Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:32].[Li+].[Br:34][C:35]1[C:47]2[S:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[C:43]=2[C:42]([C:52]2[CH:57]=[C:56]([Br:58])[C:55]([O:59][C@@H:60]([CH2:68]O)[CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:54]([Br:70])[CH:53]=2)=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[CH:40]2>C1COCC1>[Br:34][C:35]1[C:47]2[S:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[C:43]=2[C:42]([C:52]2[CH:53]=[C:54]([Br:70])[C:55]([O:59][C@@H:60]([CH2:68][Br:32])[CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[C:56]([Br:58])[CH:57]=2)=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[CH:40]2
Reactant: [Br-]
Reactant: OC[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
Diethylazodicarboxylate (0.151 mL, 0.96 mmol) was added dropwise to a 0° C., stirred solution of triphenylphosphine (0.257 g, 0.98 mmol) in THF (6 mL) under a dry nitrogen atmosphere. After 20 min., lithium bromide was added to a nearly colorless reation mixture, followed by adding a solution of (R)-6-bromo-1 1-[3,5-dibromo-4-(1-hydroxymethyl-2-phenyl-ethoxy)-phenyl]-benzo[b]naphtho[2,3-d]thiophene (0.273 g, 0.392 mmol) in THF (3 mL). After 1 h, the solution was allowed to warm to ambient temperature. After 2 h, the reaction mixture was quenched with water (0.2 mL) and further diluted with ethyl ether (50 mL). Silica gel (8 mL) was added. Solvent was removed and the silica adsorbate was flash chromatographed (eluent 98:2 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.23 g, 73%): mp >90° C. (dec.): MS (EI): [M+], 4 bromine isotope pattern, 756, 758, 760, 762, 764; Anal. Calc. for C28H17Br3N203S.0.25 hexane: C, 49.97, H, 2.97, N, 0.00. Found: C, 49.97, H, 2.83, N, 0.02.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[O:16]=[C:15]1[C:9]2[S:8][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[N:11][C:10]=2[CH2:12][CH2:13][CH2:14]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 50 °C
Reaction time: 15 h

Procedure:
572 μl of methyl chloroformate (7.3 mmol) are added to a solution of 500 mg of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (2.4 mmol) in 5 ml of pyridine. The reaction mixture is stirred at 50° C. for 15 h and then diluted with ethyl acetate; the mixture is then extracted by shaking, in each case 2×, with water and cold 1 N hydrochloric acid. The organic phase is dried and evaporated. Yield: 290 mg
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:10]2[S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C2CN(C(=O)OC(C)(C)C)CCS2(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C2CNCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In a 150 mL round-bottomed flask, 2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (435 mg, 1.27 mmol) was combined with dichloromethane (15 ml) to give a light yellow solution. To that was added 4 mL TFA. The resultant reaction mixture was stirred at room temperature for 1 h. Reaction was complete by LCMS. Reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, poured onto 10% NaHCO3 and extracted 3 times with dichloromethane. Combined organic layers were washed with water, dried over Na2SO4, filtered and filtrate concentrated in vacuo to afford 2-(3-methoxyphenyl)-thiomorpholine 1,1-dioxide (252 mg) which was used as is in the next step. (M+H)+=242 m/e.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:30]=1.Cl[C:32]1[C:37]2=[N:38][O:39][N:40]=[C:36]2[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:6]2[CH:30]=[C:2]([NH:1][C:32]3[C:37]4=[N:38][O:39][N:40]=[C:36]4[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][CH:33]=3)[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Solvent: c1ccncc1
Product: CCCCc1nc2ccc(Nc3ccc([N+](=O)[O-])c4nonc34)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared from 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid and 4-chloro-7-nitro-benzofurazan in pyridine at ambient temperature.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[NH:44][C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[N:48]8C(OC(C)(C)C)=O)=[N:46][C:42]=7[CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[N:44]=[C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[NH:48]8)[NH:46][C:42]=7[CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(-c3ccc4nc(-c5ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c6c5)cnc4c3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2nc(-c3ccc4nc([C@@H]5C[C@H]6C[C@H]6N5)[nH]c4c3)cnc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 127.5 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of a TFA salt of tert-butyl (1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinoxalinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (65 mg) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed and the residue was triturated with Et2O. The resulting solid was collected via filtration funnel and rinsed with Et2O to yield a TFA salt of 2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxaline (60 mg) as yellow solid. LC-MS retention time 1.51 min; m/z 525 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.52 (1H, s), 8.58 (1H, s), 8.36 (1H, s), 8.22-8.33 (2H, m), 8.30 (1H, d, J=9.5 Hz), 8.08 (1H, s), 7.76-7.94 (2H, m), 7.83 (1H, d, J=9.5 Hz), 4.80-5.05 (2H, m), 3.45-3.61 (2H, m), 2.70-2.92 (2H, m), 2.50-2.67 (2H, m), 2.00-2.18 (2H, m), 1.26 (2H, br s), 1.04 (2H, br s).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[O:12][CH3:13])=[C:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[O:12][CH3:13])=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]4=[O:21])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc4[nH]ncc4c3)ccn2c1=O
Yield: 51.4 %

Procedure:
Methyl 8-(1H-indazol-5-yl)-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.16 mmol), and 1H-Indazole-5-boronic acid pinacol ester (47.6 mg, 0.20 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as an orange foam (32 mg, 46%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)[CH:3]([O:5][C:12](=[O:13])[CH3:9])[CH3:4])(=[O:1])[CH3:3]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(OC(C)=O)C(C)OC(C)=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (6 mg) in pyridine (0.1 ml), acetic anhydride (50 μl) was added at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was evaporated under N2 gas. The residue was applied to a silica gel plate (Kiesselgel GF254, 10×10 cm, Merck trademark) and developed with chloroform-methanol (95:5) to give methyl 5-(1,2-diacetoxypropyl)-2-pyridinecarboxylate: white amorphous powder; molecular formula C14H17NO6 ; LRFAB-MS m/z 296 [M+H]+ ; 1H-NMR (CDCl3) δ 8.68 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=8.1 Hz), 8.03 (1H, dd, J=8.1 and 2.2 Hz), 5.95 (1H, d, J=4.3 Hz), 5.28 (1H, dq, J=6.5 and 4.3 Hz), 3.97 (3H, s), 2.12 (3H, s), 1.99 (3H, s), 1.18 (3H, d,J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:14](=[O:15])[CH2:13][Cl:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Cl)CCl
Reactant: Brc1ccc2c(c1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-bromo-1,2,3,4-tetrahydroquinoline (2.09 g, 9.85 mmol) in 55 mL toluene was treated with 2-chloroacetyl chloride (0.863 mL, 10.84 mmol) dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 1.5 hour then heated at 95° C. for 30 minutes. After cooling to room temperature, the yellow solution was diluted with 20 mL ethyl acetate and treated with 25 mL of a saturated aqueous sodium bicarbonate solution. The mixture was poured into a separatory funnel and extracted. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate:70% hexanes as eluant. A white solid was obtained after drying under reduced pressure (Yield: 2.4 g, 84%). 1H-NMR (CDCl3) δ 7.35-7.33 (m, 3H), 4.19 (s, 2H), 3.80 (t, J=6.3 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.04-1.98 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.I[CH2:37][CH3:38].[H-].[Na+].O>CN(C=O)C>[CH2:37]([N:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:16][CH:17]=2)[C:9]1=[O:11])[CH3:38]
Reactant: CCI
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.15 g), iodoethane (0.027 mL) and sodium hydride (0.015 g) (60% in oil) in DMF (4.0 mL) was stirred at room temperature for 4 h. To the mixture was added H2O, and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([CH2:27][CH:28]=[CH2:29])[C:24](O)=[C:23]([CH2:31][CH:32]=[CH2:33])[CH:22]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH2:31][CH:32]=[CH2:33])[C:24]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:25]([CH2:27][CH:28]=[CH2:29])[CH:26]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCc1cc(CCC(=O)OC)cc(CC=C)c1O
Solvent: c1ccncc1
Product: C=CCc1cc(CCC(=O)OC)cc(CC=C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 149.8 %

Procedure:
Trifluoromethane sulphonic anhydride (1.68 g) was added dropwise at 0-5° C. to a stirred solution of methyl-3(3,5-diallyl-4-hydroxyphenyl)propionate (2.5 g) in dry pyridine (20 ml). The mixture was then stirred at ambient temperature for a further 16 hours. The pyridine was removed by evaporation. The residue was treated with water (30 ml) and the mixture was extracted with ether (3×30 ml). The ethereal extracts were combined, washed with water (30 ml), dried (MgSO4) and evaporated. The residue was purified by filtration through a short pad of silica gel (Merck Art 7736) using a mixture of 50% ether in n-pentane as eluent to give methyl-3-[3,5-diallyl-4-(trifluoromethylsulphonyloxy)phenyl]propionate (3.5 g) as a pale yellow oil; NMR: 2.52(2H,t), 2.75(2H,t), 3.34(4H,d), 3.48(3H,s), 4.87-5.03(4H,m), 5.68-5.9(2H,m) and 7.03(2H,s).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:15][OH:16])=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: CC1(C)OB(O)c2ccc(C=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2ccc(C=NO)cc21
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (10 mg, 0.053 mmol) and NH2OH.HCl (4.4 mg, 0.063 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (6 mg, 0.074 mmol). The reaction mixture was stirred for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to provide 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (8 mg; yield 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.55 (m, 2 H), 2.81 (s, 1 H,), 1.61 (s,6 H) ppm.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([OH:24])(=O)=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([Cl:27])(=[O:24])=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)Cl)CC1
Temperature: 42 °C
Reaction time: 1 h

Procedure:
To a mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonic acid (34 mg, 0.092 mmol) in methylene chloride (0.30 mL) was added 1 drop of DMF and thionyl chloride (33 μL, 0.46 mmol). The resulting mixture was stirred at 42° C. for 1 h, then the solvents were evaporated to give the crude {trans-4-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonyl chloride. To the crude sulfonyl chloride made above was added 2.0 M methylamine in THF (0.30 mL, 0.60 mmol). The mixture was stirred at room temperature for 30 h. LCMS showed a small amount of starting material remaining More 2.0 M methylamine in THF (0.15 mL) was added and stirred for 30 min, to give a complete reaction. The solvents were evaporated and the resultant residue was dried in vacuo to give the crude product which was used in the next step without further purification. LCMS calculated for C15H21N4O4S2 (M+H)+: m/z=385.1. Found: 385.1.
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl.[NH4+].[Cl-]>ClCCl>[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27][O:1][C:2]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OC1(c2nccs2)CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclohexyl]thiazole from Step 1 (5.8 g, 32 mmol) and Hunig's base (14 mL, 67 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 15 min, was heated at reflux temperature for 15 h and then cooled to room temperature. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 7:3) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclohexyl}thiazole (8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].[F:10][CH:11]([F:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>>[F:10][CH:11]([F:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: Cc1cc(I)ccc1F
Product: Cc1cc(C#Cc2ccc(OC(F)F)cc2)ccc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Fluoro-4-iodo-2-methyl-benzene (0.125 g, 0.53 mmol), and 1-Difluoromethoxy-4-ethynyl-benzene (0.09 g, 0.53 mmol), and was obtained as a yellow semi solid, (0.141 g, 96%), and identified by NMR and mass spectral analyses. MS (EI+): 276 (M+).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH:9](C(OCC)=O)[C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)C1C(O)=C(C(=O)CC)C(=O)CC1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 70 °C

Procedure:
A mixture of 54 g (0.13 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)-4-(carboethoxy)cyclohex-2-en-1-one 30 g (0.37 mol)of 50 percent sodium hydroxide in 450 mL of 95 percent ethanol and 100 mL of water was stirred mechanically and heated at about 70° C. for 16 hours. The resulting clear yellow solution was cooled to about 60° C. and treated with 50 mL of concentrated HCl (some material was lost as the ensuing decarboxylation reaction erupted from the reaction vessel). The product precipitated from the solution and was isolated by filtration. Recrystallization from absolute ethanol gave the above named product as a beige crystalline solid in a yield of 24 g (54 percent of theoretical). The product melted at 114°-115° C.: 1H NMR (CDCl3) δ1.17 (t, 3H, --CH3), 2.60-3.48 (m, 7H, ring protons and --CH2CH3), 5.05 (s, 2H, ArCH2O--), 6.83-7.55 (m, 9H, ArH's), 18.1 (s, 1H, enol, H).
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C(O[CH:14]=[C:15]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:16](=O)[C:17]([F:20])([F:19])[F:18])C>CO>[CH:23]([C:22]([C:15]1[C:16]([C:17]([F:18])([F:19])[F:20])=[N:9][CH:8]=[N:10][CH:14]=1)=[O:26])([CH3:25])[CH3:24]
Reactant: CCOC=C(C(=O)C(C)C)C(=O)C(F)(F)F
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C(=O)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
46 g (0.85 mol) of sodium methoxide was dissolved in 700 ml of methanol, and 76 g (0.73 mol) of formamidine acetate was added, followed by stirring at room temperature for 15 minutes. Then, 146 g (0.61 mol) of 3-ethoxymethylene-1,1,1-trifluoro-5-methyl-2,4-hexanedione was added under cooling with ice, followed by heating and refluxing for further 2 hours. The solvent was distilled off under reduced pressure, and 1,000 ml of ice water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=6:1) to obtain 89 g (yield: 67%) of 5-isopropylcarbonyl-4-trifluoromethylpyrimidine as slightly yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:15]([O:14][CH3:13])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Br)cc1F
Reactant: CNOC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ncc(Br)cc1F

Procedure:
A solution of crude 5-bromo-3-fluoropyridine-2-carboxylic acid (40.65 g, 184.8 mmol), O,N-dimethylhydroxylamine hydrochloride (21.63 g, 221.7 mmol), 1-ethyl-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride (70.85 g, 369.6 mmol), 1-hydroxy-7-azabenzotriazole (2.497 g, 18.48 mmol), and triethylamine (16.48 mL, 118.3 mmol) in 200 mL DMF was stirred at room temperature overnight. The solution was partially concentrated in vacuo and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate. The aqueous layer was extracted 4× with ethyl acetate, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 5-bromo-3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 263.01 for M+H+(79Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg of biphenyl-4-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H), 7.77-7.84 (m, 3H), 8.73 (d, 2H, J=4.4 Hz), 10.01 (s,1H). MS: m/z 449.0 (M++1).