Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1C1CCCCC1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one (280 mg, 1.0 mmol) in 10 mL of dry dichloromethane was added triethylamine (1.39 mL, 10 mmol), cupric acetate (363 mg, 2.0 mmol), phenylboronic acid (244 mg, 2.0 mmol) and 4 Å molecular sieves (2.0 g). The reaction mixture was allowed to stir at room temperature with air balloon on. The reaction mixture was then filtered over Celite, washed with dichloromethane and the organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel flash chromatography, using dichloromethane-methanol mixture (v:v=99:1) as eluent, to give titled compound (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.20-1.22 (m, 1H), 1.47-1.49 (m, 6H), 1.72-1.77 (m, 3H), 1.87-1.89 (m, 2H), 2.10-2.13 (m, 1H), 4.44-4.49 (m, 2H), 7.17 (s, 1H), 7.20-7.24 (m, 2H), 7.48-7.56 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:11]2(O)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCCCCC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CC=C(c2ccc(OCC)c(Cl)c2F)CC1
Yield: 57.4 %

Procedure:
39.5 g of the compound (3), 0.4 g of p-toluenesulfonic acid and 120 mL of toluene were mixed, and the mixture was refluxed under heating for 2 hours while water distilled out was removed. After cooling the resulting reaction mixture to 30° C., 200 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture, which was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and then further purified by recrystallization from Solmix A-11 (produced by Japan Alcohol Trading Co., Ltd.) to obtain 21.5 g of 2-chloro-1-ethoxy-3-fluoro-4-(4-pentylcyclohexa-1-enyl)benzene (No. 23). The yield based on the compound (2) was 58.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1>C(O)(C)C>[Cl:19][C:20]1[N:25]=[C:24]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: COc1ncccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a suspension of 2-methoxy-pyridin-3-ylamine (1.00 g, 0.00806 mol) and N,N-diisopropylethylamine (2.1 mL, 0.012 mol) in isopropyl alcohol (20 mL) was added 2,4,5-trichloropyrimidine (1.0 mL, 0.0089 mol). The mixture was stirred at room temperature overnight. The suspension was filtered, the solid was washed with isopropanol (10 mL) then hexane (20 mL). The solids were dried under vacuum to provide (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-pyridin-3-yl)-amine (1.23 g, 56%) as a white solid. LC/MS (ESI+): 271.40 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26]C)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:29]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24](=[O:26])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 63 %

Procedure:
A solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (0.92 g, 2.56 mM) in 38 ml THF and 154 mL concentrated aqueous ammonium hydroxide was sonicated for 6 h at 30-40° C. The precipitated solid was filtered, washed with water to afford 0.55 g (63%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.15 (dd, J=8 and 8 Hz, 1H), 7.05 (m, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 6.8 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H), 2.2 (s, 3H). MS (ES) m/e 328, 345.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(4-fluorobenzoyl) benzyl bromide (645 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (371 mg, yield 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3cccc(Cl)c3)nc2n1
Temperature: 120 °C
Yield: 75.9 %

Procedure:
2-Amino-7-chloro-1,8-naphthyridine (17.95 g) is added to a mixture, preheated to 60° C., of 3-chlorophenol (51.4 g) and potassium hydroxide pellets (85% pure; 13.2 g). The reaction mixture is heated to 120° C. for 3 hours. The product is separated by filtration, washed with water to a pH of approximately 7 and then dried in the air. 2-Amino-7-(3-chlorophenoxy)-1,8-naphthyridine (20.6 g), m.p. 166° C., is obtained.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([CH3:51])[O:44]C3CCCCO3)[CH:35]=[CH:36][CH:37]=2)[CH:18]=[C:19]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:20]=1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:22][CH2:21][C:19]1[CH:18]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([OH:44])[CH3:51])[CH:35]=[CH:36][CH:37]=2)[CH:16]=[C:15]([CH2:14][OH:13])[CH:20]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C=Cc2cc(CO)cc(CO)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.5 ml of concentrated sulphuric acid with 2.04 g (3 mmol) of 2-[6-(3-{2-[3,5-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 30 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 80-heptane 20), white crystals (m=646 mg; Y=58%) are obtained. m.p.=108-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(N)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 4-amino-2-methyl-3-nitrobenzoic acid (synthesized in reagent preparation 22, step 1) (500 mg, 2.6 mmol) methanol (25 mL) and concentrated sulfuric acid (1.25 mL) was stirred at 60° C. for 18 hours. The reaction mixture was cooled concentrated, diluted with ethyl acetate (50 mL), washed with water (50 mL), saturated aqueous sodium bicarbonate solution (2×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the methyl 4-amino-2-methyl-3-nitrobenzoate (400 mg, 75% yield), MS (EI) for C9H10N2O4: 211 (MH+).
Reaction SMILES: ClC1SC(S([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:61][S:58]([C:54]1[CH:53]=[C:52]([CH2:51][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:23])=[O:24])=[N:12]2)[CH:57]=[CH:56][CH:55]=1)(=[O:59])=[O:60]
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(S(N)(=O)=O)c1
Temperature: 65 °C
Reaction time: 7 h
Yield: 22 %

Procedure:
To a solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (120 mg, 0.229 mmol), triphenylphosphine (120 mg, 0.458 mmol) and 3-(hydroxymethyl)benzenesulfonamide (85.8 mg, 0.458 mmol) in THF (3 mL) was added at rt diisopropyl azodicarboxylate (DIAD) (0.090 mL, 0.458 mmol). The resulting mixture was stirred at 65° C. for 7 hours. The mixture was partitioned between DCM (3 mL) and water (3 mL). The organic phase was separated and the aqueous layer was further extracted with 3 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The residue was loaded in dichloromethane on a silica cartridge (50 g) and purified by chromatography on Flashmaster using a 0-100% EtOAc in DCM over 40 min. The appropriate fractions were combined and evaporated in vacuo, and the residue was dissolved in methanol (3 mL) and treated with sodium hydroxyde (2M, 1.146 mL, 2.291 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in DCM (2 mL) and 3 mL of water was added, followed by dilute HCl solution until the pH of the aqueous layer was around 1. The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and concentrated under a stream of nitrogen in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound, (51.6 mg, 22%). LCMS (System A) RT=1.02 min, ES+ve m/z 513/515 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:49])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:30][C:31](=[O:40])[O:32]CC1C=CC=CC=1)[NH:14][C:15](=[O:29])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:49])=[O:8])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:41])[CH2:30][C:31](=[O:32])[OH:40])=[O:29])[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=C(CN1CCN(c2ccncc2)CC1)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C[C@H](NC(=O)CN1CCN(c2ccncc2)CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of O-benzyl-N-[O-benzyl-N-[2-[4-(4-pyridyl)-piperazin-1-yl]acetyl]-L-aspartyl]-L-phenylalanine (0.92 g) in methanol (125 ml) under argon was added 10% Pd on C (0.45 g). The mixture was covered with a blanket of hydrogen and stirred at room temperature until deprotection was complete. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. The resultant white solid was dissolved in water and lyophilised overnight to yield the title compound (274 mg) as a white solid: m.p. 153° C. (dec.); NMR (d6DMSO+CD3CO2D) δ 2.65 (6H, m), 3.02 (4H, m), 3.63 (4H, m), 4.44 (1H, m), 4.67 (1H, m), 7.13 (2H, d), 7.23 (5H, m), 8.22 (2H, d); m/Z 484 (M+H)+ ; calculated for C24H29N5O6. m/Z 484 (H+H)+ ; amino acid analysis: found; Asp, 1.00; Phe 0.99; requires; Asp, 1.00; Phe, 1.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:31]#[N:32])=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(Oc2nc(C#N)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 15 %

Procedure:
A mixture of Compound 1e (0.4 g; 0.92 mmol), Zn(CN)2 (0.11 g; 0.92 mmol), and Pd(PPh3)4 (0.106 g; 0.092 mmol) in DMF (2.4 mL) was irradiated at 160° C. in a CEM microwave reactor for 16 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6a (0.059 g; 15% yield). MS: m/z 426.2 (M+H)+.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[C:17](=O)[O:16]1.O>CN(C=O)C>[N+:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:15]=[N:6][NH:7][C:17]2=[O:16])([O-:27])=[O:26]
Reactant: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Reactant: NN
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for one hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.F[C:14]1[CH:15]=C(O)C=C(F)[C:19]=1[N+]([O-])=O.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:19]
Reactant: O=[N+]([O-])c1c(F)cc(O)cc1F
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1cc(F)cc(F)c1[N+](=O)[O-]

Procedure:
A solution of 3,5-difluoro-2-nitrophenol and 3,5-difluoro-4-nitrophenol (3.54 g, 20 mmol), allyl bromide (2.9 g, 24 mmol) and potassium carbonate (8.3 g, 60 mmol) in acetone (50 mL) was refluxed for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure at 25° C. The residue was diluted with water extracted with ether. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure at 25° C. The residue obtained was purified by silica gel column chromatography (0-1% ethyl acetate-hexane) to yield 1-(allyloxy)-3,5-difluoro-2-nitrobenzene (934 mg). 1H-NMR (400 MHz, CD3OD): δ 4.72 (2H, d), 5.32 (1H, d J=10.8), 5.42 (1H, d, J=17.2), 5.98-6.02 (1H, m), 6.85 (1H, dt), 6.96 (1H, d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][Br:9])=[O:7].[BH4-].[Na+]>CO>[Br:9][CH2:8][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: O=C(CBr)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CBr)c1cccs1
Temperature: 0 °C

Procedure:
A solution of the haloketone, bromomethyl 2-thienyl ketone (6.0 g), described in Example 3, in 40 ml of methanol is cooled to 0° C. Sodium borohydride (1.11 g) in 10 ml of methanol is added rapidly to the solution. After 15 minutes the reaction mixture is diluted with ice-water and extracted with ether. The extract is washed with water and brine, dried (MgSO4) and concentrated to give α-(bromomethyl)-2-thiophenemethanol; γmaxCHCl 3 3550, 3400, 1060, 1035 cm-1 (ArCHOHCHR2Y; Ar = 2-thienyl, R2 = H and Y = Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)=[O:13])=[N:7][C:6]=2[CH:24]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:24][C:6]=3[N:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a 0° C. solution of compound 50 (160 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added methanesulfonyl chloride (70 μL, 0.90 mmol)) followed by dropwise addition of pyridine (100 μL, 1.40 mmol). The reaction was stirred overnight under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with 1N HCl (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 54 as a pale yellow solid (117 mg, 60%); MS m/z: 434 (M+H)+. Anal. Calcd. For, C19H19N3O3S2: C, 52.63; H, 4.42; N, 9.69; S, 22.19. Found: C, 52.69; H, 4.49; N, 9.54; S, 22.11.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)C>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry diethyl ether (150 mL) is added triethylamine (12.8 mL, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 mL, 69 mmol). The reaction mixture is allowed to warm to RT and then stirring is continued for 3 h. The resulting mixture is washed with water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution, brine then dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[CH3:12][CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A solution of ethyl 4-methyl-3-oxopentanoate (3.0 g, 19.0 mmol) and potassium carbonate (7.86 g, 56.9 mmol) in THF (40 mL) was stirred at room temperature for 3 h under N2 (g). The mixture was cooled to 0° C. and methyl iodide (3.23 g, 22.8 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Subsequent filtration and concentration provided ethyl 2,4-dimethyl-3-oxopentanoate (2.89 g, 89% yield) as a clear yellow oil that was used without further purification. MS (EI) for C9H16O3: 172 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl (R)-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).