Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ncnc2occ(-c3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A 0° C. suspension of Example 13E (74 mg, 0.33 mmol) in dichloromethane (3 mL) was treated with pyridine (0.032 mL, 0.4 mmol) and benzoyl chloride (0.040 mL, 0.34 mmol), stirred at 0° C. for 1 hour, warmed to room temperature, and stirred overnight. The mixture was triturated with hexanes and the precipitate was collected by vacuum filtration, washed with dichloromethane and water, and purified by flash column chromatography on silica gel with ethyl acetate to provide 46 mg (42%) of the desired product. MS (ESI(+)) m/e 331 (M+H)+; 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 8.26 (s, 1H), 7.99-7.94 (m, 5H), 7.62-7.50 (m, 5H), 6.50 (br s, 2H); Anal. Calcd. for C19H14N4O2.0.25H2O: C, 68.15; H, 4.36; N, 16.73. Found: C, 68.20; H, 4.21; N, 19.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.Cl.[C:16]([O:20][NH2:21])([CH3:19])([CH3:18])[CH3:17].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[C:16]([O:20][NH:21][C:12](=[O:14])[CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(SCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(SCCC(=O)NOC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
To a solution of the compound prepared in Example 8(11) (1.00 g) in DMF (20 ml), t-butoxyamine hydrochloride (652 mg), triethylamine (0.8 ml), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (995 mg) and 1-hydroxybenzotriazole (HOBt) hydrate (795 mg) were added at 0° C. The mixture was stirred for 16 hours at room temperature. To the reaction mixture, ethyl acetate and water were added. The organic phase was washed with 0.1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.35 g) having the following physical data.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[CH:3]1([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1)CCN=C2C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Sodium borohydride (0.512 g, 13.5 mmol) was added in small portions to a solution of 1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline (0.822 g, 3.38 mmol) in MeOH (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, warmed to rt and stirred at rt for 15 hr, then quenched by the dropwise addition of H2O (5.0 ml). The resulting mixture was concentrated in vacuo to remove the MeOH and the remaining aqueous solution was extracted with CHCl3 (4×10 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 0.775 g (93% yield) of yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17]Br.C(OCC)(=O)C>C(O)(=O)C>[Br:17][C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2ccccn2c1=O
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (2.33 g, 10.7 mmol) in 20 ml acetic acid was rapidly added a solution of bromine (1.9 g, 12 mmol) in 10 ml acetic acid. The reaction was complete after 5 min, as indicated by thin layer chromatography (ethyl acetate). The solvent was evaporated in vacuo and the remaining yellow solid was dissolved in 20 ml dichloromethane. To this solution, silica gel (3 g) was added and the solvent was evaporated in vacuo. The silica gel was poured on a prepacked column and eluted with ethyl acetate to give ethyl 1-bromo-4-oxo-4H-quinolizine-3-carboxylate (9) as a bright yellow solid (2.1 g, 71%). M.p. 156-158° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz, 3H), 4.43 (q, J=7 Hz, 2H), 7.03 (dd, J=7 Hz, J=7 Hz, 1H), 7.30 (dd, J=7 Hz, 2H), 7.80 (dd, J=7 Hz, J=7 Hz, 1H), 8.63 (s, 1H), 9.49 (d, J=7 Hz). MS: m/z 294.9839; required for C12H10BrNO3: 294.9843.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[N+](CC)([O-])=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (2.3 g, 13 mmol) in nitroethane (20 mL) was added aluminum chloride (3.5 g, 26 mmol) followed by fluorobenzene (1.2 mL, 13 mmol). The mixture was stirred at rt for 4 h, then quenched carefully with 6M HCl. The reaction mixture was washed with dilute aqueous NaOH and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude product as a light yellow solid. The solid was purified by recrystallization from hexanes to give (4-fluoro-phenyl)-(4-nitrophenyl)-methanone (2.0 g, 65%). 1H NMR (CHCl3-d) δ 8.41-8.32 (m, 5H), 7.90 (m, 1H), 7.84 (m, 1H), 7.20 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[Mg]Br>>[Cl:14][C:13]1[C:2]([F:1])=[C:3]([C:4]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][C:21]=2[O:23][CH3:24])=[O:5])[CH:10]=[CH:11][CH:12]=1
Reactant: CON(C)C(=O)c1cccc(Cl)c1F
Reactant: COc1ccc([Mg]Br)c(OC)c1
Product: COc1ccc(C(=O)c2cccc(Cl)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2-fluoro-3-chloro-N-methoxy-N-methyl-benzamide (2.44 g, 11.2 mmol) and 2,4-dimethoxyphenylmagnesium bromide (20 mL, 0.5 M in THF) to give 0.95 g of the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]1[CH3:16].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: CC1=CC(=Nc2nccs2)C(C)C(C)=C1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccs2)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.3 %

Procedure:
4-(2-Thiazolylimino)-2,3,6-trimethylphenol (0.60 g) was dissolved in 10 ml of tetrahydrofuran. To the solution was added a solution of 7.6 g of sodium hydrosulfite in 29 ml of water. The mixture was stirred at room temperature for 45 minutes and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Recrystallization of the crude product obtained from acetonitrile gave 0.56 g of the desired compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33][NH2:34])[CH:29]=2)[CH:23]=1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:34][CH2:33][C:30]1[CH:29]=[C:28]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[O:32][N:31]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCc1cc(-c2cccnc2)on1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-Chloro-3-nitroquinoline (2.09 g, 9.99 mmol) and triethylamine (2.10 mL, 15.0 mmol) were sequentially added to a solution of (5-pyridin-3-ylisoxazol-3-yl)methylamine (2.09 g, 9.99 mmol) in dichloromethane, and the solution was stirred overnight at room temperature. The resultant red solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 2% to 5% methanol in dichloromethane) to provide 1.17 g of 3-nitro-N-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinolin-4-amine as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([CH3:15])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:16][C:4]1[S:3][C:2]2=[N:1][C:18]([CH3:17])=[C:19]([C:20](=[O:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[C:5]=1[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1sc(N)c(C(=O)c2ccccc2)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc(C)c(C)c2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a stirred solution of 70 mg (0.30 mmol) (2-Amino-4,5-dimethyl-thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.02 ml (0.30 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 10 mg (11%) 1-(2,3,6-trimethyl-4-phenyl-thieno[2,3-b]pyridine-5-yl)-ethanone as an orange solid. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][OH:23].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][O:23][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH2:14]3)[CH2:8]1)[CH2:10]2)=[O:18].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Reactant: O=S(=O)([O-])C(F)(F)CO
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)OCC(F)(F)S(=O)(=O)[O-])(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To 3.3 g (11 mmol) of the 3-methacryloyloxyadamantane-carbonyl chloride were added 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate in Synthesis Example 1-13 and 20 g of methylene chloride. To the mixture under ice cooling, a solution containing 1.1 g (11 mmol) of triethylamine and 0.25 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at a temperature below 5° C., and the resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, from which the residual water was distilled off in vacuum together with methyl isobutyl ketone. Diethyl ether was added to the residue for recrystallization. The resulting crystals were recovered and dried, obtaining the target compound, triphenylsulfonium 1,1-difluoro-2-(3-methacryloyloxy-adamantane-1-carbonyloxy)-ethane-1-sulfonate. White crystals, 5.5 g (yield 82%). The compound has the following structure.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:3]=1[CH2:4][NH:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]1[N:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][N:33]=1.[C:46](Cl)(=[O:48])[CH3:47]>N1C=CC=CC=1>[F:1][C:2]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:3]=1[CH2:4][N:5]([CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9][N:8]1[C:32]1[N:33]=[CH:34][C:35]([CH2:38][CH2:39][CH3:40])=[CH:36][N:37]=1)[C:46](=[O:48])[CH3:47]
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CNCc2cc(F)ccc2F)nc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN(Cc2cc(F)ccc2F)C(C)=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
160 mg (0.258 mmol) (2S,4R)-(2,5-Difluoro-benzyl)-[1-(5-propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-amine in 2 ml pyridine were treated with 37 μl (0.52 mmol) acetyl chloride at 0° C. The solution was stirred at RT for 1.5 h, poured on ice water and was extracted with EtOAc. The combined organic layers were washed with 1N HCl and brine, dried over Na2SO4 and were evaporated. Column chromatography with EtOAc:hexane 1:2 to 1:1 yielded 170 mg (quant) (2S,4R)-N-(2,5-Difluoro-benzyl)-N-[1-(5-propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-acetamide as white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[N:29]=[N:30][NH:31][CH:32]=2)=[CH:21][CH:20]=1.[S:33](=[O:37])(=[O:36])([OH:35])[OH:34].C(O)(C)C>C(O)(C)C.O>[S:33]([OH:37])([OH:36])(=[O:35])=[O:34].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[NH:29][N:30]=[N:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4cnn[nH]4)cc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a stirred suspension of N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (49 mg, 0.11 mmol) in 4:1 isopropanol/water (0.8 mL) was added dropwise 0.5 M sulfuric acid in isopropanol (0.65 mL, 0.33 mmol). The mixture was then stirred for 2 h and the solvent removed under reduced pressure to give the title compound as an amorphous off-white solid which was characterized by XRPD. FIG. 7 shows a characteristic X-ray powder diffraction (XRPD) pattern of amorphous N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide monosulfate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH3:14])=[O:13]
Reactant: CC1CCCCC1N
Reactant: COc1ccccc1C=CC(=O)O
Product: COc1ccccc1C=CC(=O)NC1CCCCC1C

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxyphenyl)-acrylic acid and 2-methyl-cyclohexylamine. MS (M+H, 274.2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[O:25]=[C:6]1[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH:2]=[O:1]
Reactant: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a solution of 1′-(3-hydroxypropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (4.82 g, 14.2 mmol) in dichloromethane (150 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.00 g, 16.7 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h, diluted with ethyl acetate, washed sequentially with 10% Na2S2O3 solution, saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography and the product was recrystallized from ethyl acetate/hexanes to afford the title compound (3.86 g) in 80% yield: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.33-6.92 (m, 4H), 6.48 (s, 1H), 6.08 (s, 1H), 4.86 (m, 1H), 4.61(m, 1H), 4.15-3.98 (m, 2H), 2.97-2.84 (m, 2H); MS (ES+, m/z) 338.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC.C([O:37][C:38](=O)[CH:39]=[CH2:40])C>CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH2:40][CH2:39][C:38](=[O:37])[NH:5]2
Reactant: C=CC(=O)OCC
Reactant: Nc1cccc(Cl)c1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CS(C)=O
Product: O=C1CCc2c(Cl)cccc2N1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-chloro-2-iodoaniline (143-3; 1.1 g, 0.0043 mol), AIBN (0.282 g, 0.0017 mol), tributyl tinhydride (1.8 g, 0.0064 mol) in dimethyl sulphoxide (10 mL) was added ethylacrylate (1.7 g, 0.173 mol) portion wise at 0° C. Reaction mixture was allowed to stir at 120° C. for 12 h. The reaction mixture was diluted with ice cold water (150 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.159-7.119 (t, J=7.6 Hz, 1H), 7.021-7.002 (d, J=7.6 Hz, 1H), 6.819-6.800 (d, J=7.6 Hz, 1H), 2.941-2.651 (t, J=8 Hz, 4H). MS (M+1): 181.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([F:22])[C:14]=1F.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([F:22])[C:14]=1[N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccn(-c2c(F)cc([N+](=O)[O-])cc2F)c(=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.00 g), 1,2,3-trifluoro-5-nitrobenzene (3.54 g), potassium carbonate (3.73 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent (10 mL) of isopropyl ether/ethyl acetate=4/1, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (3.75 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Substituted benzyl bromide compounds can also be prepared from commercially available substituted benzaldehydes, benzoic acids and benzoic esters by first converting these compounds to the corresponding alcohol. Exemplary synthetic methodology to provide substituted benzyl bromide from benzyl aldehyde is described below. For example, as illustrated in Scheme 12, treatment of 4-hydroxy-3-nitro-benzaldehyde 73 with benzyl bromide in the presence of K2CO3 in DMF at 65° C. gives 4-benzyloxy-3-nitro-benzaldehyde 74. Reduction of compound 74 in methanol with NaBH4 affords the alcohol 75 and subsequent bromination using PBr3 in diethyl ether provides the desired bromide compound 76.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C[Si]([C:27]#[N:28])(C)C>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:27]#[N:28])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CCCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-propoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH:22]([NH:25][OH:26])([CH3:24])[CH3:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:25]([OH:26])[CH:22]([CH3:24])[CH3:23])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: CC(C)NO
Agent: Cl
Product: CC(C)N(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-isopropyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (CDCl3) δ ppm 8.59 (s, 1H), 8.46 (s, 1H), 7.39 (s, 1H), 7.10 (m, 2H), 7.02 (d, 2H, J=8.6 Hz), 6.73 (s, 1H), 5.41 (s, 2H), 5.08 (m, 1H), 1.33 (d, 6H, J=6.6 Hz). LCMS (APCI, M+H+): 328.1 HRMS calcd for C18H18FN3O2 (M+H) 328.1456, found 328.1456. HPLC: 95.8% purity.