Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[CH:27]=O)([CH3:23])([CH3:22])[CH3:21].C1C=CC=CC=1>O>[C:33]([C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:31]=1[OH:32])[CH:27]=[N:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:15])([Cl:17])[Cl:16])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12)([CH3:35])([CH3:36])[CH3:34]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC1=CS[C@@H]2[C@H](N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1=CS[C@@H]2[C@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of 2.14 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-2-cephem-4-carboxylate and 1.3 g. of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde in 60 ml. of benzene was refluxed for 1.5 hours in a vessel equipped with a water separator. After evaporation of the solvent, a small amount of cyclohexane was added to the residue. Insolubles were filtered off, and the filtrate was purified by a dry silica gel column chromatography (4.5 × 15 cm, eluent; ethyl acetate-cyclohexane, 1 : 10) to give the desired product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2
Reactant: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)nc(-n3cncn3)c12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2.53 g (1.54 ml, 16.51 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.57 g (5.50 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 8A in 10 ml of dry pyridine at 0° C., and the mixture is stirred for 30 min at 20° C. Subsequently, 3.42 g (49.53 mmol) of 1,2,4-triazole are added, and the mixture is stirred overnight at RT. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution, and the mixture is extracted using dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:21]([OH:26])[OH:22])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 24 (31.4 g, 0.15 mol), n-butyllithium (15 cm3, 10.0M in hexanes, 0.15 mol) and triisopropyl borate (56.4 g, 0.3 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O)=[O:4].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[N:24][NH2:25])=[O:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccccc1F
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1ccncc1C(=NN)c1ccccc1F
Temperature: 0 °C
Yield: 68.2 %

Procedure:
A solution of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone (9.8 g)and hydrazine monohydrate (3.3 g) in 100 mL ethanol was stirred at reflux for five hours, cooled, stirred with ice-water and extracted with ethyl acetate-ether. The dried organic layer was filtered and evaporated. The residue was eluted through silica with dichloromethane then 15% ethyl acetate in dichloromethane via flash column chromatography and then was triturated with hexane-ether to yield 7 g of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone-hydrazone, as a solid, m.p. 78°-82° C. Four grams were converted to the maleate salt in methanol-ether and thereafter recrystallized from methanol-ether to yield 2.3 g of crystals, d 161°-162° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:27](=[O:29])[CH3:28])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-amine monohydrochloride (17.6 g) in pyridine (85 mL) was added acetic anhydride (12.6 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane/ethyl acetate to give the title compound (12.0 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(F)(F)F)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)o1
Yield: 78.6 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)furan (4 g, 26.6 mmol) in chloroform (60 ml) were added N-bromosuccinimide (5.2 g, 29.3 mmol) and 2,2′-azobis(isobutyronitrile) (220 mg, 1.33 mmol). The reaction solution was heated under reflux for 15 min. The reaction solution was cooled, poured into water (200 ml) and was extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 2-(bromomethyl)-5-(trifluoromethyl)furan (4.79 g, 78%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45]CC)=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:15]1[C:10]2[N:9]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:8]=[C:7]([C:37]3[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:39][CH:38]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(-c1ccc(OCC(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate obtained in Step A of Example 152 (250 mg) in DMF (3 mL)/water (0.3 mL) were added ethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (241 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (23 mg) and cesium carbonate (367 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate, and neutralized 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (166 mg).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCn1ccc(C=CC(=O)OCC)cc1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCn1ccc(CCC(=O)OCC)cc1=O
Yield: 97 %

Procedure:
Ethyl β-(N-n-butyl-2-oxo-4-pyridyl)acrylate (59.50 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal (0.45 g) at 315 KPa (45 psi), with gentle warming. When the theoretical uptake of hydrogen had been exceeded the reaction mixture was filtered and the filtrate evaporated under reduced pressure to afford an oil. This oil was washed with petroleum ether (40°-60°) to yield ethyl β-(N-n-butyl-2-oxo-4-pyridyl)propionate (58.19 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:28]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Reactant: OB(O)C1=CCCCC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (20 mg, 0.043 mmol) and cyclohexen-1-ylboronic acid (13 mg, 0.103 mmol) in 2M Na2CO3 (1.3 mL) and DME (2.6 mL) for 6 min. Pd(PPh3)4 (4.4 mg) was added and the mixture was refluxed for 1 h and 30 min. It was cooled, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane:EtOAc—9:1 and 4:1 as eluents) yielding pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccc(F)cc1Br
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)cc2Br)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.601 g, 6 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.004 mL, 7.20 mmol). The solution was then cooled to 0° C. before 2-bromo-4-fluorobenzoyl chloride (1.567 g, 6.60 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (40 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL), before being dried over anhydrous sodium sulphate. The sodium sulphate was then removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (40 mL) at 55° C. for 30 minutes. The solid was then removed by filtration to yield the product in 1.625 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 3-benzyloxyestra-1,3,5(10)-trien-17-one (40, 2.70 g, 7.5 mmol) in THF (5.0 mL) and MeOH (30 mL) was added sodium borohydride (284 mg, 7.5 mmol) at 0° C. The reaction mixture was stirred for 30 min, then quenched with saturated aqueous NH4Cl, and H2O added. The precipitate was collected by filtration and washed with H2O to afford 2.73 g of 41 (100% yield) mp: 118-119° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].O1CCCC1.[CH3:13][C:14](=O)[CH2:15][C:16](=[O:18])[CH3:17]>O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:14]([CH3:13])=[CH:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: COC(CN)OC
Solvent: O
Solvent: C1CCOC1
Product: COC(CNC(C)=CC(C)=O)OC
Reaction time: 8 h

Procedure:
21.0 g of aminoacetaldehyde dimethylacetal (0.2 moles) were dissolved into 100 ml of tetrahydrofuran to which 20.0 g of 2,4-pentanedione (0.2 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH(OMe)2)Me=25.0 g (72% of theoretical).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[C:3]=2[F:17])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, white solid (61 mg, 73%), MS (ISP) m/z=335.2 [(M+H)+], mp 305° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1)=[O:4]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
N,N-Dimethylcarbamoyl chloride (7.91 g) and aluminum chloride (9.80 g) are added to toluene (100 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-t-butylisoxazole (9.81 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water, stirred at room temperature and shaken with toluene. The organic layer is evaporated to remove the toluene, whereby 1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)urea (14.63 g) is obtained. Yield is 98.9%. Melting point of the colorless crystalline product is 119 to 120.5° C. (after recrystallization from benzene).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2].O.[CH2:26](OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[C:7]([CH:8]2[CH2:11][C:10](=[CH2:26])[CH2:9]2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2]
Reactant: CCOCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=C1CC(c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C#N)C1
Temperature: -5 °C

Procedure:
Methyltriphenylphosphonium bromide (304 mg, 0.85 mmol) was suspended in dry diethyl ether (5 ml) in a nitrogen-flushed flask and cooled to -5° C. n-Butyl lithium (0.34 ml, 2.5M in hexanes) was added dropwise producing a yellow colour. The mixture was warmed to room temperature before heating to reflux for 1 hr. The amber homogeneous solution thus obtained was cooled to -78° C. and 3-cyano-4-(3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (300 mg, 0.80 mmol, Example 3), dissolved in dry diethyl ether (5 ml), added dropwise keeping the internal temperature at ca. -70° C. The mixture was allowed to slowly warm to room temperature before refluxing for 1 hr. The mixture was then cooled, poured into water (20 ml) and extracted with diethyl ether (3×10 ml). The combined organics were washed with brine, dried (MgSO4), filtered and ether solvent evaporated in vacuo. The residue was purified by silica chromatography (eluting with 20% DCM/hexane) yielding 40 mg of a white solid. This was further purified by hplc (Microsorb™C18, eluting with acetonitrile/methanol/water 6:1:3 v/v) to give 18 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.O=[C:11]([CH3:26])[CH:12]([C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C(O)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:12]1[C:18]([OH:19])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=[C:11]1[CH3:26]
Reactant: NNc1ccc(Cl)nn1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccc1
Solvent: CCO
Product: COC(=O)CC1C(C)=NN(c2ccc(Cl)nn2)C1(O)c1ccccc1

Procedure:
0.296 g (2.049 mmol) of 3-chloro-6-hydrazinylpyridazine in 5.00 ml of ethanol was added to 0.400 g (1.708 mmol) of methyl 4-oxo-3-(phenylcarbonyl)pentanoate, and the mixture was stirred at reflux for 8 h. The solvent was removed under reduced pressure which gave, after chromatography of the residue, 0.300 g (48% of theory) of a viscous yellow oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of hydroquinone (Aldrich, 11.01 g, 100 mmol) in DMF (300 mL), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (Aldrich, 12.0 g, 50 mmol), cesium carbonate (40.7 g, 125 mol) were added and the mixture was stirred at 60° C. overnight. The mixture was poured into water (300 mL) and 6N HCl was added to adjust the “pH” to 6. The mixture was extracted with EtOAc (3×60 mL) and the extracts were combined and dried. Removal of solvent gave the crude, which was chromatographied on a ISCO machine eluting with EtOAc/hexane (0-30%) to give a light brown solid. 5.71 g.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:8][C@@H:9]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc([N+](=O)[O-])c3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc([N+](=O)[O-])c3)OC(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
Acetic anhydride (1.67 ml, 17.6 mM) is added to a solution of (S)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)-1-(3-nitrophenoxy)propane (1.99 g, 4.4 mM) (Example 27) in CH2Cl2 (4 ml) and pyridine (2 ml). The mixture is maintained in agitation for 21 hours at room temperature. Then it is treated with 1N HCl, followed by a saturated aqueous NaHCO3 solution. The two phases are separated and the organic phase dried over Na2SO4, filtered and the solvent removed under vacuum. An oil is obtained from which the product (S)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]-1-(3-nitrophenoxy)propane is isolated (yield of 69%) by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate=1:1). [α]D=−10.0 (c 1.04, CHCl3). FT-IR (neat): 3092, 2930, 2850, 1740, 1597, 1576, 1531, 1499, 1458, 1373, 1350, 1329, 1307, 1259, 1234, 1164, 1095, 944, 805, 737 cm−1. 1NMRs (400 MHz CDCl3, δ): 7.82-7.79 (m, 1H, aromatic proton); 7.68-7.65 (m, 3H, aromatic protons); 7.42-7.38 (t, 1H, J=8.2 Hz, aromatic proton); 7.21-7.18 (dd, 1H, J=8.4 Hz, 2.6 and 0.9 Hz, aromatic proton); 7.00-6.97 (m, 2H, aromatic protons); 5.30-5.20 (m, 1H, CHOAc); 4.17-4.13 (dd, 1H, J=10.3 and 3.5 Hz, CH2OAr), 4.12-4.08 (dd, 1H, J=10.3 and 6.4 Hz, CH2OAr); 3.86 (s, 3H, OCH3); 3.10-2.90 (m, 4H, 2 CH2N of piperazine); 2.70-2.50 (m, 6H, 2 CH2N of piperazine and CHOHCH2N); 2.04 (s, 3H, CH3CO). 13C NMRs (100 MHz CDCl3, δ): 170.29, 163.03, 158.88, 149.03, 129.99, 129.81, 126.92, 121.81, 116.15, 114.21, 108.63, 94.40, 68.08, 57.36, 55.56, 52.74, 46.01, 21.04. MS-ESI m/z (%): 494 [M+H]+ (22); 516 [M+Na]+ (100). MS-MS (516): 516 (3), 435 (22), 434 (100), 295 (10), 269 (26), 263 (13). Anal. Calc. for C22H27N3O8S: C, 53.55; H, 5.48; N, 8.52. Found: C, 53.51; H, 5.41; N, 8.69.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]=O)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH3:16])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1c(C)[nH]c3ccccc13)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.