Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[NH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[N:29][C:30]=3[NH2:32])[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=2)=[C:17]([F:46])[CH:16]=1>N1C=CC=CC=1>[NH2:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=[C:23]([C:18]3[C:17]([F:46])=[CH:16][C:15]([NH:14][C:3](=[O:4])[C:2]([CH3:13])([CH3:1])[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:20]([O:21][CH3:22])[CH:19]=3)[C:31]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)C(C)(C)Cc1ccccc1
Reaction time: 5 h

Procedure:
2,2-Dimethyl-3-phenylpropanoyl chloride (52 mg, 0.264 mmol) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL). After 5 hours, the solvent was evaporated and the residue was first purified by flash column chromatography chromatography using dichloromethane/methanol (95:5 to 85:15) as mobile phase then by preparatory LC/MS to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (22 mg, 19%). 1H NMR (CDCl3-d) δ 1.33 (s, 6H), 1.57 (m, 2H), 1.92 (m, 2H), 2.15 (m, 6H), 2.30 (s, 3H), 2.49 (m, 4H), 2.66 (m, 3H), 2.95 (s, 2H), 3.84 (s, 3H), 4.76 (m, 1H), 5.51 (bs, 2H), 6.98 (d, J=6.86 Hz, 1H), 7.15 (m, 2H), 7.23 (m, 3H), 8.01 (s, 1H), 8.35 (s, 1H), 8.47 (d, J=11.88, 1H). LCMS LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=615.3, Rt=2.18 min.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>CO>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CO
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
0.5 g 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (4.38 mmoles) are heated at 115° C. (external temperature) for 12 h with stirring by a magnetic stirrer, with 0.57 g ethyl 3,4-epoxybutanoate ((4); X=C2H5) (4.38 mmoles). The mixture is cooled, taken up with methanol and filtered. Oxiracetam is obtained, m.p. 167°-70° C.
Reaction SMILES: FC(S(O[C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)(=O)=O)(F)F.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C>[C:36](=[N:49][C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(OS(=O)(=O)C(F)(F)F)c3ccoc23)C1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(N=C(c3ccccc3)c3ccccc3)c3ccoc23)C1=O
Temperature: 25 °C

Procedure:
Heat a mixture of 7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl (trifluoromethyl)sulfonate (100 mg, 0.2 mmol), benzophenone imine (0.037 ml, 0.22 mmol), tris-(benzylideneacetone)-dipalladium(0)(9 mg, 0.01 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol), and cesium carbonate (91 mg, 0.28 mmol) in anhydrous toluene (1 ml) to 80° C. for 19 hours under a nitrogen atmosphere. Allow the reaction to cool to room temperature, dilute with diethyl ether, and filter through Celite. Wash the filtrate with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (ethyl acetate: hexanes) affords the title compound as a red oil. MS(ES+): 536.1.
Reaction SMILES: [NH2:1][C:2]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)[CH:6]([CH2:7][OH:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Br:17][C:12]1[CH:11]=[C:10]([C:2]2([NH:1][C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[CH2:3][CH:4]([OH:9])[CH2:5][CH:6]2[CH2:7][OH:8])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(c2ccc(F)c(Br)c2)CC(O)CC1CO
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2ccc(F)c(Br)c2)CC(O)CC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of racemic (1RS,3SR,4RS)-3-amino-3-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)cyclopentanol (0.48 g, 1.58 mmol) in THF (6.31 mL) is added benzoyl isothiocyanate (0.263 g, 1.58 mmol) and the mixture is stirred at room temperature for 1.5 h. The solvent is removed under reduced pressure and the crude product is purified by silica gel chromatography, eluting with a linear gradient of 0% to 10% methanol in dichloromethane over 20 minutes to give the title compound as racemic mixture (0.602 g, 76%). ES/MS m/e (79Br/81Br) 467, 469 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Yield: 67.7 %

Procedure:
A mixture of 3-nitrobenzyl bromide (17.3 g, 0.08 mol), triethyl phosphite (13.3 g, 0.08 mol) in toluene (200 mL) was stirred at reflux for 24 h. The reaction mixture was cooled and evaporated in vacuo. Chromatography of the residues on SiO2 eluting from 0–100% ethyl acetate in petroleum ether (60–80° C.) gave the title compound (14.8 g, 68%) as a yellow liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CC(C)=O>CCCCCC>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: ClCCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1CCc2ccc(OCCCCCl)cc2N1
Yield: 78 %

Procedure:
1-bromo-4-chloro-butane (3.4 g, 20 mmol), anhydrous potassium carbonate powder (4.14 g, 30 mmol) and 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.63 g, 10 mmol) are added to 10 ml of acetone and reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is slurried with n-hexane (20 ml×3), filtered, and dried to obtain 1.98 g of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone, with a yield of 78%.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:16]([O-:18])=[O:17])[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc2nc(O)c(O)nc2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 24 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
2 g 6-azido-2,3-dihydroxyquinoxaline is suspended in 100 ml glacial acetic acid. To the suspension is added 16 ml fuming nitric acid at 24° C. The mixture is stirred at 24° C. for 4 h giving a precipitate of 1.9 g (78%) 6-azido-2,3-dihydroxy-7-nitroquinoxaline. IR: a peak at 2120 cm−1. NMR: two singlets (7.0 and 7.7 ppm downfield from TMS).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:22]([NH:23][CH3:24])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 66 %

Procedure:
A solution of 1-benzyl-3-butyl-6-hydrazinouracil (4.0 g, 13.9 mM) and methyl isothiocyanate (2.85 ml, 41.7 mM) in DMF (50 ml) was stirred at 120° C. for 20 hours. To the solution was added methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (3.0 g, 66%), m.p. 282°-284° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C@@H:30]1[O:32][CH2:31]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:28][CH2:29][C@H:30]3[CH2:31][O:32]3)[CH2:7][C:6]=2[CH:20]=1
Reactant: BrCC[C@H]1CO1
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Temperature: 45 °C
Reaction time: 14 h
Yield: 160 %

Procedure:
A solution 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.13 g, 0.29 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.14 mL, 1.41 mmol) and was heated to 45° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with sat. sodium bicarbonate (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.17 g, 67%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene (0.62 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.79 g, 61%).
Reaction SMILES: [Se](=O)=O.O.[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].CC[O:19]C(C)=O>O1CCOCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH:5]=[O:19])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1cccc([N+](=O)[O-])c1
Yield: 76 %

Procedure:
To a solution of Selenium dioxide (9.4 g, 85 mmol) in 1,4-Dioxane (50.0 mL) and Water (1.70 mL, 94.4 mmol), was added 3-Nitroacetophenone (12.0 g, 72.9 mmol). The reaction mixture was refluxed for 4 hours with stirring, then taken up with EtOAc (100 mL) and washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and conc. in vacuo. Purification was by ISCO column chromatography (20-70% EtOAc/Hex) to afford (3-Nitro-phenyl)-oxo-acetaldehyde (9.98 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:26]([O:28]CC)=[O:27])[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1.[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCn3ccnc3C)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nccn1CCOc1ccc(-n2c(=O)ccc3c(-c4ccccc4)c(C(=O)O)sc32)cc1

Procedure:
To a solution of the compound of Example 91 (134 mg, 0.27 mmol) in EtOH (0.5 mL) and water (0.73 mL) was added sodium hydroxide (0.27 mL of a 1M solution, 0.27 mmol) and the mixture heated at reflux for 5 h. The reaction was freeze dried to give 7-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylic acid as a solid. LCMS (ES+) RT 2.34 minutes, 472 (M+H)+. This compound was dissolved in DMF (2 mL) and thionyl chloride (30 μL, 0.405 mmol) was added and the reaction stirred at r.t. for 5 mins. Aqueous ammonia (2 mL of a 25% solution) was added and the reaction stirred for 30 mins. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc extracts were washed with water (2×10 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a solid (104 mg, 82%). δH (CDCl3) 7.52–7.48 (3H, m), 7.37–7.33 (2H, m), 7.29–7.26 (2H, m), 7.20–7.18 (1H, m), 7.01–6.96 (3H, m), 6.90–6.88 (2H, m), 6.50 (1H, d, J 9.6 Hz), 4.23–4.20 (4H, m), 2.42 (3H, s). LCMS (ES+) RT 2.28 minutes, 471 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH2:22]([NH2:24])[CH3:23]>O1CCCC1.O>[CH2:22]([NH:24][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1)[CH3:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred solution of 70% ethylamine (0.5 ml) in water (5 ml) at 5° to 10° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Water (30 ml) was added to the reaction mixture. The precipitates were filtered, washed with water, and dried under reduced pressure to give a yellow powder of N-ethyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.94 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26].Cl.CC1N(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)C=C(OC2CCNCC2)C=1.Cl[C:54]1[N:59]=[CH:58][C:57]([CH2:60][CH2:61][CH3:62])=[CH:56][N:55]=1.ClC1N=CC(C2CC2)=CN=1>>[Cl:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:54]3[N:59]=[CH:58][C:57]([CH2:60][CH2:61][CH3:62])=[CH:56][N:55]=3)[CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26]
Reactant: CCCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)c(Cl)c1
Agent: Cc1cc(OC2CCNCC2)cc(=O)n1-c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: Clc1ncc(C2CC2)cn1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4Cl)c(=O)c3)CC2)nc1

Procedure:
Example 169 was prepared according to the procedures described in Example 168 and Example 162 substituting 1-(2-chloro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride for 6-methyl-1-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride and 2-chloro-5-propylpyrimidine for 2-chloro-5-cyclopropylpyrimidine in Step C. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (s, 2 H), 8.16 (s, 1 H), 7.99 (dd, J=8.25, 2.20 Hz, 1 H), 7.62 (d, J=8.25 Hz, 1 H), 7.06 (d, J=7.70 Hz, 1 H), 6.10 (dd, J=7.70, 2.75 Hz, 1 H), 6.05 (d, J=2.75 Hz, 1 H), 4.55-4.64 (m, 1 H), 4.23 (dd, J=11.55, 6.05 Hz, 2 H), 3.59-3.69 (m, 2 H), 3.14 (s, 3 H), 2.43 (t, J=7.42 Hz, 2 H), 2.11 (td, J=6.32, 3.30 Hz, 2 H), 1.88 (ddd, J=8.39, 4.40, 4.26 Hz, 2 H), 1.55-1.61 (m, 2 H), 0.96 (t, 3 H). MS (ESI) 503 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CN(C=O)C>[NH2:1][C:2]1[C:3](/[CH:11]=[CH:10]/[C:9]([O:13][CH3:14])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncccc1N
Temperature: 145 °C
Yield: 133.5 %

Procedure:
The following reaction was performed in duplicate: A glass microwave reaction vessel was charged with 3-amino-2-bromopyridine (2.00 g, 11.56 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.250 g, 0.353 mmol). DMF (10 mL) was added followed by methyl acrylate (4.00 mL, 44.3 mmol) and triethylamine (4.00 mL, 28.7 mmol). The reaction mixture was sealed under argon and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 145° C. for 40 min. The reaction mixtures were combined and the solvent was removed in vacuo. The residue was dissolved in DCM, evaporated onto silica gel and purified by flash chromatography (ISCO, (120 gram HP)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1-1:39) to give 2.75 g (69%) of a yellow amorphous solid. ESI-MS 179.0 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]([OH:32])([C:30]#[CH:31])[CH3:29])[CH:24]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:25]4[CH:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCCO)n(-c4ccnc(N)n4)c3c2)no1
Yield: 30 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (80 mg, 0.19 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (80 mg, 0.53 mmol), bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (3 mL) under nitrogen in a 10-mL sealed tube was irradiated with microwave radiation for 30 min at 70° C. The reaction mixture was concentrated and the crude product (80 mg) was purified by Flash-Preparative HPLC to give 24 mg (28%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 8.39 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06 (s, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 5.03 (t, J=5.2 Hz, 1H), 4.62 (s, 2H), 3.82 (d, J=4.0 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+455 (M+H)+.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[CH:32]=[CH:31][C:24]4[N:25]=[C:26]5[N:30]([C:23]=4[CH:22]=2)[CH2:29][CH2:28][S:27]5)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:27]1[C:26]2=[N:25][C:24]3[CH:31]=[CH:32][C:21](/[CH:20]=[C:15]4\[C@@H:16]5[N:13]([C:14]\4=[O:37])[C:12]([C:10]([OH:11])=[O:9])=[CH:18][S:17]5)=[CH:22][C:23]=3[N:30]2[CH2:29][CH2:28]1
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCS5)C(=O)N12
Yield: 8.1 %

Procedure:
6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (690 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 32 mg of product (Yield 3%) was collected. MP: >250° C.; H-NMR(D2O): □ 7.08(m, 6H), 7.36(s, 1H), 4.05(m, 2H), 3.90(b, 1H); MS: 358.3 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([CH:44]([CH3:47])[CH2:45][OH:46])[CH:38]=[CH:37]2.[C:48](O)(=[S:50])[CH3:49]>C1COCC1.C(OCC)(=O)C>[C:48]([O:46][CH2:45][CH:44]([C:39]1[CH:38]=[CH:37][C:36]2[C:41](=[CH:42][CH:43]=[C:34]([O:33][CH3:32])[CH:35]=2)[CH:40]=1)[CH3:47])(=[S:50])[CH3:49]
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Reactant: CC(O)=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)COC(C)=S)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of diethylazodicarboxylate (4.03 g, 23.14 mmol) and triphenyl phosphine (6.06 g, 23.14 mmol) at 0° C. in THF (50 mL) was added 2-(6-methoxy-2-naphthyl)propan-1-ol (2.5 g, 11.57 mmol) and thioacetic acid (1.76 g, 23.14 mmol). The reaction mixture was stirred for 30 minutes before it was allowed to warm to room temperature and then stirred overnight. The reaction mixture was diluted with ethyl acetate ("EtOAc") (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate-hexane (1:9)) to give 1.5 g of the title compound as an oil. 1H NMR (CDCl3)δ1.38 (d, 3 H, CH3), 2.29 (s, 3 H, SCH3), 3.10 (m, 1 H), 3.18 (m, 2 H), 3.91 (s, 3 H, OCH3), 7.11-7.72 (m, 6 H).