Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.[NH2:33][C:34]1[S:38][N:37]=[C:36](/[C:39](=[N:47]/[O:48][CH2:49][C:50]([OH:52])=[O:51])/[C:40](OS(C)(=O)=O)=[O:41])[N:35]=1.C(OCC)C>O1CCCC1>[NH2:33][C:34]1[S:38][N:37]=[C:36]([C:39](=[N:47][O:48][CH2:49][C:50]([OH:52])=[O:51])[C:40]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:41])[N:35]=1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CS(=O)(=O)OC(=O)/C(=N\OCC(=O)O)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (6.96 g) and N-(trimethylsilyl)acetamide (21.8 g) in tetrahydrofuran (150 ml) was added methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetate (4.86 g) at ambient temperature. After being stirred for 30 minutes at the same temperature, the mixture was poured into diethyl ether (2 l), and the resultant precipitate was collected by filtration. The precipitate was dissolved in water, and the solution was adjusted to pH 2.0 with aqueous sodium bicarbonate solution. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin, Diaion HP-20. The desired product was eluted with 5% isopropyl alcohol solution and lyophilized to give 7β[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer)(5.20 g).
Reaction SMILES: [Cl-].[Cl-].[CH3:3][N:4](B)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: BN(C)c1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CNc1ccccc1C(O)c1ccccc1
Yield: 75.7 %

Procedure:
To a solution of N-methylanilinoborane dichloride (100 mg) in methylene chloride (5 ml), a solution of benzaldehyde (56 mg) and tri-n-butylamine (99 mg) in methylene chloride (2 ml) is added with ice cooling, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with ice pieces and shaken with methylene chloride. The methylene chloride layer is washed with aqueous sodium carbonate and a saturated brine in that order, and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, and the product is recrystallized from chloroform-petroleum ether to give 2-methylaminobenzhydrol (85 mg) as crystals melting at 124° to 126° C. The yield is 75.0%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(OC(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-Methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL). The resultant mixture was added with 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and stirred at 0° C. for 45 minutes. The reaction solution was added with ethyl acetate, a saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg, yield 6%) was obtained as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[N:18][C:17]=2[Cl:24])(=[O:15])=[O:14])[CH:5]=1.[CH3:25][NH2:26]>C1COCC1>[Cl:24][C:17]1[N:18]=[C:19]2[N:23]([C:16]=1[S:13]([N:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH2:3][CH2:2][NH:26][CH3:25])=[CH:5]1)(=[O:14])=[O:15])[CH:22]=[CH:21][S:20]2
Reactant: CN
Reactant: O=S(=O)(c1c(Cl)nc2sccn12)n1cc(CCBr)c2ccccc21
Solvent: C1CCOC1
Product: CNCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Temperature: 50 °C

Procedure:
A solution of 3-(2-bromoethyl)-1-(6-chloroimidazo[2,1-b]thiazole-5-sulfonyl)indole (92 mg, 0.20 mmol) in THF is treated with methyl amine (2M in methanol, 0.4 mL, 2 eq.), heated at 50° C. for 24 h, cooled and concentrated in vacuo. The resultant residue is purified by HPLC1 to give the title product as a white solid, 18.5 mg, identified by HPLC2 and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccsc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C., the resulting precipitate was collected, then dried and recrystallised twice from ethanol to give the title pyrimidinone (460 mg), m.p. 227°-230° C., λmax (EtOH) 250 nm (ε 15,770), 333 nm (ε 2,690).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(OC)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Yield: 73 %

Procedure:
5-Methoxy-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (33D) (0.600 mmol, 0.182 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.8 mmol, 0.198 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.660 mmol, 0.251 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-80% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) as a clear oil. (0.333 mmol, 0.205 g, 73% yield). ESI-MS: m/z 616.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](SC)=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CO>[NH2:11][C:10]1[NH:20][N:19]=[C:8]([NH:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]#[N:13]
Reactant: CSC(NCc1ccc(N)cc1)=C(C#N)C#N
Reactant: NN
Solvent: CO
Solvent: O
Product: N#Cc1c(NCc2ccc(N)cc2)n[nH]c1N
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 15.71 g (64.3 mmol) of 3-(4-amino-benzylamino)-2-cyano-3-methylmercapto-acrylonitrile, 3.35 ml (67.5 mmol) of hydrazine hydrate and 90 ml of methanol is stirred for 1 hour at 20° C., heated under reflux for 4 hours and then concentrated by evaporation in vacuo. Digestion of the crystalline residue in 70 ml of diisopropyl ether, filtering and digestion again in 100 ml of isopropanol yield the title compound; m.p. 168-170° C.
Reaction SMILES: N.Cl.[CH2:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[NH:8][CH2:7][C:6]1=[O:12])[CH3:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][N:8]1[CH2:7][C:6](=[O:12])[N:5]([CH2:3][CH3:4])[CH2:10][C@@H:9]1[CH3:11])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCN1C[C@H](C)NCC1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CN1CC(=O)N(CC)C[C@@H]1C)C(=O)OCC
Temperature: 100 °C

Procedure:
Anhydrous ammonia gas was bubbled into a cold (0° C.) solution of (5S)-1-Ethyl-5-methylpiperazin-2-one hydrochloride (5.8 g, 32.3 mmol) in chloroform for 30 minutes. The resultant slurry was filtered and concentrated under vacuum. The residual oil was concentrated as a solution in toluene under vacuum, redissolved in toluene (120 mL) and treated with diethyl ethoxymethylenemalonate (7.0 g, 32.3 mmol) and heated in a sealed flask in an oil bath at 100° C. overnight. The resultant solution was concentrated under vacuum. The residual oil was concentrated as a solution in toluene under vacuum to provide the corresponding diethyl{[(2S)-4-ethyl-2-methyl-5-oxopiperazin-1-yl]methylene}malonate. Without further purification, to a solution of the malonate (10.5 g, 33.5 mmol) in anhydrous THF (330 mL) warmed with an external oil bath at 65° C. under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (35.1 mL, 1 M, 35.1 mmol) was added. The solution was heated at the same temperature for one hour and concentrated under vacuum. The residue was partitioned between dichloromethane and hydrochloric acid (1M). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether. The solid precipitated was filtered, washed with diethyl ether to provide the title compound as pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[NH:16].[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(C)(C)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[N:16][C:24]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[N:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N=c1ccccn1CCc1ccccc1Br
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: Brc1ccccc1CCn1ccccc1=NC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Yield: 12 %

Procedure:
A solution of 1-[2-(2-bromophenyl)ethyl]-2-iminopyridine (2.77 g, 0.01 mole) and dicyclohexylcarbodiimide (2.06 g, 0.01 mole) in 30 ml of t-butanol is heated at reflux for 21.5 hours under a nitrogen blanket. The solution is cooled to room temperature and diluted with 60 ml of hexane. The diluted solution is cooled and scratched in a dry ice bath to induce crystallization. The mixture is allowed to warm to room temperature and is filtered to give 0.58 g of material which sinters at 121°C and melts at 125°-129°C. The filtrate is concentrated in vacuo and the residual oil is cooled in an ice bath and scratched under 40 ml of hexane to give 1.32 g of material which sinters at 100°C and melts at 108°-110°C. The two batches of material are combined and dissolved in a boiling solution of 60 ml of cyclohexane and 60 ml hexane and filtered. The solution is cooled for several hours at -30°C, filtered and washed with cooled hexane to yield 1.33 g of the title compound, melting point 127°-129.5°C.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:37].O>CN(C=O)C.Cl>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (400 mg, 0.85 mmol) was slowly added to an ice-cooled slurry of NaH (68 mg, 60% dispersion on mineral oil, 1.7 mmol) in DMF (10 ml). After 0.5 h iodomethane (0.90 mmol) was added. The reaction mixture was stirred at room temperature, under argon for 16 h. 2N HCl (9 drops) then water (100 ml) were added. The aqueous phase was extracted with EtOAc(2×) and the combined organics washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 50-100% pentane-ethyl acetate). Residual DMF was removed by dissolving in ethyl acetate/diethyl ether and washing with water (2×). Drying (Na2SO4) and removal of the solvent in vacuo afforded the title compound as a pale yellow solid (142 mg, 34%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([OH:25])=O)[CH2:12]1.[ClH:26].[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)#[N:28]>CN(C=O)C>[ClH:26].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:27]#[N:28])=[O:25])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2nc3ccccc3o2)C[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@H](Nc2nc3ccccc3o2)CN1

Procedure:
(2S,4S)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 5, 1.04 g) and (S)-2-cyanopyrrolidine hydrochloride (0.40 g) were dissolved in DMF (5 mL), and triethylamine (0.84 mL), HOBT (0.51 g) and EDC hydrochloride (0.63 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]1-2-cyanopyrrolidine (0.86 g) as amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:30])[N:5]([C@@H:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:6]2=[O:12].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:30])[N:5]([C@@H:13]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:6]2=[O:12]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione (1 mmol) in anhydrous CH2Cl2 (20 mL), is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. This mixture is diluted with brine (20 mL) and is extracted with CH2Cl2 (2×30 mL). The extracts are combined, and the solvent is removed in vacuo to give crude (S)-4-amino-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione. The product is purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15]3)[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)c2ccc(C)c(B3OC(C)(C)C(C)(C)O3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2 g) was dissolved in DMF (20 ml). To this was added 3-methoxyaniline (0.985 g), DIPEA (4 ml) and HATU (3.05 g). The mixture was stirred for 18 h at room temp. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic layer was dried (magnesium sulphate) concentrated under vacuum and purified using a silica Biotage cartridge (90 g) eluting with 1:4 ethyl acetate/cyclohexane to give the title compound as a white solid (2.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=O)[CH:12]=[N:11]1.S(Cl)(Cl)=O.S(N)([NH2:26])(=O)=O>S1(CCCC1)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]#[N:26])[CH:12]=[N:11]1
Reactant: NS(N)(=O)=O
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 76 %

Procedure:
By the method of Example 1, Step E, 25.6 g (0.0838 mole) of 1-(2,4,6-trichlorophenyl)-4-carboxy-5-methyl-1H-pyrazole, 114.3 g (0.961 mole) of thionyl chloride, and 12.7 g (0.132 mole) of sulfamide were reacted in 100 mL of sulfolane, yielding 18.25 g of 1-(2,4,6-trichlorophenyl)-4-cyano-5-methyl-1H-pyrazole as an oil which subsequently solidified. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([N:23]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27](Br)=[CH:28][N:29]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC#N>[C:58]([O:57][C:55]([N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=2)=[CH:28][N:29]=1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc([C@@H]3COCCN3C(=O)OC(C)(C)C)cc2)no1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
A mixture of (4-isopropylsulfonylphenyl)boronic acid (892.7 mg, 3.914 mmol), tert-butyl (3R)-3-[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]morpholine-4-carboxylate (2.5 g, 3.558 mmol), Na2CO3 (3.558 mL of 2 M, 7.116 mmol), water (17.60 mL) and MeCN (25.00 mL) were degassed by vacuum/nitrogen cycles (3×) then Pd[P(tBu)3]2 (90.92 mg, 0.1779 mmol) was added and vessel flushed with nitrogen via vacuum/nitrogen cycles (2×). Mixture then heated at 50° C. (drysyn block temp) for 3 h. The reaction was cooled to rt, and then diluted with EtOAc (10 mL) and water (10 mL) and the organic layer separated and then washed with water (2×10 mL) and brine (1×10 mL), dried MgSO4, filtered and concentrated in vacuo. The crude product purified by ISCO (120 g SiO2, 0 to 50% EtOAc/petroleum ether) to leave product as a white foam (2.52 g, 88% yield)
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 210 mg (0.64 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 132 mg (0.97 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 234 mg of crude imine are cyclized in the same way as in Example 29 at −40° C. with 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 33-100%) yields 25 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([NH:19][CH2:30][CH3:31])[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CCI
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNc1cc(C#N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 140 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μL, 1.2 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water. (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3:1:4 afforded 6 mg (38%) of 3-(5-fluoroprid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 7.80 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.12 (br, s, 1H), 3.26 (q, 2H), 1.32 (t, 3H).