Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:61]=[CH:60][C:48]([O:49][CH2:50][CH2:51][NH:52]C(=O)OC(C)(C)C)=[C:47]([C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)[CH:46]=1.Cl.CCOCC>ClCCl>[NH2:52][CH2:51][CH2:50][O:49][C:48]1[CH:60]=[CH:61][C:45]([NH:44][C:3](=[O:5])[C:2](=[O:1])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[CH:46][C:47]=1[C:62]1[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
The 2-oxo-2-p-tolylacetic acid (14.82 mg, 1.2 eq), triethylamine (31.45 μL, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 20 minutes. At this time tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg, 75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and the reaction was stirred at room temperature for 118 hr. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid in ether (188 μL, 5 eq) and the reaction was stirred at room temperature overnight. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 32.2% yield. LCMS m/z (%)=379 (M+H, 100. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H), 3.12-3.21 (m, 2 H), 3.71 (s, 3 H), 4.19 (t, J=5.56 Hz, 2 H), 6.37 (d, J=1.52 Hz, 1 H), 7.26 (d, J=9.09 Hz, 1 H), 7.42 (d, J=8.59 Hz, 2 H), 7.49 (d, J=2.02 Hz, 1 H), 7.70 (d, J=2.53 Hz, 1 H), 7.82 (dd, J=9.09, 2.53 Hz, 1 H), 7.97 (d, J=8.08 Hz, 2 H), 10.96 (s, 1 H).
Reaction SMILES: [Si]([O:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:33])[N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:18][CH:17]=2)[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>C(#N)C>[OH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:10]1[NH:11][C@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:33])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1
Reaction time: 1 h
Yield: 26 %

Procedure:
The crude tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{methyl[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate was dissolved in a 3:3:1 mixture of acetonitrile (1.4 mL):TFA (1.4 mL):water (0.47 mL), and the mixture was heated to 55° C. and stirred for 1 hour. The mixture was then concentrated in vacuo and purified by mass directed reverse phase HPLC using acetonitrile/water with 0.1% NH4OH buffer. Lyophilization of the desired fractions gave the title compound (21 mg, 26% yield over three steps) as a brown oil.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:21][OH:22]>>[C:1]([N:9]1[CH:14]([O:22][CH3:21])[CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCN1C(=O)c1ccccc1
Reactant: CO
Agent: F[B-](F)(F)F
Product: COC1CCCC(C)N1C(=O)c1ccccc1
Yield: 77.6 %

Procedure:
In the same manner as in Example 5, there are electrolyzed 43.8 g of 1-benzoyl-2-methylpiperidine and 60.2 g of methanol in the presence of 0.3 of tertramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-benzoyl-2-methylpiperidine the current is switched off. After work-up of the electrolysis solution, 39.0 g of 1-benzoyl-2-methyl-6-methoxypiperidine (boiling point 78°-81° C./0.1 mm Hg; nD25 = 1.5340) are obtained which corresponds to a product yield of 77.5% and a current efficiency of 62.0%.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (191.8 mg) obtained in step 1 was dissolved in dimethylformamide (DMF, 1.5 ml), to which benzylbromide (0.07 ., 0.55 mmol) and potassium carbonate (K2CO3, 82.9 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Dimethylformamide was distillated under reduced pressure, followed by extraction with ethylacetate (EtOAc). The extracted organic layer was dried over MgSO4, filtered and concentrated. The concentrated reactant was separated by column chromatography (developing solvent: hexane/ethylacetate=15/1) to give 220 mg of the target compound (yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:5][N:6]([CH2:29][C:30](=[O:44])[C:31]1[CH:35]=[CH:34][N:33](COCC[Si](C)(C)C)[N:32]=1)[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]2)[C:13]=1[C:14]([F:17])([F:16])[F:15])=[O:8].Cl>O1CCOCC1>[F:48][C:46]1[CH:45]=[C:4]([CH:3]=[C:2]([F:1])[CH:47]=1)[CH2:5][N:6]([CH2:29][C:30](=[O:44])[C:31]1[CH:35]=[CH:34][NH:33][N:32]=1)[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[C:13]=1[C:14]([F:15])([F:16])[F:17])=[O:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3ccn(COCC[Si](C)(C)C)n3)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CN(Cc1cc(F)cc(F)c1)C(=O)c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)(F)F)c1cc[nH]n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 8-3 (75 mg, 0.107 mmol) in 1,4-dioxane (2 mL) was added HCl (12 M, 0.5 mL). The mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 1,4-dioxane (2 mL) and NH4OH (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography (C18 silica gel, 70% CH3CN/water as eluent) to provide the compound of example 8 (10 mg, 16%) as a white solid. 1H NMR (CD3OD) rotamers present δ 7.74-7.50 (2H, m); 6.98-6.95 (1H, m); 6.87-6.78 (3H, m); 5.00 and 4.78 (2H, 2×s); 4.74 and 4.64 (2H, 2×s); 4.28-4.21 (1H, m); 2.36-2.28 (1H, m); 2.17-2.09 (2H, m); 2.02-1.93 (4H, m); 1.62-1.55 (2H, m); LCMS (APCI): 540 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Cl:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Cl)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-chlorosuccinimide (257 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0-+40% ethyl acetate/hexane) to give the title compound (437 mg, 79%) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[CH2:18]([NH:26][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc(-c2ccc(CNCCc3ccccc3)cn2)c1
Reaction time: 16 h

Procedure:
To a solution of 3-(5-formylpyridin-2-yl)benzamide (40 mg, 0.18 mmol) in MeOH (2.5 mL) was added phenethylamine (27 μL, 0.21 mmol). The mixture was stirred for 16 h before adding sodium borohydride (33 mg, 0.88 mmol). After 16 h water (1 mL) was added and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 5% MeOH:DCM) gave the title compound: RT=2.32 min; m/z (ES+)=332.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(B(O)O)C=CC=CC=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>O>[C:17]1([CH:23]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:7])[CH2:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C1C=CCCC1
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: CO
Product: O=C1CCCCC(c2ccccc2)C1
Temperature: 50 °C
Yield: 83 %

Procedure:
Next, the scope of boronic acids that can be utilized was briefly examined. More specifically, the general experimental procedure for the 1,4-addition of arylboronic acids to enones will be described using 2-cyclohexen-1-one and phenylboronic acid. A mixture of 2-cyclohexen-1-one (96 mg, 1 mmol) and phenylboronic acid (158 mg, 1.3 mmol) was taken in a round bottom flask. A toluene solution (3 ml) containing Rh(acac)(CO)2 (5 mg, 0.02 mmol) and JanaPhos (70 mg, 0.03 mmol, Rh/P=1/3) was added to it in an inert atmosphere. A solution of methanol and water (1:1, 0.5 ml) was added to it via syringe. The reaction mixture was heated at 50° C. for 15 hours until the starting material was consumed as indicated by TLC. Then 25 ml methanol was added to it mixture and the catalyst was precipitated out as a white solid. It was filtered out by a Schlenk filter and underwent for the consecutive runs. The filtrate was evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography (10% ethyl acetate in hexane) to obtain the pure product (144 mg, 83% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc([N+](=O)[O-])cc1

Procedure:
4.2 g (29.7 mmol) of N-tert.butoxycarbonyl-ethylenediamine, 5.0 g (31.2 mmol) of 4-fluoro-nitrobenzene and 7.0 g (50.6 mmol) of potassium carbonate are stirred in 25 ml of DMSO for 9 hours at 60° C. After cooling the mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is stirred with petroleum ether, decanted off and evaporated down again. The product is stirred with ether and suction filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCc1ccccc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCc1ccccc1
Yield: 90.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and benzylamine (54 μL, 0.5 mmol) to give 170 mg of the title compound (89%): mp 220°~223° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 8.46~8.55 (m, 1H), 7.19~7.37 (m, 6H), 7.14 (d, 1H, J=2 Hz), 5.09~5.19 (m, 1H), 4.21~4.35 (m, 2H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.77 (dm, 1H, J=17.1 Hz), 2.41~2.54 (m, 2H), 2.00 (dm, 1H, J=13.5 Hz), 1.72~1.90 (m, 1H).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:17]([NH:20][CH2:21][C:22]([CH3:25])([NH2:24])[CH3:23])([CH3:19])[CH3:18].C(O)C>>[CH3:23][C:22]1([CH3:25])[CH2:21][N:20]([CH:17]([CH3:19])[CH3:18])[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:24]1
Reactant: CC(C)NCC(C)(C)N
Reactant: CCCCCCCCCCCC(=O)OCC
Solvent: CCO
Product: CCCCCCCCCCCC1=NC(C)(C)CN1C(C)C
Yield: 56.8 %

Procedure:
22.84 g. (100 mmoles) of ethyl laurate and 15.34 g. (118 mmoles) of Nl -isopropyl-2-methyl-1,2-propanediamine is heated at 130°-230° C. until approximately 100 mmoles of ethanol is collected. Toluene is then cautiously added and the heating is continued until no more water separates. The solution is acidified, the aqueous layer is separated and basified with NaOH. This is extracted with ethyl acetate, the organic extract is dried and concentrated. The oil is distilled at 150-152° C./1.2 mm to give 16.74 g (58%) of product.
Reaction SMILES: Br[C:2]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[P:20]([O:23][CH3:24])([O:21][CH3:22])([O:8][C:7](=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[O:25]
Reactant: COc1ccc2c(C(=O)C3(Br)CCCC3)n[nH]c2c1
Reactant: COP(OC)OC
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1

Procedure:
The title compound was prepared from (1-bromocyclopentyl)(6-methoxy-1H-indazol-3-yl)methanone and trimethyl phosphite using the procedure described in Method I Step B of Example 1 followed by RP-HPLC purification using 20-100% MeCN gradient. It was isolated as a white solid following lyophilization. 1H NMR (CDCl3, 500 MHz) δ 7.79 (d, 8.9 Hz, 1H), 6.85 (dd, 2.1 & 9.0 Hz, 1H), 6.81 (d, 1.8 Hz, 1H), 3.88 (s, 3H), 3.67 (d, 11.3 Hz, 6H), 2.72˜2.79 (m, 2H), 2.53˜2.59 (m, 2H), 1.70˜1.81 (m, 4H). LC-MS: 3.00 min. (n/Z=227.2, 353.2, 375.2).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][C:13](=O)[CH2:14][CH3:15])[CH:3]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:47]([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:13]([CH2:14][CH3:15])=[N:12]2)=[CH:9][C:10]=1[F:11]
Reactant: CCC(=O)Nc1cc(Cl)c(F)cc1C(=O)O
Reactant: NCCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Cl)c(F)cc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.3 %

Procedure:
The crude solid (3 g) from step 3 above mixed with triphenyl phosphite (4 mL, 14.81 mmol) in pyridine (15 mL) was stirred at rt for 4 h. The mixture was added with phenethylamine (1.55 mL, 12.18 mmol), irradiated with microwave 250 W to refluxing for 15 min. The mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL). The ethyl acetated solution was mixed with water (50 mL) and kept at rt to give solid form. The solution was filtered to give yellow solid title compound (1.1 g, 27.2%). mp=150-152° C. (recrystallized from ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.2 Hz, 3H, CH3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.93 (br t, J=7.6 Hz, 2H, CH2), 4.19 (br t, J=7.6 Hz, 2H, CH2), 7.20-7.31 (m, 5H, ArH), 7.80 (d, J=6.4 Hz, 1H, ArH), 7.91 (d, J=8.8 Hz, 1H, ArH); 13C NMR (100 MHz, DMSO-d6) δ 10.6, 26.9, 33.5, 44.8, 112.2, 112.4, 119.8, 119.9, 126.6, 126.8, 127.0, 128.5, 128.7, 128.8, 138.0, 144.1, 153.6, 156.1, 158.9, 160.0; Anal. (C18H16ClFN2O) C, H, N. Calcd: 65.36, 4.88, 8.47. Found: 65.09, 4.77, 8.50.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2.C(=O)(O)[O-:10].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][C@@H:2]1[O:10][C:7](=[O:8])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2
Reactant: O=C([O-])O
Reactant: C[C@@H]1C(=O)C[C@H]2O[C@@H]12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(=O)C[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5.6 g (50 mmol) of (1S,2S,5R)-2-methyl-6-oxabicyclo[3.1.0]hexan-3-one (4) in 400 ml of anhydrous methylene chloride was added 15 g of sodium bicarbonate and 12.9 g (64 mmol) of 85% m-chloroperbenzoic acid. The suspension was stirred at room temperature for 72 hr and filtered through Celite Filter-Aid. The filtrate was evaporated to dryness under reduced pressure, the residue was triturated with 40 ml of methylene chloride and insolubles were removed by filtration. The filtrate was washed twice with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under educed pressure. Heating at 70° (0.1 mm) removed 0.95 g of volatile material. The oily residue slowly crystallized on standing to give (1S,2S,6R)-2-methyl-3,7-dioxabicyclo[4.1.0]heptan-4-one: mp 51°-52°. Recrystallization from 12 ml of ether yielded end product: mp 51° -52°. Several recrystallizations from ether gave analytically pure (1S,2S,6R)-2-methyl-3,7-dioxabicyclo-[4.1.0]heptan-4-one: mp 52.5°-53.5°; [α]25D +147.26 (c 0.995, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccc(F)cc2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Yield: 57 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-fluorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 57%). NMR(DMSO-d6) δ:7.22 (1H, t, J=54.1 Hz), 7.39-7.47 (1H, m), 7.53 (1H, s), 7.56 (2H, brs), 7.75-7.80 (2H, m), 7.93-8.00 (3H, m), 8.09-8.13 (1H, m); mp 255° C. (ethanol-water)
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.[C:17](=O)([O-])O.[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:17])=[O:12])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Concentrated sulfuric acid (500 μL) was added to a methanol (20.0 mL) solution of 4-bromo-2-methylbenzoic acid (2.00 g, 9.30 mmol), and the mixture was stirred for 5 hours at 80° C. The reaction mixture was cooled to room temperature, subsequently a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate. The organic layer thus obtained was washed once with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and thus, the title compound (2.02 g, yield: 95%) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:21]([OH:28])[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](=[O:28])[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnc2c(c1)cc(C(O)CC1CCCO1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cnc2c(c1)cc(C(=O)CC1CCCO1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a 250 mL round bottomed flask charged with 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanol (2.5 g, 6.2 mmol) in dichloromethane (200 mL) was added Dess-Martin periodinane (6.6 g, 15.5 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanone (1.7 g, 71%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C20H20N2O5S [M+H]+ 401.46, observed 401.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC1CCNCC1
Solvent: C1CCOC1
Product: CC1CCN(c2nc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: -40 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (194 mg, 1.00 mmol) in THF (10 mL) at −40° C., 4-methylpiperidine (118 μL, 1.00 mmol) was added dropwise. The resulting mixture was stirred at −40° C. for 3 h and the solvent was removed in vacuo. The resulting yellow residue was chromatographed on silica (5-20% EtOAc:hexane) to obtain the title compound (103 mg, 40%). 1H-NMR (CDCl3; 400 MHz): δ 8.69 (s, 1H), 4.24 (br m, 2H), 3.10 (m, 2H, J=12.9, 2.7 Hz), 1.82-1.71 (m, 3H), 1.36-1.25 (m, 2H), 1.01 (d, 3H, J=4.8 Hz).