Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:29](=[N:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=Cc1ccccc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12

Procedure:
reacting diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (free base form) with benzaldehyde to form the Schiff's base, i.e. diphenylmethyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate,
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][OH:15])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1CCC(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1CCC(=NO)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 801 mg (5.0 mmol) of 4-methyl-1-tetralone in 20 mL of dry methanol was treated with 417 mg of hydroxylamine hydrochloride (6.0 mmol, 1.2 eq) and 504 mg (6.0 mmol, 1.2 eq) of sodium bicarbonate and the resulting mixture was stirred at room temperature for 16 hours. The solid was filtered off and the solvent was removed under vacuum. The white residue was redissolved in 10 mL of methylene chloride and filtered. The filtrate was evaporated to dryness under vacuum to give the product in quantitative yield. 1H NMR (400 MHz, CDCl3): 1.30 (d, 8 Hz, 3H), 1.69 (m, 1H), 2.45 (m, 1H), 2.88 (m, 3H), 7.15-7.35 (m, 3H), 7.86 (d, 8 Hz, 1H).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([Cl:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:60][C:38]1[CH:39]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:41]=[C:20]([Cl:19])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(C(=O)N[C@@H](CNC(=O)c3cccs3)C(=O)O)c(Cl)c2)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.94 mL, 3.94 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl) dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.38 g, 3.6 mmol) in tetrahydrofuran (30 mL). The solution was stirred at room temperature for 3 h, then diluted with ethyl acetate and concentrated. The residue was chromatographed (50–100% ethyl acetate/hexanes then 10% methanol/ethyl acetate) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.68 g, 85%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:17])C(F)(F)F.C([OH:20])C.[OH-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([OH:17])=[O:20]
Reactant: O=C(c1cccn1Cc1ccco1)C(F)(F)F
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccn1Cc1ccco1

Procedure:
1-Furfurylpyrrole (2.3 g, 15.6 mMol), 15 ml of trifluoroacetic anhydride (22.35 g, 106 mmol), 50 ml of nitromethane and 25 ml anhydrous diethylether were combined in a 100 ml round bottom flask. The mixture was stirred overnight under positive argon. The reaction was heated and the excess solvents distilled off. The mixture was evaporated to dryness under reduced pressure to give 3.9 g of a dark oil. The oil was distilled in a Kugel-rohr apparatus. The fraction collected at 80° C. to 90° C. at 0.2 mm Hg pressure gave 3.0 g of the colorless oil. 1-(2-furanylmethyl)-2-trifluoroacetyl-1H-pyrrole. This oil was combined with 50 ml ethylalcohol in a 100 ml round bottom flask equipped with a reflux condenser. The mixture was heated to reflux. Sodium hydroxide, 3.0 g in 15 ml of water, was added, and the reaction mixture was refluxed for 3 hours. The ethanol was distilled off and 50 ml of water was added. The mixture was cooled and acidified by addition of 5.0 g malonic acid. A precipitate formed which was collected by filtration. The solid precipitate was recrystallized from acetonitrile to give the title compound a white powder, mp =117° C. to 118° C., infrared spectrum absorption at 3400 cm-1, 1675 cm-1, 1530 cm-1, 1440 cm-1, 750 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]([CH3:19])[CH2:13]1.C1COCC1>[Ni].O>[CH3:18][CH:16]1[CH2:15][CH:14]([CH3:19])[CH2:13][N:12]([C:3]2[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH2:17]1
Reactant: CC1CC(C)CN(c2c(F)cc([N+](=O)[O-])cc2F)C1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2c(F)cc(N)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,6-Difluoro-4-nitrophenyl)-3,5-dimethylpiperidine (14.01 g, 51.8 mmol) and THF (240 mL) were added to Raney-nickel 2800, water slurry (14.01 g, 239 mmol) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 8 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a 250 ml dichloromethane solution containing 89 g (1.0 mol) 2-amino-2-methyl-1-propanol at 0° was added dropwise with stirring 70 g (0.5 mol) benzoyl chloride in 250 ml dichloromethane. The reaction mixture was warmed to room temperature and stirred for several hours. The 2-amino-2-methyl-1-propanol hydrochloride was removed from the reaction mixture by filtration and was thoroughly washed with dichloromethane. The filtrate and washings were combined and the dichloromethane removed under reduced pressure to afford 67.55 g (0.35 mol), 70%, 2-benzoylamino-2-methyl-1-propanol as a white solid, mp 80°-82°, sublimation at 75° (0.2 mm); ir (KBr) 1630 (c=o) cm-1 ; pmr (CDCl3) δ 1.50 (s, 6H), 3.67 (s, 2H), 5.27 (bs, 1H), 6.92 (bs, 1H) and 7.1 - 8.3 (m, 5H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1)#[N:2].CO.C(OCC)C.[C-:24]#[N:25].[K+]>O>[C:1]([CH:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[C:24]#[N:25])#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1OC)CCC=C2C#N
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1OC)CCC(C#N)C2C#N
Reaction time: 48 h
Yield: 41.3 %

Procedure:
A suspension of the compound of example 1 (29.2 g, 0.14 mole), 315 mL MeOH, and 110 mL diethyl ether was stirred mechanically, just below reflux temperature as a 45° solution of KCN (34 g, 0.52 mole) in 94 mL water was added dropwise, quickly. The reaction mixture was stirred at reflux for 1.5 hr. After cooling briefly a solution of NH4OAc (21 g, 0.27 mole) in 34 mL water was added. Water was added until cloudy and the solution was stored at 0° for 2 days. The solid was filtered, washed with 60° water, cold 50% aqueous MeOH, and dried (high-vacuum) to yield 14.0 g tan solid (41%); mp 107°-8°; M+ 242.
Reaction SMILES: IC1C=C2C(C(C=CC3C=CC=CC=3)=NN2COCC[Si](C)(C)C)=CC=1.[CH3:27][N:28]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:46]=[CH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:34][N:35]2COCC[Si](C)(C)C)=[CH:31][CH:30]=1.[K+].[Br-]>CCOC(C)=O.CCCCCC>[CH3:27][N:28]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:46]=[CH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: CN(c1ccccc1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(c1ccccc1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-Iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole was converted to methyl-phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine as described in Example 11, step (v). Rf sm 0.35 Rf p 0.13 (EtOAc:hexane 1:9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248, 1212, 1076, 835, 694 cm−1; MS (ESI) [M+H]/z Calc'd 456, Found 456.
Reaction SMILES: O.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[OH2:6].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:28])[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=S
Reaction time: 1 h

Procedure:
To a suspension of 17.4 g (0.043 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-disulfide in ~300 ml of toluene was added 20 g (0.078 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrate [1:1]. The mixture was heated to reflux for 3 hr and 4.0 g (0.01 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and heating was continued for 1 hr. After cooling, toluene was decanted off and washed with 3×100 ml 1N sodium hydroxide and 100 ml water. The organic layer was then extracted with 2×100 ml of 2N hydrochloric acid. The aqueous layer was made basic to litmus with conc. sodium hydroxide causing the product to precipitate out. Of the 25 g of crude collected, 2 g were recrystallized from diisopropyl ether to give pale yellow crystals, m.p. 80°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C(N(CC)CC)C.C[CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27].C(O)(=O)C[C:34](CC(O)=O)(C(O)=O)[OH:35]>ClCCl.O>[CH3:34][O:35][C:29](=[O:30])[CH2:25][C:26]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:12][CH:11]=1)=[O:27]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: Nc1ccc(COc2cccc(F)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC(=O)Nc1ccc(COc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
211 mg (1 mmol) of the crude 4-(3-fluoro-phenoxymethyl)-phenylamine is dissolved in 3 ml dichloromethane. 110 mg (1.1 mmol) of triethylamine is added and the reaction mixture cooled in an ice-bath 132 mg (1 mmol) of methyl malonyl chloride is then added dropwise. The reaction mixture is stirred for additional 30 minutes in the ice-bath, then for 45 minutes at room temperature. The reaction mixture is treated with water, acidified with citric acid and extracted 3 times with dichloromethane. The organic phase is dried and evaporated. Chromatography (silica gel, ethyl acetate/hexane 1:1) yields 98 mg (32%) of the title compound as a colorless solid. MS: m/e=318.2 (M++H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10]>O1CCOCC1>[N:1]1[CH:6]=[C:5]2[C:4]([NH:8][C:9](=[O:10])[NH:7]2)=[N:3][CH:2]=1
Reactant: Nc1cncnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2cncnc2[nH]1
Temperature: 90 °C
Reaction time: 48 h
Yield: 567.7 %

Procedure:
Pyrimidine-4,5-diamine (1.1 g, 10 mmol) and 1,1′-carbonyl diimidazole 1.78 g, 1.1 mmol) were added to dioxane (15 mL) and the reaction mixture was stirred at 90° C. for 48 hours. The mixture was cooled and the precipitate was recovered by filtration, rinsed with cold dioxane, and dried to give 850 mg (61%) of 7,9-dihydro-purin-8-one.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:14][CH:13]=3)[CH:25]=2)[CH:21]=[N:22]1)[CH3:34]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cn[nH]c3c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ncc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Temperature: 90 °C
Yield: 80.1 %

Procedure:
6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.15 g, 0.331 mmol), ethyl bromoacetate (0.055 g, 0.331 mmol), cesium carbonate (119 mg, 0.364 mmol) in 6 mL DMF was stirred at RT overnight and then heated to 90° C. for 35 min. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-30% ethyl acetate in hexanes to yield [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid ethyl ester as a white solid (120 mg, 80.1%).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=2)#[N:2].Cl.[NH2:25]O.[OH-].[K+].[CH2:29]([OH:31])[CH3:30]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:4]2[C:5]3[C:10](=[CH:9][C:8]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][CH:6]=3)[CH:11]=[C:3]2[C:1]2[N:25]=[C:29]([CH3:30])[O:31][N:2]=2)=[CH:22][CH:21]=1
Reactant: NO
Reactant: CCO
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C#N)n2Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)no1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of the compound obtained in Example 24 (1) (68 mg), hydroxylamine hydrochloride (22 mg), potassium hydroxide (18 mg) and ethanol (1 ml) was heated under reflux for 2 hours. After the insolubles were filtered off, the reaction mixture was concentrated under reduced pressure. A mixture of the resulting residue and dimethylacetamide dimethylacetal (1 ml) was stirred at 100° C. for 1 hour. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 50 mg of the desired product as a white crystal.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1)(=O)=O.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:7]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=2)=[CH:8][C:9]([C:19]([F:20])([F:21])[F:22])=[N:10]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl)C(F)(F)F
Product: CS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1

Procedure:
1-(2-chlorophenyl)-5-[3-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole was prepared in a manner similar to that described in Examples 1c by using 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate and 3-(methylsulfonyl)phenylboronic acid. 1H-NMR (CDCl3): δ 7.90 (1H, m), 7.76 (1H, d), 7.57-7.47 (3H, m), 7.46-7.42 (3H, m), 6.92 (1H, s), 2.92 (3H, s). MS (ES): 401 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=O.O1CCCC1.[NH2:23][CH:24]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]2[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=2[N:26]([CH3:41])[C:25]1=[O:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([NH:23][CH:24]1[C:25](=[O:42])[N:26]([CH3:41])[C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:30]1)=[O:11]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 0.073 g (0.3 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid in 5 ml of tetrahydrofuran 0.080 g (0.3 mmol) of (3RS)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 0.058 g (0.3 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 0.040 g (0.3 mmol) of 1-hydroxybenzotrizole hydrate and 0.039 g (0.3 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (5 ml) was added and the mixture was extracted with dichloromethane (three times 5 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 0.099 g (67%) of the diastereomeric mixture of title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.CC[N:18]([CH:22]([CH3:24])C)[CH:19]([CH3:21])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>CN(C=O)C>[Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:18]1[CH2:19][CH2:21][CH2:24][CH2:22]1)=[O:9]
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCC1
Temperature: 25 °C
Yield: 252.4 %

Procedure:
2-Chloro-5-phenyl-thiophene-3-carboxylic acid (28 mg, 0.11 mmol) was dissolved in DMF (1 mL). DIPEA (0.22 mmol), HATU (0.11 mmol) and pyrrolidine (0.11 mmol) were added and the reaction mixture stirred at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic solution was separated and dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by preparative HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (81 mg). LCMS m/z 292.10 [M+H]+ R.T.=11.27 mins (Analytical Method 1)
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]([C:23](=[O:25])[CH3:24])[OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:8]([O:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]([O:22][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccc(OCc2ccccc2)cc1)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pivaloylchloride (1.36 ml) was added dropwise to a solution of N-(4-benzyloxybenzyl)acetohydroxamic acid (2.71 g) and triethylamine (1.7 ml) in methylene dichloride (15 ml) and dimethylaminopyridine (100 ml). The mixture was stirred for 2 hours at room temperature, then neutral material was isolated with ether. The product, N-(4-(Benzyloxybenzyl)-N-(t-butylcarbonyloxy)acetamide, was a colourless oil.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(I)C=C>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:22][O:21][C:19]([C:13]1([CH2:7][CH:5]=[CH2:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20]
Reactant: COC(=O)C1CCCCC1
Reactant: CC(C)NC(C)C
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
To a solution of diisopropylamine (10 mL, 72 mmol) in tetrahydrofuran (100 mL) pre-cooled to −69° C. was added a 2.5 M solution of n-butyllithium in hexanes (29 mL, 72 mmol) dropwise. Following addition, the reaction mixture was warmed to 0° C. for 30 min and then re-cooled to −70° C. To the mixture was added a solution of methyl cyclohexane carboxylate (8.9 mL, 60 mmol) in tetrahydrofuran (30 mL) dropwise. After stirring for 30 min, a solution of allyl iodide (7.2 mL, 78 mmol) in HMPA (5 mL) was added dropwise. The cooling bath was removed to allow the mixture to warm to 20° C. After 1.5 h, the reaction mixture was poured into H2O (200 mL). The two layers were separated and the aqueous layer was extracted with Et2O (100 mL). The organic solutions were combined and dried over K2CO3, filtered and concentrated to afford 11 g of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O-:23])=[O:22].[C:24]([O-])(O)=O.[Na+]>CC(C)=O>[CH3:24][O:22][C:21]([C:20]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])=[CH:2][N:14]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2)=[O:23]
Reactant: O=C([O-])O
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])Cc1ccccn1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1c(-c2ccccc2[N+](=O)[O-])cn2ccccc12

Procedure:
First, 2.2 mmol of 2-bromo-2′-nitroacetophenone, 3.3. mmol (1.5 eq.) of 2-pyridylacetate and 4.4 mmol (2 eq.) of NaHCO3 are dissolved into 10 ml of acetone and the reaction mixture is allowed to react at 90° C. for 16 hours. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure, dissolved into 10 ml of dichloromethane, and washed with 10 ml of water to remove impurities. Then, 10 ml of dichloromethane is added to the aqueous layer to carry out extraction once more. The resultant organic layer is dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using hexane:ethyl acetate:dichloromethane=10:1:2 as a solvent to obtain the target compound.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](OCC)(OCC)[CH2:18][CH3:19])[CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:16][C:17](=[C:10]1[S:9][C:8](=[S:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12])[CH2:18][CH3:19])[CH3:15]
Reactant: O=C1CSC(=S)N1c1ccccc1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(CC)=C1SC(=S)N(c2ccccc2)C1=O

Procedure:
A mixture of 8.4 g. (0.04 m.) of 3-phenylrhodanine, 21 g. (0.12 m.) of triethylorthopropionate and 80 ml. of acetic anhydride is heated under reflux for six hours, cooled and filtered. The solid is washed with 50% aqueous acetic acid to afford 5-(1'-ethoxypropylidene)-3-phenylrhodanine, m.p. 178°-181°C.