Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[F:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=2)[CH:16]=[C:17]([F:19])[CH:18]=1.N1C=CC=CC=1>CC#N>[F:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([S:25]([NH:1][C:2]3[S:3][C:4]([CH3:11])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=3)(=[O:27])=[O:26])=[CH:22][CH:21]=2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: COC(=O)c1nc(N)sc1C
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(F)cc(F)c2)s1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1sc(NS(=O)(=O)c2ccc(-c3cc(F)cc(F)c3)s2)nc1C(=O)O
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (25 mg, 0.15 mmol), 5-(3,5-difluorophenyl)thiophene-2-sulfonyl chloride (43 mg, 0.15 mmol) (Intermediate 21) and pyridine (23 mg, 0.29 mmol) in MeCN (1 mL) was stirred at 50° C. for 2 days. After evaporation of the solvents, the residue was dissolved in THF (1 mL) and 2 M LiOH (1 mL) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was neutralized with 4 M HCl (0.3 mL) and the solvents were removed by evaporation. The crude material was dissolved in MeCN/water (1:1). The product precipitated and the title compound was obtained in 9% yield (5.8 mg). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.56 (s, 3 H) 6.97 (tt, J=9.05, 2.27 Hz, 1 H) 7.26-7.34 (m, 2 H) 7.45 (d, J=3.91 Hz, 1 H) 7.58 (d, J=3.91 Hz, 1 H). MS (ESI+) m/z 417 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:27]=[CH:28][C:29](B(O)O)=[N:30][CH:31]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(F)cn1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cn1
Yield: 3.6 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 5-fluoropyridine-2-boronic acid (available from Combi-Blocks Inc.; 71 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(5-fluoro-pyridin-2-yl)-benzoic acid (4 mg, 4%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm. LRMS m/z 444.8 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[N:23][OH:24])[NH2:22])=[CH:16][N:15]=2)[C@H:11]([C:25]([O:27][CH3:28])=[O:26])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=O)=[CH:32][C:31]=1[CH2:40]OC.[CH2:43](Cl)[CH2:44]Cl>CC#N.N1C=CC=CC=1>[Cl:20][C:19]1[C:14]([N:12]2[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C@H:11]2[C:25]([O:27][CH3:28])=[O:26])=[N:15][CH:16]=[C:17]([C:21]2[N:22]=[C:40]([C:31]3[CH:30]=[CH:39][C:38]([C:25]4[CH:11]=[CH:10][CH:9]=[CH:13][C:43]=4[CH3:44])=[C:33]([CH2:34][O:36][CH3:37])[CH:32]=3)[O:24][N:23]=2)[CH:18]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C(N)=NO)cc1Cl
Reactant: ClCCCl
Reactant: COCc1cc(C(=O)OC)ccc1Br
Solvent: c1ccncc1
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3cnc(N4C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]4C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-(N′-hydroxycarbamimidoyl)pyridin-2-yl)pyrrolidine-2-carboxylate (0.320 g; 0.75 mmol) and Intermediate A1 (0.210 g; 0.82 mmol) in MeCN (3 mL) was added EDC (0.157 g; 0.82 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. in the microwave for 30 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (6:1) to afford the title product. 1H NMR (CDCl3, 400 MHz) δ 8.69 (1H, d, J=2 Hz), 8.30 (1H, d, J=1.6 Hz), 8.15 (1H, d, J=1.6 Hz), 8.06-8.03 (1H, m), 7.24-7.16 (4H, m), 7.04 (1H, d, J=7.2 Hz), 4.82 (1H, m), 4.50 (1H, m), 4.22-4.18 (1H, m), 4.13-4.12 (2H, m), 3.76 (1H, m), 3.64 (3H, s), 3.23 (3H, s), 2.20 (1H, m), 1.99-1.98 (4H, m), 0.79 (9H, s), 0.00 (3H, s), −0.02 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[O:31][CH3:32])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 mL) were added methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine (3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. After concentration, the crude was purified by chromatography on silica gel to afford 3.4 mg (46%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H). LCMS (method B): [MH]+=421, tR=1.95 min.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A solution of 35.08 g of methyl 2-(4-methylphenoxy)benzoate, 25.7 g of N-bromosuccinimide, 0.57 g of azobisisobutyronitrile, and 1200 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 4.51 g of crude methyl 2-(4-bromomethylphenoxy)benzoate which was used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ7.92 (d of d, 1H); 7.45 (t of d, 1H); 7.16 (m, 3H); 6.90 (m, 3H); 4.49 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH3:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:22][CH2:21]3)[CH3:19])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(C(C)Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of (±)-2-[4-(methylsulfonyl)phenyl]-5-{[1-(4-piperidinyl)ethyl]oxy}pyridine (0.27 g, 0.75 mmol) in CH2Cl2 (10 mL) and THF (5 mL) was treated with diisopropylethylamine (0.27 mL, 1.50 mmol). The mixture was cooled to 0° C., and then isopropyl chloroformate (1.0M in toluene, 0.82 mL, 0.82 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, diluted with CH2Cl2 (100 mL) and washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:5 acetone/CH2Cl2 to give 0.31 g (93%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.9 Hz), 8.13 (d, 2H, J=8.5 Hz), 8.01 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.35-4.15 (m, 3H), 3.08 (s, 3H), 2.80-2.65 (m, 2H), 1.95-1.65 (m, 3H), 1.45-1.25 (m, 5H), 1.23 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6]CC)=O.Cl.[C:11](=[NH:14])([NH2:13])[CH3:12].C([O-])C.[Na+].O>C(O)C>[CH3:12][C:11]1[N:14]=[C:4]([OH:6])[CH:3]=[C:2]([CH3:9])[N:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)nc(C)n1
Yield: 35.9 %

Procedure:
Ethyl 3-oxobutanoate (10.0 g, 77 mmol) and acetimidamide hydrochloride (7.23 g, 77 mmol) were added to the solution of sodium ethanolate (10.5 g, 154 mmol) in ethanol (200 mL). And the mixture was refluxed for 20 hours. Water (10 mL) was added to the mixture. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 2,6-dimethylpyrimidin-4-ol as a yellow solid (3.43 g, 36%). LRMS (M+H) m/z: calcd 124.06. found 124.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(Cl)[Cl:42].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: CCOCCOC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 95 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 5 ml of ethoxyethyl acetate. The solution was cooled in an ice bath with stirring. Thereto was added dropwise over 10 minutes 1.21 ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 202 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Temperature: 100 °C

Procedure:
To the product of Step B (1.5 g) was added POCl3 (5 mL). The reaction was heated to 100° C. for 17 hours. After cooling to room temperature the excess POCl3 was removed in vacuo before the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel eluted with 10% EtOAc in hexane affording the title compound. HPLC/MS: 358.9 (M+1), 360.9 (M+3); Rt=4.07 min.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:14]=1[N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[N:26]=[N:25]1.[NH2:33][C:34]1[C:35](=[O:48])[N:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])[N:37]([CH3:40])[C:38]=1[CH3:39].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:21])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[N:24]1[C:28]([CH3:29])=[C:27]([C:30]([NH:33][C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[N:37]([CH3:40])[C:38]=2[CH3:39])=[O:31])[N:26]=[N:25]1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(OC(F)(F)F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(OC(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMF (43 μL, 0.56 mmol) was dissolved in DCM (1 mL) and cooled to 0° C. Oxalyl chloride (27 μL, 0.308 mmol) was added followed by 1-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (90 mg, 0.28 mmol) and the reaction mixture was stirred for 10 min. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (62 mg, 0.28 mmol) was added, followed by triethylamine (117 μL, 0.839 mmol). The reaction was allowed to warm to RT and stirred for 4 h. Saturated aqueous NaHCO3 was added to the reaction mixture and the product was extracted with DCM. The organic extract was dried and concentrated under reduced pressure. The crude material was purified by reversed phase chromatography (Prep Method G) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:45])([F:44])[C:27]1[CH:43]=[CH:42][C:30]([CH:31]=[N:32][N:33]2[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:45][C:26]([F:25])([F:44])[C:27]1[CH:43]=[CH:42][C:30]([CH:31]=[N:32][N:33]2[CH2:34][CH2:35][N:36]([C:39]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:40])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: O=C(Cl)N1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@](O)(COC(=O)N1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (2.75 g, 11.66 mmol), N,N-diisopropylethylamine (2.71 ml, 15.54 mmol) and 4-dimethylaminopyridine (0.19 g, 1.55 mmol) were added to a suspension of 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carbonylchloride (2.48 g, 7.77 mmol) in toluene (40 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carboxylate (4.03 g, quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]=[CH:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>C1COCC1>[CH3:22][O:21][P:20]([CH:6]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:12][CH3:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:25])[O:23][CH3:24]
Reactant: CCOC(=O)Cl
Reactant: COP(OC)OC
Reactant: COC(CN=Cc1cccs1)OC
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(OC)OC)C(c1cccs1)P(=O)(OC)OC
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To the oil obtained in Step i (16.3 g, 82.3 mmol) was added 60 mL THF under a N2 atmosphere. The reaction was cooled to −10° C. (MeOH/ice) and fitted with an internal thermometer. Ethyl chloroformate (7.9 mL, 82.3 mmol) was added dropwise keeping the internal temperature at or below −9.5° C. The reaction was stirred for 10 minutes at −10° C. and then the bath was removed and the reaction was allowed to warm to room temperature. Using an ice bath as a heat sink, trimethyl phosphite (10.7 mL, 90.5 mmol) was added. The reaction was allowed to gradually warm to room temperature and was stirred overnight. The solvent was removed on a rotary evaporator. Toluene was added and evaporated on a rotary evaporator. The toluene addition and evaporation was then carried out a second time.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(Cl)Cl>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][S:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:19])=[O:20]
Reactant: CC(C)(CN)CO
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.2 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient temperature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s,1 H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: C([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:46]([OH:54])(=[O:53])[CH:47]([CH2:49][C:50]([OH:52])=[O:51])[OH:48].[H][H]>O1CCCC1.CCOCC>[CH2:23]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][C:18]([O:53][C:46](=[O:54])[CH:47]([CH2:49][C:50]([OH:52])=[O:51])[OH:48])=[O:19])=[CH:21][CH:22]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: [H][H]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C=CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OC(=O)C(O)CC(=O)O)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(hexadecylamino)cinnamoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% Pd(C) at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated and the residue is crystallized from acetic acid to yield the reduced and deblocked title compound as a tan, crystalline mass.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1cc2ccccc2nc1Cl
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2nc1-c1ccccc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 2-chloroquinoline-3-carboxylate (2.01 g, 10 mmol), prepared as described in the Journal of Organic Chemistry 2003, 68, 9517-9520, 2-methoxyphenylboronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:16][C:9]=12>C(O)(C)C>[C:17]1([N:14]2[C:10]3=[N:11][CH:12]=[N:13][C:8]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[C:9]3[CH:16]=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc2c1cnn2-c1ccccc1
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: c1ccc(-n2ncc3c(N4CCNCC4)ncnc32)cc1
Yield: 88 %

Procedure:
To an isopropanol solution (10 mL) of piperazine (3.74 g, 43.4 mmol), 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine (100 g, 4.34 mmol) described in J. Org. Chem., 21: 1240-1256 (1956) was added, followed by heating under reflux for 6 hours. The reaction solution was concentrated, saturated brine was added thereto, the mixture was extracted with chloroform, the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to give the target compound (1.07 g, 3.82 mmol).