Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:23])[O:21]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 92.7 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (480 mg, 1.10 mmol) and benzaldehyde (138 mg, 131 jut, 1.30 mmol) in 1,2-dichloroethane (1 mL) was stirred for 20 minutes then treated with sodium triacetoxyborohydride (420 mg, 2.20 mmol). After 5 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (50 mL) and extracted with dichloromethane (3×40 mL). Organic layers were collected, dried over MgSO4, filtered and concentrated. MPLC purification (25 g column, 1-10% methanol in dichloromethane) gave 2-acetamido-2-(1-benzylpiperidin-4-yl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (538 mg, 93%), which was used immediately in the subsequent step (approximately 10% of the product had the boronic acid deprotected).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]([CH2:19][CH3:20])=[N:9][C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:11][C:6]2=[N:5][N:4]=1)[CH3:2].C(O)=O.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C:3]1[N:7]=[C:6]2[N:5]([C:8]([CH2:19][CH3:20])=[N:9][C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:11]2)[N:4]=1)[CH3:2]
Reactant: CCc1nnc2cc(N3CCN(C)CC3)nc(CC)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCc1nc2cc(N3CCN(C)CC3)nc(CC)n2n1

Procedure:
A mixture of 3.3 g of 3,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine and 50 ml of 97% formic acid was heated at reflux for 18 hours. The mixture was cooled and evaporated in vacuo to provide a residue which was diluted with 100 ml of water and carefully neutralized with sodium bicarbonate. The solution was extracted with chloroform. The extracts were dried and then concentrated to provide an oil which solidified and was collected by filtration, washed with water and dried. Recrystallization from hexane provided off-white crystalline solid 2,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[1,5-c]pyrimidine, m.p. 87°-88° C. Analysis: Calculated for C14H22N6 : %C, 61.3; %H, 8.1; %N, 30.6; Found: %C, 60.6; %H, 8.1, %N, 30.6. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:23]3[CH:24]=[C:25]4[N:32]([CH3:33])[CH2:31][CH2:30][N:26]4[C:27](=[O:29])[N:28]=3)=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cnc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 2-((5,6-difluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile (131 mg, 0.5 mmol) in THF (4 mL), NaH (30.0 mg, 0.750 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (93 mg, 0.500 mmol).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH2:14][CH:15]([CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25])[O:16][C:17](=[O:20])[CH:18]=[CH2:19])(=[O:12])[CH:10]=[CH2:11]>C(O)(=O)C>[CH3:1][N:2]([CH2:11][CH2:10][C:9]([O:13][CH2:14][CH:15]([O:16][C:17](=[O:20])[CH2:18][CH2:19][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:21][O:22][C:23](=[O:26])[CH2:24][CH2:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: C=CC(=O)OCC(COC(=O)C=C)OC(=O)C=C
Solvent: CC(=O)O
Product: CN(CCC(=O)OCC(COC(=O)CCN(C)c1ccccc1)OC(=O)CCN(C)c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
Propoxylated glycerol triacrylate (GPTA—OTA 480, 5.08 g) was added to N-methylaniline (6.42 g—an equivalent amount required to react with the three acrylate groups, had the reactant been glycerol triacrylate) in glacial acetic acid (10 ml). The reaction mixture was heated at 100° C. for 2 hours and then the acetic acid removed by vacuum distillation. A portion of the residue (11 g) was then subjected to steam distillation to remove the excess N-methylaniline and the product extracted with dichloromethane (25 ml). The extract was dried over anhydrous magnesium sulphate, filtered and the dichloromethane removed by distillation in vacuo to leave a pale brown-coloured oil (6.46 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:26][S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28]>CO>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:14][CH:15]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)[CH2:31][CH2:30][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: C=CS(C)(=O)=O
Reactant: CNCC1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Solvent: CO
Product: CN(CCS(C)(=O)=O)CC1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a stirred solution of N-methyl-1-{4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine (230 mg, 0.66 mmol) in methanol (2 mL) was added methanesulfonyl-ethene (64 μL, 0.72 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and triturated with diethyl ether to give the title compound as a white solid (274 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 1.81 (m, 2H), 1.97 (m, 2H), 2.04 (s, 3H), 2.13 (m, 2H), 2.42-2.58 (m, 8H), 2.62 (t, 2H), 2.74 (s, 3H), 2.81 (t, 2H), 3.50 (m, 2H), 3.70-3.80 (m, 6H), 4.00 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 455.2570 [MH]+. Microanalysis: Found: C, 60.61; H, 8.47; N, 6.09%. C23H38N2O5S requires C, 60.76; H, 8.42; N, 6.16%.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]\[CH2:10][PH:11]([CH2:13][OH:14])=[O:12])/[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[H][H]>CO>[C:1]([NH:4][C@H:5]([CH2:9][CH2:10][PH:11]([CH2:13][OH:14])=[O:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Reactant: [H][H]
Solvent: CO
Product: CC(=O)N[C@H](CC[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(Z)-2-acetylamino-4-hydroxymethylphosphinyl-2-butenoic acid (4.0 g, 18 mmol), (RuCl((R)-segphos)2(μ-Cl)3(Et2NH2) (0.150 g, 0.09 mmol), and methanol (40 ml) were added to a 200 ml autoclave, and a nitrogen substitution and a hydrogen substitution were performed. The temperature in the autoclave was set to 70° C., hydrogen gas was charged to 1 MPa, and the reaction solution was stirred at the same temperature for 5 hours. A part of the reaction solution was taken as a sample. After completion of the reaction was confirmed with HPLC analysis on the sample, reaction solution was cooled to room temperature, hydrogen was released, and then the reaction solution was moved to a 100 ml flask. After methanol was removed in vacuo and adding water (20 ml), the water phase was washed with toluene (10 ml) twice and a solution of (R)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was obtained. The optical purity of the obtained (R)-2-acetylamino-4-hydroxymethylphosphinylbutanoic acid was 92.8% ee. Further, the conversion rate was 100%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:17]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH2:17])=[O:9])=[CH:2]1
Reactant: [NH4+]
Reactant: O=C(O)Cc1ccsc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)Cc1ccsc1
Reaction time: 8 h

Procedure:
Commercially available 3-thiophene acetic acid (2.0 g, 14.07 mmol) was dissolved in DCM (45 mL) under nitrogen. Then oxalyl chloride (1.35 mL, 15.48 mmol) was added and the reaction was stirred overnight. Then ammonium hydroxide (30% as NH3 solution) (8.22 mL) was added dropwise with stirring. The reaction mixture was evaporated to provide 2-(3-thienyl)acetamide as a beige solid (3.2082 g). LCMS: (M+H)+=142.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]3([CH2:35][CH2:34]3)[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]3([CH2:35][CH2:34]3)[CH2:32]2)[N:3]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC12CC2
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC12CC2
Yield: 57.1 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0961 g, 0.165 mmol) in 4:1 HOAc-water (5 mL) was stirred for 3 days. The solution was concentrated in vacuo and diluted with DCM (100 mL). The solution was washed with sat. aq. NaHCO3 (25 mL), and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC, and the desired fractions were concentrated in vacuo and azeotroped first with MeOH and then with EtOAc. The residue was crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0469 g, 57%, mixture of diastereomers) as a white solid. LCMS: (M+H)+: 498.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.Br[CH2:21][C:22]#[N:23].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:21]=[C:22]([NH2:23])[N:19]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: N#CCBr
Reactant: CC(c1ccc(N)nn1)c1nnc2ccc(Br)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(c1ccc2nc(N)cn2n1)c1nnc2ccc(Br)cn12
Temperature: 100 °C
Yield: 55.3 %

Procedure:
A mixture of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)pyridazin-3-amine (1.0 g, 3.13 mmol), 2-bromoacetonitrile (0.251 ml, 3.76 mmol) and NaHCO3 (0.053 g) in IPA (10 mL) was heated at 100° C. in a sealed tube for 2 hrs. The solid was filtered off, rinsed with IPA, and stripped to dryness via rotary evaporation. The resulting residue was purified by LCMS and lyophilized as a TFA salt to provide the title compound, 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-amine 48G (0.62 mg, 1.73 mmol, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (d, J=7.07 Hz, 3 H) 5.17 (d, J=7.07 Hz, 1 H) 7.38-7.57 (m, 3 H) 7.80 (d, J=9.60 Hz, 1 H) 7.99 (d, J=9.09 Hz, 1 H) 8.78 (s, 1 H). ESI-MS:m/z 358.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[CH:8]=[C:9]3[C:14](=[O:15])O[C:11](=[O:12])[C:10]3=[CH:16][C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.O.C([NH2:31])=O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[CH:16]=[C:10]3[C:11](=[O:12])[NH:31][C:14](=[O:15])[C:9]3=[CH:8][C:7]=2[NH:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)=[CH:20][CH:21]=1
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
A suspension of 1000 mg (2.73 mmol) of 4,5-bis(4-fluoroanilino)phthalic anhydride in 5 ml of formamide under argon atmosphere is heated at 125°-130° for 5 hours. The reaction mixture is cooled to 60°, and 20 ml of water are slowly added. This mixture is cooled to 0° for 3 hours, and the reddish crystals are filtered off, washed with water and dried. Recrystallization from dichloromethane yields the title compound in the form of orange crystals, m.p. 244°-246° C., FAB-MS: 366 [M+ +H].
Reaction SMILES: [CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH:20]([CH3:22])[CH3:21])[C:8](=[O:23])[NH:7][C:6]1=[O:24])[C:2]#[C:3][CH3:4]>CO.[Pd]>[CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH:20]([CH3:21])[CH3:22])[C:8](=[O:23])[NH:7][C:6]1=[O:24])[CH:2]=[CH:3][CH3:4]
Reactant: CC#CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: CC=CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 0.25 h
Yield: 101.5 %

Procedure:
1-But-2-ynyl-6-(3,5-dimethyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (116) (50 mg, 0.15 mmol) was stirred in the presence of palladium on barium sulfate (15 mg) in methanol (5 mL) under a hydrogen atmosphere. After 15 min., the mixture was filtered through a plug of celite and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 50 mg (100%) of a white solid. m.p. 141-142° C.; 1H-NMR (200 MHz, CDCl3) δ 1.13 (6H, d, J=7.0 Hz), 1.61 (3H, dd, J=6.9 Hz, 1.4 Hz), 2.31 (6H; s), 2.79 (1H, m), 4.35 (2H, d, J=6.8 Hz), 5.38 (1H, m), 5.60 (1H, m), 6.54 (2H, s), 6.77 (1H, s); m/z (EI) 328(M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][NH2:29]>CS(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Yield: 12.5 %

Procedure:
[2-(4-Chloro-2-methylquinolin-8-yloxy)-ethyl]-carbamate tert-butyl ester (1.30 g, 3.86 mmole), 3,4-dichlorobenzylamine (1.36 g, 7.72 mmole) and a catalytic effective amount of copper(II)sulphate pentahydrate in dimethylsulfoxide (0.2 mL) were stirred at 155° C. for 30 min in a microwave oven. The organic phases were washed with water and saturated NaCl solution, dried and the solvent was removed. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:water 90:10. Precipitation in ethyl acetate gave a brownish solid (230 mg, 13%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1([CH2:24][OH:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1([CH:24]=[O:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C=O)CCOCC1
Temperature: -65 °C
Reaction time: 0.05 h
Yield: 92.6 %

Procedure:
Anhydrous dimethyl sulfoxide (3.0 mL, 42.2 mmol) was added to a −65° C. solution of oxalyl chloride (2.0 mL, 22.9 mmol) in anhydrous dichloromethane (100 mL) and allowed to stir at −65° C. under N2 blanket for 3 minutes, after which time a solution of (4-hydroxymethyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (4.89 g, 21.1 mmol) in anhydrous dichloromethane (25 mL) was added. When 25 minutes had elapsed, triethylamine (14.7 mL, 105.5 mmol) was added and the reaction solution allowed to stir for a further 20 minutes at −65° C.; then the cold bath was removed and the reaction warmed to ambient temperature, washed with saturated aqueous sodium chloride (500 mL), dried (MgSO4), and evaporated to afford 4.48 g of clear yellow viscous liquid which was used without further purification. LRMS (ESI) m/z 230.2 [(M+H)+, calcd for C11H20NO4230.3].
Reaction SMILES: [CH3:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>C(Cl)Cl>[CH3:21][S:22]([O:11][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1])(=[O:24])=[O:23]
Reactant: CCCCCCCCC(C)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCC(C)OS(C)(=O)=O
Reaction time: 0.17 h
Yield: 105.8 %

Procedure:
To a solution of 2-decanol (5.0 ml, 26.0 mmol) in dry CH2Cl2 (52 ml) under an N2 atmosphere was added diisopropylethylamine (5.6 ml, 32.1 mmol). The reaction flask was immersed in an ice/water bath. After stirring for 10 minutes, methanesulfonyl chloride (2.8 ml, 36.1 mmol) was added via syringe over a period of 10 minutes. After stirring for 3 hrs, the reaction was diluted with cold CH2Cl2 (200 ml) and poured into cold 5% aqueous HCl (100 ml). The layers were separated and the organic phase washed with cold 5% aqueous HCl (50 ml) followed by brine (2×50 ml). The CH2Cl2 layer was dried (Na2SO4), filtered and evaporated in vacuo at 25° C. The resulting light yellow oil was pumped under reduced pressure for 2 hrs to provide 2-methanesulfonyloxydecane (6.5 g, 93.5%) as a light yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2nc1-c1cccs1
Product: Clc1nc2ccccc2nc1-c1cccs1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 3-(2-thienyl)quinoxalin-2(1 H)-one (500 mg, 2.19 mmol.) and POCl3 (6 mL) was heated to reflux at 120° C. After the material was consumed, the reaction mixture was taken up with water and ice. The solid was collected and dried in vacuo to give 2-chloro-3-(2-thienyl)quinoxaline (400 mg, 74%). 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J=4.8 Hz, 1 H), 8.00 (d, J=10.4 Hz, 1 H), 7.91 (d, J=10.4 Hz, 1 H), 7.72˜7.61 (m, 2 H), 7.52 (d, J=6.8 Hz, 1 H), 7.13 (t, J=6.0 Hz, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1.CS([C:20]1[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:22][N:21]=1)(=O)=O>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][C:20]2[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[S:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1nsc(Nc2ccncc2)c1C(N)=O
Reactant: SCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Potassium tertbutoxide (318 mg, 2.84 mmol) is dissolved in anhydrous THF (5 mL) and (4-Chlorophenyl)-methanethiol (0.375 mL, 2.84 mmol) is then added and stirred for 30 min room temperature. This resulting solution is then added to a solution of crude 9 (170 mg) dissolved in anhydrous THF (3 mL). The reaction is stirred for 4 hours at room temperature and then heated to 60° C. for 18 hours. The reaction is diluted with water and extracted with a solution containing 5% methanol and 95% methylene chloride (10 mL×3). The combined organics are dried over sodium sulfate, filtered and then concentrated in vacuo. Chromatography (3% MeOH/methylene chloride) provides 3-(4-Chloro-benzylsulfanyl)-5-(pyridin-4-ylamino)-isothiazole-4-carboxylic acid amide (18 mg, 2.5%-2 steps). 1H NMR (d6 DMSO): δ 8.17 (2H, broad s), 7.45 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 6.99 (2H, broad s), 4.32 (2H, s); LRMS (M+): 376.9, (M−): 375.0.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][NH:28][C:22]=2[CH:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:42][CH:41]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc(N5CCN(C)CC5)cc4)c3cn2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. LCMS (M+H)+=466.2.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[N+:14]([C:17]1[C:18]([CH:27]=[O:28])=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)([O-:16])=[O:15].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:27]([C:18]2[C:17]([N+:14]([O-:16])=[O:15])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[OH:28])=[N:8][CH:9]=1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Fc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1c(C(O)c2ccc(F)cn2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
n-BuLi (1.6M in hexane; 5.5 ml, 8.9 mmol) was added to anhydrous toluene (35 ml) at −78° C. under an N2 atmosphere followed by dropwise addition of a solution 2-bromo-5-fluoropyridine (1.56 g, 8.9 mmol) in anhydrous toluene (10 ml). The mixture was stirred at −78° C. for 45 min. The mixture was added to a solution of 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (1 g, 5.0 mmol) in THF (50 ml) at −78° C. over 10 min. The mixture was stirred at −78° C. for a further 1 h. NH4Cl solution (10 ml) was added at −78° C. and the mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in DCM (50 ml) and the organic phase was washed with sat. NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography DCM/MeOH (99:1) as the eluent to give the title compound (700 mg, 46%).