Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].S(=O)(=O)(O)[OH:13]>O.CC(C)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[C:6]([OH:13])=[O:7])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [Cr+3]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Chromium oxide (14.77 mmol; 1.48 g) was dissolved in a solution of sulfuric acid (1.1 mL) and water (3.4 mL) at 0° C. To this solution was added to a mixture of 3-cyano-4-fluorobenzaldehyde (13.4 mmol; 2.0 g) in acetone (17 mL) at 0° C. The reaction mixture was warmed to rt and stirred for 6 h. The reaction was then quenched with methanol (20 mL) and water (50 mL) and the product was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 2.25 g of product: 1H NMR (500 MHZ, CDCl3) δ 8.39 (d, J=5.0, 1H), 8.28-8.29 (m, 1H), 7.64 (t, J=8.9, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8]O)[N:5]=[CH:4]1)[CH3:2].S(Cl)([Cl:12])=O>O1CCCC1>[ClH:12].[Cl:12][CH2:8][C:6]1[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cnc(CO)c1
Solvent: C1CCOC1
Product: CCn1cnc(CCl)c1
Product: Cl
Yield: 100.3 %

Procedure:
To a solution (100 mL) of (1-ethyl-1H-imidazol-4-yl)methanol (5.80 g) in tetrahydrofuran was added thionyl chloride (14.59 g). The reaction mixture was heated under reflux for 1 hr and concentrated. Diethyl ether was added to the residue to allow crystallization, and the obtained crystals were collected by filtration, and washed with diethyl ether. The obtained crystals were recrystallized from methanol-tetrahydrofuran to give 4-chloromethyl-1-ethyl-1H-imidazole hydrochloride as colorless crystals (8.35 g, yield 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[CH2:23][CH2:24]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)nc2)C1=O
Yield: 36.8 %

Procedure:
Using 1-acetyl-2-imidazolidinone (128 mg) and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (155 mg) was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]5[O:34][CH2:35][O:36][C:28]=45)=[N:21][CH:22]=[N:23]3)=[C:18]([O:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[Cl:33][C:32]1[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]4)=[CH:17][C:18]=3[O:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:23]=[CH:22][N:21]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Agent: C=O
Solvent: O=CO
Product: CN1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 100 °C
Yield: 46.5 %

Procedure:
A mixture of 7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.25 g), a concentrated aqueous formaldehyde solution (37%, 0.5 ml) and formic acid (5 al) was stirred and heated to 100° C. for 2 hours. The mixture was cooled to ambient temperature and evaporated. The residue was purified by column chromatography on silica using a 24:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was partitioned between methylene chloride and an aqueous ammonium hydroxide solution. The organic layer was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.1 g); NMR Spectrum: (CDCl3) 1.4–1.6 (m, 2H), 1.75–1.9 (m, 3H), 1.9–2.1 (m, 4H), 2.2–2.3 (m, 2H), 2.29 (s, 3H), 2.9 (d, 2H), 3.6–3.7 (m, 2H), 3.95 (d, 2H), 4.0–4.1 (m, 2H), 4.75 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.72 (d, 1H ), 6.81 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 527 and 529.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1)#[N:2].[Br:11][P:12](Br)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:32](N(CC)CC)C>C1C=CC=CC=1>[Br-:11].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([P+:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH3:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(NN)cc1
Solvent: c1ccccc1
Product: CNN(c1ccc(C#N)cc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A mixture of 78.9 g of 4-cyanophenylhydrazine, 250 g of dibromotriphenylphosphorane, 71.9 g of triethylamine and 1,200 ml of benzene was stirred at 80° C for 30 minutes. The resulting crystals were collected by filtration and then washed with benzene and water successively to give 261.0 g of the title compound as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.0509 g, 0.000209 mol) was dissolved in tetrahydrofuran (3.00 mL, 0.0370 mol) in a capped 40 mL EPA vial equipped with a magnetic stir bar. Cis-4-tert-butylcyclohexanol (0.0392 g, 0.000251 mol) was added, followed by triphenylphosphine (0.0878 g, 0.000335 mol) and the reaction was heated to reflux. Diisopropyl azodicarboxylate (0.0659 mL, 0.000335 mol) was added and the reaction was heated at reflux overnight with stirring. TLC analysis showed that the reaction was complete. The mixture was concentrated under vacuum. The resulting product was purified by flash chromatography (0-30% EtOAc in methylene chloride) to give 0.3141 g of the title compound (66% yield).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C@H:16]([NH:18]S(C2C=C(C)OC=2C(F)(F)F)(=O)=O)[CH3:17])=[CH:12][CH:11]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:18][C@@H:16]([C:13]2[CH:12]=[CH:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:32])[F:33])=[CH:15][CH:14]=2)[CH3:17])(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cc1cc(S(=O)(=O)N[C@H](C)c2ccc(-c3ccccc3OC(F)(F)F)cc2)c(C(F)(F)F)o1
Product: C[C@@H](NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F)c1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Prepared in a similar manner to (R)-5-methyl-2-trifluoromethyl-furan-3-sulfonic acid [1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethyl]-amide (Example 3) using 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride instead of 5-methyl-2-trifluoromethyl-4-furan-3-sulfonyl chloride. Title compound: 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.55-7.4 (m, 5H), 7.25 (s, 4H), 4.5 (m, 1H), 1.38 (d, 3H) ppm; MS (ESI) m/z: 584.0 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([C:5]1[S:6][C:7]([C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccs1
Reactant: CC(C)(C)N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(=O)NC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To 2-iso-butylthiophene (1 g, 7.143 mmol, see step (a) above) in THF (15 mL) was added n-BuLi (1.6 M in hexane, 5.3 mL, 8.48 mmol) at −78° C. and the reaction mixture was stirred at 0° C. for 2 hours. tert-Butylisocyanate (897 μL, 7.86 mmol) was then added to the mixture at −78° C. The stirred solution was kept at 0° C. for an additional 2 hours. The reaction mixture was then quenched with H2O (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over MgSO4, concentrated and purified using silica gel column chromatography (10:90 petroleum ether-EtOAc) to give the sub-title compound (1.2 g, 5.01 mmol) as white needles in 70% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([NH2:22])=[O:21])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 60 °C

Procedure:
A mixture of (R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45 mmol) and piperidine (0.20 g, 2.2 mmol) in 5 mL 1,2-dichloroethane was heated to 60° C. for 30 min. The reaction mixture was cooled and treated with NaBH(OAc)3 and a drop of HOAc. The resulting mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, quenched with H2O, and extracted with CHCl3 (3×). The combined extracts were dried over MgSO4, concentrated and purified by SiO2 (5% MeOH/CH2Cl2) to give a white solid. MS (m/z): 537.4 (m+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH2:10][CH:11]=[CH2:12])[C:3]=1[OH:13].[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH2:10][CH2:11][CH3:12])[C:3]=1[OH:13]
Reactant: C=CCc1c(C#N)ccc(N)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(C#N)ccc(N)c1O
Yield: 283.7 %

Procedure:
A mixture of 2-amino-5-cyano-6-prop-1-ene-3-yl-phenol (0.5 g, 2.4 mmol) and 10% palladium on carbon (0.05 g) in ethyl acetate (50 mL) was stirred at rt under 1 atm of hydrogen for 2 hours. The mixture was filtered through Celite to remove the palladium and the filtrate was concentrated under reduced pressure to afford the title compound as a pinkish-white solid (1.2 g, 78%). MS(ES+) m/e 177 [M+H]+; MS(ES−) m/e 175[M−H]−.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([OH:7])[CH3:6].[CH:8]([OH:10])=[O:9]>>[C:8]([OH:10])(=[O:9])[CH:1]([CH3:2])[OH:3].[CH3:6][CH:5]([OH:7])[CH:1]([OH:4])[CH3:2]
Reactant: O=CO
Reactant: CCO
Reactant: CC(=O)O
Product: CC(O)C(=O)O
Product: CC(O)C(C)O

Procedure:
Bacteria which can be used to produce succinic acid include strains that are unable to produce acetic acid, lactic acid, ethanol, 2,3-butanediol and formic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)=O.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>C(#N)C>[ClH:1].[CH3:25][C:23]1[CH:22]=[CH:21][N:20]2[CH:2]=[C:3]([C:5]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[C:6]=3[CH:7]=[CH:8][C:9](=[O:17])[NH:10]4)[N:18]=[C:19]2[CH:24]=1
Reactant: COc1ccc(C(=O)CCl)c2ccc(=O)[nH]c12
Reactant: Cc1ccnc(N)c1
Solvent: CC#N
Product: COc1ccc(-c2cn3ccc(C)cc3n2)c2ccc(=O)[nH]c12
Product: Cl
Temperature: 0 °C
Yield: 58.9 %

Procedure:
5-Chloroacetyl-8-methoxycarbostyril (5 g), 2-amino-4-picoline (6.45 g) and acetonitrile (40 ml) were reacted with refluxing for 3 hours, and the reaction mixture was cooled with ice water. Crystals which formed were collected by filtration. The crystals were suspended in acetone-methanol and the suspension was adjusted to pH of about 1 by the addition of concentrated hydrochloric acid. Crystals which formed were collected by filtration and recrystallized from methanol to give 4.0 g of 5-(7-methylimidazo[1,2-a]pyridine-2-yl)-8-methoxycarbostyril monohydrochloride 3/2 hydrate.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].[H][H].Br[CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23].[Br-]>CN(C)C=O>[CH3:1][S:2][CH:3]1[N:6]([CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: COc1ccc(COC(=O)c2ccccc2C#CCBr)cc1
Reactant: [H][H]
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccccc2C#CCN2C(=O)CC2SC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
4-Methylthioazetidin-2-one (470 mg., 4 mmole) was dissolved in dry dimethylformamide (10 ml.) and the solution was stirred at -20° with exclusion of moisture while sodium hydride (50% dispersion in oil, 200 mg., 4 mmole) was added. When evolution of hydrogen had ceased (ca 10 minutes), 3-bromo-1-[o-(p-methoxybenzyloxycarbonyl)-phenyl]-prop-1-yne (1.44 g., 4 mmole) in dry dimethylformamide (5 ml.) was added dropwise to the stirred mixture at -20°. After addition of the bromide was complete, the mixture was warmed to 0° and stirred at that temperature for 30 minutes. The mixture was poured into ice-water (50 ml.) and the aqueous mixture was extracted twice with ethyl acetate (50 ml. portions). The combined ethyl acetate extracts were washed three times with water (30 ml. portions). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield a yellow gum. The gum was chromatographed on silica gel (25 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless gum (400 mg., 26% yield). (Found: M+, 395.11850. C22H21NO4S requires 395.11912). νmax (CHCl3): 1760 (β-lactam C=O), 1730 (ester C=O), 1620 and 1520 (aromatic C=C) cm-1. δ (CDCl3): 2.10 (s, 3H, SCH3), 2.91 (dd, J 15, J' 3 Hz, 1H, β-lactam CHH), 3.35 (dd, J 15, J' 6 Hz, 1H, β-lactam CHH), 3.75 (s, 3H, OCH3), 3.86 (d, J 16.5 Hz, 1H, NCHH), 4.42 (d, J 16.5 Hz, 1H, NCHH), 4.94 (dd, J 6, J' 3 Hz, 1H, β-lactam CH), 5.35 (s, 2H, OCH2Ar), 6.95 (d, J 8.5 Hz, 2H, Ar-H), 7.2-7.6 (m, 5H, Ar-H), 7.95 (m, 1H, Ar-H). m/e: 395 (M+, 1%), 348 (14), 274 (63), 205 (37), 168 (56), 159 (68), 158 (44), 122 (76), 121 (100).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]>C1COCC1.CCOC(C)=O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (2.83 g, 12.86 mmol) was added THF (38.2 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (14.03 ml, 14.03 mmol), faster than dropwise. After 15 min, a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (4.92 g, 11.69 mmol) in THF (30 ml) was added. The mixture was allowed to warm to rt over 1.5 h, providing a brown solution and product as the primary species according to LC-MS (m/z=605). The solution was added to ice, diluted with EtOAc and extracted with water (brine added to help resolve emulsion). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (70 ml) and the resulting light brown solution cooled in an ice water bath prior to the addition of TFA (20 ml) and the mixture stirred at 0° C. for 20 mins and at room temperature for 1 h affording a purplish solution. The mixture was concentrated under reduced pressure and the resulting brownish oil purified with a 330 g ISCO gold column ramping EtOAc in heptane (0-45%, then isocratic at 45% with 10% DCM isocratic throughout, sample loaded with DCM providing product (˜3.9 g) as a slightly off-white solid. The solid was triturated with MeOH to afford a white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (3.208 g, 6.62 mmol, 56.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80-3.88 (m, 2 H) 4.28-4.35 (m, 2 H) 6.64 (d, J=11.64 Hz, 1 H) 6.84 (d, J=4.69 Hz, 1 H) 7.23 (d, J=6.75 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.77 (d, J=8.61 Hz, 1 H) 8.09 (dd, J=8.90, 1.96 Hz, 1 H) 8.41 (d, J=1.66 Hz, 1 H) 12.81 (s, 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[C:27]([CH:36]=O)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:36][C:27]3[CH:26]=[C:25]([CH3:24])[N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:28]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 58 %

Procedure:
Compound 92 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11]2[NH:20][N:19]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2sccc2Cl)CC1=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Yield: 60 %

Procedure:
A solution of 5-(3-chlorothiophen-2-yl)-2-(1-hydroxyethylidene)-cyclohexane-1,3-dione (2.2 g) and hydrazine hydrate (0.45 g) in ethanol (60 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(3-chlorothiophen-2-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.3 g).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=O)[NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.P(Br)(Br)([Br:24])=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:24][C:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][N:7]=2)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:28]([NH:32][C:33](=[O:40])[NH:34][C@H:35]([CH3:39])[C:36](O)=[O:37])([CH3:31])([CH3:30])[CH3:29].C(OC(=O)NCCCC(N1CCC(N2N=C(C3C=CC(OC)=C(OC)C=3)[C@@H]3[C@@H](CC=CC3)C2=O)CC1)=O)(C)(C)C>>[C:28]([NH:32][C:33]([NH:34][C@@H:35]([CH3:39])[C:36]([N:25]1[CH2:26][CH2:27][CH:22]([N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14]2=[O:21])[CH2:23][CH2:24]1)=[O:37])=[O:40])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: C[C@@H](NC(=O)NC(C)(C)C)C(=O)O
Agent: COc1ccc(C2=NN(C3CCN(C(=O)CCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)[C@H](C)NC(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound 5c and (R)-2-(3-tert-butyl-ureido)-propionic acid (N-boc-L-alanine) as described for compound 5b. M. p. 153-154° C.