reactant: O
Reactant: CCCSc1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: CCCS(=O)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester (Example 135) (116 mg, 0.18 mmol) was dissolved in methanol (2 mL) and water (2 mL) followed by the addition of magnesium bis(mono peroxy phthalate hexahydrate) (MMPP) (267.1 mg, 0.54 mmol). The resulting mixture was stirred at room temperature overnight. The sample was diluted with methylene chloride and washed one time with water andone time with brine. The organic phase was dried, filtered and concentrated by rotary evaporation. The resulting sample was dried overnight under vacuum. (Biotage Horizon HPFC chromatography system, SiO2, 70:80 hexanes: ethyl acetate) gave a whit solid (80 mg, 72%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:9])[CH3:8]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:9][CH2:7][CH3:8]
Reactant: C=CC(=O)OC
Reactant: CCN
Solvent: CO
Product: CCNCCC(=O)OC
Temperature: -20 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure to afford the title compound as a colorless liquid (2.41 g, 30% yield). 1H NMR (CDCl3) δ 1.11 (t, 3H, J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t, 2H, J=6.58 Hz), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:17][CH2:16]1)=[O:14])[CH:9]=[CH:8]2.C([O-])(O)=O.[Na+].[CH3:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([CH3:46])[C:39]=1[S:47](Cl)(=[O:49])=[O:48]>C1COCC1.O.C1COCC1.O>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH3:37])[C:39]([S:47]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[C:11]=2[N:10]([CH2:12][C:13](=[O:14])[N:15]2[CH2:20][CH2:19][C:18]4([CH2:21][CH2:22][N:23]([C:26]5[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=5)[CH2:24][CH2:25]4)[CH2:17][CH2:16]2)[CH:9]=[CH:8]3)(=[O:48])=[O:49])=[C:40]([CH3:46])[CH:41]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NCc1cccc2ccn(CC(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)NCc2cccc3ccn(CC(=O)N4CCC5(CC4)CCN(c4ccncc4)CC5)c23)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
A mixture of 2-(7-(aminomethyl)-1H-indol-1-yl)-1-(9-(pyridin-4-yl)-3,9-diazaspiro-[5.5]undecan-3-yl)ethanone (220 mg, 0.53 mmol, 1.0 equiv.) and NaHCO3 (134 mg, 1.59 mmol, 3.0 equiv.) in THF-water(1:1, 20 ml) was added at 0° C. to a solution of 2,6-dimethyl-4-methoxyphenylsulfonyl chloride (136 mg, 0.58 mmol, 1.1 equiv.) in THF (5 ml), and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with sat. NaCl solution (40 ml) and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by column chromatography (silica gel; 6-8% MeOH/DCM), and the desired product was thus obtained in the form of a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To an ice cold solution of 1-benzhydrylazetidin-3-ol 9a (1.0 g, 4.2 mmole) in DMF (10 ml) was added 60% dispersion NaH in mineral oil (0.25 g, 6.3 mmole). After 30 min at 0° C., 5 ml more DMF was added along with methyl iodide (0.39 ml, 6.3 mmole). The ice bath was removed, and the reaction was stirred at room temperature (rt). After 1.5 hr, the reaction was poured into brine and extracted with Et2O (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting Hexanes/EtOAc (1:1) to give 919 mg (92%) of a colorless oil which crystallized on standing. 1H NMR (DMSO-d6) δ 7.42 (4H, d, J=7.3 Hz), 7.27 (4H, t, J=7.3 Hz), 7.13 (2H, t, J=7.3 Hz), 4.39 (1H, s), 3.95 (1H, p, J=5.8 Hz), 3.35 (2H, t, J=6.3 Hz), 3.11 (3H, s), 2.75 (2H, t, J=5.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)n1c(=O)sc2cc(F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)n1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
6-Fluoro-3-(1-methylethyl)-2-(3H)-benzothiazolone (299 g) was dissolved in concentrated sulfuric acid (8750 g), and the resultant mixture was cooled to a temperature of -5° to 0° C. 98% fuming nitric acid (d=1.52) (94.68 g) was dropwise added thereto while maintaining the temperature at 0° C., followed by stirring for 1 hour. The reaction mixture was poured into ice-water (16 kg), and the precipitated crystals were collected by filtration. Crystals were washed with water and dried to give 325 g of 6-fluoro-3-(1-methylethyl)-5-nitro-2(3H)-benzothiazolone. m.p., 153°-153.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:27][C:25]([F:28])([F:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[NH:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=3[O-:37])=[O:9])[C:18]=2[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccccn1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1cccc[n+]1[O-])c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To a solution of N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (10; 100 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added mCPBA (140 mg, 0.81 mmol) under nitrogen. The mixture was stirred at room temperature for 12 h. A saturated aqueous solution of K2CO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure. The resulting residue was purified by chromatography (CH2Cl2:methanol=20:1) to give 2-(2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamido)pyridine 1-oxide (Compound 329) (60.0 mg, 58%) as a colorless solid. MS (ESI) calcd for C20H13F3N4O2: 398.10; found: 399 [M+H].
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-])=O)C.N[C:21]1C=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=C[C:22]=1NCC>[Ni]>[CH3:21][CH2:22][NH:17][C:5]1[C:4]([NH2:3])=[CH:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[CH:7][CH:6]=1
Reactant: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CCNc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: CCNc1ccc(N2CCN(C)CC2)cc1N
Yield: 90 %

Procedure:
N-Ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was reduced with Raney-Ni as described previously for the synthesis of tert-butyl 4-[4-amino-3-(ethylamino)phenyl]-1-piperazinecarboxylate to give N-2-ethyl-4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (yield>90%) as a red oil. The product is very sensitive to oxidation and was therefore used immediately in the next reaction step. HPLC purity>90%; MS (posEI) m/z=234 (M+);
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH3:16])[C@H:13](O)[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][NH:48][S:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:45]=[CH2:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:44]([O:47][N:48]([C@H:13]1[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH:15]=[C:14]1[CH3:16])[S:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:45]=[CH2:46]
Reactant: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 77.5 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 8, 19.45 g, 54.40 mmol) in toluene (300 mL) at room temperature was added triphenylphosphine (17.06 g, 65.28 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 14.05 g, 54.40 mmol) and diisopropyl azodicarboxylate (12.85 mL, 65.28 mmol). After 2 hours the reaction mixture was concentrated onto silica gel and purified. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the desired product (25.2 g, 78%) as a yellow oil.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:22][C:23]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=1[CH2:25][CH2:26][C@H:27]1[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[N:29](C(OC(C)(C)C)=O)[CH2:28]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C@@H:4]([C:5]([NH:22][C:23]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=2[CH2:25][CH2:26][C@H:27]2[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:39])([F:41])[F:40])[NH:29][CH2:28]2)=[O:7])[NH:1][C:35]([O:34][CH3:33])=[O:42])=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccncc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccncc1)c1ccc(F)cc1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=680 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH2:4][CH2:3]1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[CH3:1][C:2]1([CH3:20])[CH:10]2[CH:6]([CH2:7][N:8]([C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]([CH3:33])[CH3:21])[CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH2:4][CH2:3]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: COc1ccccc1C1(O)CCC(C)(C)C2CNCC21
Product: COc1ccccc1C1(O)CCC(C)(C)C2CN(C(=O)Cc3ccccc3N(C)C)CC21

Procedure:
By working according to the experimental procedure of Example 6, from 0.6 g of (3aRS, 4RS, 7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol and 0.41 g of 2-dimethylaminophenylacetic acid, and after purification on a column of silca gel (particle size 0.04-0.06 m, diameter 2.8 cm, height 17 cm), 0.4 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)cc1
Yield: 53.5 %

Procedure:
To a solution of Example 8B (40 mg, 0.083 mmol) in a mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (54 mg, 0.83 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (20 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34-7.54 (m, 2H), 6.25-6.98 (m, 9H), 5.82-5.96 (m, 2H), 5.73-5.83 (m, 1H), 3.30-3.47 (m, 1H), 1.28-1.80 (m, 4H). MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
3.00 g (14.3 mmol) 2,6-dichloropyridine-4-carboxylic acid chloride, 1.80 g (11.0 mmol) 4-methyl-3H-benzoxazol-2-one and 9.47 g (71.0 mmol) aluminium trichloride were combined and heated for 2 h to 125° C. with stirring. Then the mixture was decomposed with ice water and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and the filtrate was evaporated down i. vac. The residue was triturated with diethyl ether, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=1.[F:15][C:16](I)([F:18])[F:17]>N1C=CC=CC=1.[Cu]>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([C:16]([F:18])([F:17])[F:15])=[CH:11][CH:10]=2)[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ccc(I)cc2c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2ccc(C(F)(F)F)cc2c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 2-iodo-7-nitronaphthalene (1 g, 3.34 mmol), trifluoromethyliodide (0.328 mL, 4.01 mmol) and copper powder (2.55 g, 40.1 mmol) in pyridine (20 mL) in a sealed tube is heated with stirring at 120° C. for 20 hours. After cooling, the reaction mixture is filtered and extracted with EtOAc. The organic extracts are washed with water, 0.1 M citric acid solution and dried (Na2SO4). Concentration and purification of the residual oil by flash chromatography on silica gel (2:1 hexanes/EtOAc) gives 2-nitro-7-trifluoromethylnaphthalene as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]>O1CCCC1>[Cl:28][C:25]1[CH:24]=[C:23]([S:29]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:31])=[O:30])[CH:22]=[C:21]([Cl:20])[C:26]=1[OH:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(O)c(Cl)c1
Reactant: c1cc2c(cn1)NCCO2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)c(O)c(Cl)c1)N1CCOc2ccncc21
Reaction time: 0.17 h
Yield: 3.4 %

Procedure:
To a 5 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (30 mg, 0.220 mmol) was dissolved in tetrahydrofuran (3 ml). Diisopropylethylamine (0.153 ml, 0.878 mmol) was added and then stirred at 0□ for 10 minutes, and then 3,5-dichloro-4-hydroxy-benzenesulfonyl chloride (69 mg, 0.264 mmol) was added thereto and then stirred at 0□ for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate=1:2. The fractions containing the product were collected and evaporated to obtain the target compound 21 as pale-yellow solid (2.7 mg, 3.4%).