Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:29][OH:30])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+].Cl>C1COCC1.O.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:29][OH:30])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1ccc(C(COc2ccc(C(=O)OC)cc2)=NO)cc1C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc(C(COc2ccc(C(=O)O)cc2)=NO)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
550 mg (1.4 mmol) of methyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]benzoate are dissolved in 10 ml of THF. 1 ml of methanol is added, followed by addition of 164 mg (4 mmol) of powdered sodium hydroxide and 100 μl water. The reaction medium is stirred at room temperature for 12 hours and then treated with saturated ammonium chloride solution. The aqueous phase is returned to pH 5 by adding 1N hydrochloric acid, and is extracted twice with ethyl acetate. The residue obtained is purified by chromatography on a column of silica (eluent: 80/20 and then 50/50 heptane/heptane). The final product is then recrystallized from a heptane/acetone system. A white crystalline solid is obtained (m.p.=185° C., m=245 mg, yield=44%); (1H NMR (CDCl3): 1.04-1.07 (t, 6H); 1.45 (s, 9H); 2.89 (m, 4H); 5.36 (s, 2H); 7.00-7.02 (d, J=8.8 Hz, 2H); 7.22-7.25 (d, J=8.3 Hz, 1H); 7.44-7.46 (dd, J=6.2 Hz, J′=2.06 Hz, 1H); 7.72 (d, J=2.0 Hz, 1H); 8.03-8.05 (d, J=8.74 Hz, 2H)).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.C([O-])=O.[NH4+].[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1-benzoyl-5-nitro-1H-indole (50 mg) was dissolved in a mixed solvent with methanol (2 ml) and tetrahydrofuran (2 ml), and ammonium formate of an excess amount and palladium/carbon (10%) of a catalytic amount were added. The reacted solution was stirred at around 30° C. for 30 minutes to complete the reduction, filtered through celite and then, concentrated under reduced pressure. Afterward, the residue was dissolved again in ethylacetate (10 ml), washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then, triturated with isooctane and isopropyleter. As a result, the present compound (25 mg, productive yield 56%) was obtained as a solid.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.[NH2:11][C:12]1[C:22]([Cl:23])=[CH:21][C:15]2[CH:16]([CH3:20])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1>O1CCOCC1>[Cl:23][C:22]1[C:12]([N:11]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[CH:13][C:14]2[O:18][C:17](=[O:19])[CH:16]([CH3:20])[C:15]=2[CH:21]=1
Reactant: CC1C(=O)Oc2cc(N)c(Cl)cc21
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: CC1C(=O)Oc2cc(-n3cccc3)c(Cl)cc21
Reaction time: 1 h

Procedure:
7 ml (0.045 mole) of 2,5-dimethoxytetrahydrofuran and 5 ml of 5 N HCl are added to a solution of 6.7 g (0.035 mole) of 6-amino-5-chloro-3-methylbenzofuran-2(3H)-one in 100 ml of dioxane. After 1 hour, the aqueous phase that has formed is removed and the upper dioxane-containing phase is concentrated to dryness by evaporation in vacuo. The dark-brown residue is filtered with methylene chloride through silica gel. After evaporating the methylene chloride, 5-chloro-3-methyl-6-(pyrrol-1-yl)-benzofuran-2(3H)-one is obtained in the form of colourless prisms having a melting point of 100°-101°.
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.FC(F)(F)S(O[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=2)(=O)=O.[NH4+].[OH-]>C1COCC1.C(Cl)(Cl)Cl.[Cl-].[Cl-].[Zn+2].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>[CH:1]1([C:7]#[C:8][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC1CCCCC1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This reaction is carried out under anhydrous conditions. Cyclohexylacetylene (700 mg; 6.47 mmol) in 10 mL. THF is cooled to 0° C. To this is added 2.5M n-BuLi (3.0 mL; 7.44 mmol) and stirred for 30 min. at 0° C. under N2 atm and then 1.0M ZnCl2 (7.4 mL; 7.44 mmol). This is allowed to warm to room temperature and stirred for 3/4 hour. The reaction mixture is transferred via cannula to a flask containing 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate (500 mg; 1.48 mmol) and Pd(PPh3)4 (83 mg; 0.074 mmol) in 4 mL of THF. This is then heated to 50° C. under N2 for 41/2 hours. The reaction mixture is then poured into 90 mL of 10% NH4OH, diluted with CHCl3 and stirred for 20 min. The aqueous layer is separated, and the organic layer washed with brine, dried over MgSO4, filtered, evaporated and chromatographed with 4:1 hexane: EtOAc to obtain 3-cyclohexylethynyl-6,7-dimethoxyquinoline, which is recrystallized from hexane, identified by NMR and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)cc1N
Yield: 99.3 %

Procedure:
10 g of 4-amino-3-nitrophenol in 180 ml of ethanol were hydrogenated under 40 bars pressure at 23° C. temperature with catalytic amound of palladium on carbon. Reaction was performed in an Inox flask for high pressure. After hydrogen uptake was complete, the catalyst was filtered off with suction, washed with methanol and the filtrate was concentred under reduced pressure yielding 8 g of crude 3,4-diaminophenol.
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:25]([O:27][CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]>C(Cl)Cl>[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:25]([O:27][CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]
Reactant: COC(=O)c1cc(C(C)O)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.1 %

Procedure:
Tribromophosphine (1.65 mL, 1.65 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (500 mg, 1.50 mmol) in DCM (10 mL) in an ice bath under nitrogen. The resulting solution was stirred at room temperature for 24 hrs. The reaction was incomplete and further tribromophosphine (0.300 mL, 0.30 mmol) was added and the reaction mixture stirred for an additional 12 hrs. The solvent was evaporated, the residue was suspended in water and ice and a sodium carbonate solution was carefully added until pH 6. The precipitate was collected by filtration, washed with water then with diethylether and dried to afford methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (470 mg, 79%) as a dark beige solid. Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([O:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])[CH2:17][CH2:16]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture 3.5 g (13.8 mmol) of cis-(4-Isopropyl-piperazin-1-yl)-(4-hydroxycyclohexyl)-methanone, 2.35 g (15.4 mmol) of methyl 4-hydroxybenzoate, 4.47 g (17.0 mmol) of triphenylphosphine in 12 ml of THF, a mixture of 3.88 g (16.9 mmol) of di-tert-butyl azodicarboxylate in 13 ml of THF was added dropwise at 0° C., and stirred for 24 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and methanol=from 98:2 to 9:1. After evaporation of the combined products, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and MeOH=from 100:0 to 19:1. The combined product fractions were evaporated to dryness to yield 1.34 g (25%) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester. A mixture of 0.6 g (1.5 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester, 42 mg (1.8 mmol) of lithium hydroxide, 6 ml of THF, 3 ml of water, and 1 ml of methanol was stirred at 80° C. for 16 h. After evaporation, the residue was acidified with 2N hydrochloric acid solution and evaporated. The precipitate was washed with water and dried to yield 0.56 g (97%) of the titled compound. MS (m/e): 375 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15](Cl)=[O:16]>>[CH3:13][O:14][C:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:16]
Reactant: COC(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: COC(=O)N1C(=O)c2ccccc2C1=O

Procedure:
A suspension comprising 25 millimoles of potassium phthalimide and 20 ml of methylchloroformate is refluxed for a period of approximately 31/2 hours. Upon completion of refluxing, the reaction mediuim is cooled, filtered, with insolubles being removed continuously by treatment with hot acteone until only potassium chloride remains. The desired product m.p. 184° - 184.5°C., is obtained from the acetone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][CH:22]=[CH:23][C:24]=5[C:17]=4[N:16](COCC[Si](C)(C)C)[N:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[ClH:33]>CO>[ClH:33].[S:21]1[CH:22]=[CH:23][C:24]2[C:17]3[NH:16][N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:13][CH:12]=4)[C:18]=3[CH2:19][C:20]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccncc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: c1cc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)ccn1
Temperature: 100 °C
Yield: 72 %

Procedure:
Pyridin-4-yl-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine (0.23 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding [4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-pyridin-4-yl-amine hydrochloride (0.13 g, 0.36 mmol) as yellow solid in 71% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>ClCCl>[O:22]=[C:3]1[C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:7][CH:6]=[CH:5][N:4]1[CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[O:10]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C(NC(=O)Cn1cccc(N)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1cccc(NC(=O)Nc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(3-Amino-2-oxo-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.43 g) and phenylisocyanate (0.175 g) were combined in dichloromethane (5 mL) and allowed to stir overnight. The mixture was poured into ethyl acetate, washed (saturated aqueous sodium bicarbonate, brine), evaporated, and purified using chromatography, eluting with ethyl acetate:dichloromethane (gradient, 0:100, 50:50, 100:0), to give the urea (0.54 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([OH:21])([CH2:19][CH3:20])[CH2:17][OH:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=O)[CH2:23][CH3:24]>S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][CH3:20])[CH2:17][O:18][CH:22]([CH2:23][CH3:24])[O:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: CCC(O)(CO)c1cc(F)cc(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Product: CCC1OCC(CC)(c2cc(F)cc(OCc3ccccc3)c2)O1

Procedure:
Using the procedures described in the last two paragraphs of the portion of Example 1 which is concerned with the preparation of starting materials, 2-(3-benzyloxy-5-fluorophenyl)butane-1,2-diol (1.02 g) was reacted with propionaldehyde (6 ml) in the presence of concentrated sulphuric acid (1 drop) to give 4-(3-benzyloxy-5-fluorophenyl)-2,4-diethyl-1,3-dioxolane, as an oil and as a mixture of diastereoisomers, and this product was hydrogenolysed to give the required starting material (0.5 g, 60%), as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:46]([O:48][C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of 25 g of (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 35.6 g of NEM and 25.3 g of TOTU in 125 ml of DMF, 12.9 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 3 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 400 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 35.4 g.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][C@@H:4]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16](=[O:28])[N:5]2[CH:6]([C:7]([O:9][CH2:10][C:11]([Cl:12])([Cl:13])[Cl:14])=[O:8])[CH:15]=1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=CC(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 2.5 h
Yield: 21.7 %

Procedure:
Titanium tetrachloride (0.19 g.) was added to a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (0.46 g.) in dried dichloromethane (5 ml.) and the mixture was stirred for 2.5 hours. After the reaction, the reaction mixture was washed in turn with 2% hydrochloric acid three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After the solvent was distilled off the residue (0.43 g.) was purified by column chromatography on silica gel (10 g.) using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.1 g.), mp 136° to 137° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28]>C1COCC1>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27](=[NH:28])[O:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
2-[4-(Trifluoromethyl)phenyl]propan-2-ol (Compound SP824) (27.0 g, 132 mmol) was azeotropically distilled with THF (54 ml) three times. This was dissolved in dehydrated THF (270 ml) under a nitrogen atmosphere, a solution of sodium bis(trimethylsilyl)amide in dehydrated THF (1.9 M, 13.9 ml, 26.4 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Trichloroacetonitrile (13.3 ml, 132 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (hexane) to afford 2-(4-(trifluoromethyl)phenyl)propan-2-yl 2,2,2-trichloroacetimidate (Compound SP853) (86%, 39.7g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
To a suspension of 7-(3-acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.95 g, 2.5 mmol) in ethanol (10 ml) was added sodium borohydride (0.1 g, 2.6 mmol) and the resultant mixture was stirred at 60° C. for 20 min. The cooled reaction mixture was concentrated under reduced pressure and the concentrate was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and concentrated to a small volume (1-2 ml) under reduced pressure. The title product precipitated upon addition of ligroin to the concentrate (0.65 g, 68%) m/z, 383.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][CH3:32])=[C:18]([C:20]([CH3:30])([CH3:29])[CH2:21][C:22]2([C:25]([F:28])([F:27])[F:26])[CH2:24][O:23]2)[CH:19]=1.[O-]CC.[Na+]>C(O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][CH3:32])=[C:18]([C:20]([CH3:29])([CH3:30])[CH2:21][C:22]([OH:23])([C:25]([F:28])([F:27])[F:26])[CH2:24][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[C:2]([CH3:1])=[CH:3]2)[CH:19]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1c[nH]c2ccccc2c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(C)c(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
A mixture of 3-methyl-1H-quinolin-4-one (0.76 g), 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.089 g) and sodium ethoxide in ethanol (0.18 mL of a 21 wt. % solution) in 2 mL of anhydrous ethanol was heated at 85° C. for 12 hours, cooled to room temperature, and most of the volatiles removed in vacuo. The residue was diluted with diethyl ether and methanol and washed with water and brine, and dried over magnesium sulfate. The residue was purified by flash silica gel chromatography using ethyl acetate as the eluent. The product-rich fractions were concentrated in vacuo and dried to afford 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H-quinolin-4-one, m.p. >225° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.CC([O-])=O.[K+].[CH3:15][NH2:16]>CN(C=O)C.[Cu]I>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH3:8])[NH:16][CH3:15]
Reactant: Cc1ccc(Br)cc1F
Reactant: CN
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1ccc(C)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a suspension of 4-bromo-2-fluoro-1-methylbenzene (1.0 g, 5.3 mmol), KOAc (1.3 g, 13.2 mmol), and CuI (1.2 g, 6.4 mmol) in DMF (20 mL) was added methylamine (26.5 mL, 2.0M in THF, 53.0 mmol) at r.t. under N2. The reaction was stirred at 100° C. overnight in a sealed tube. The reaction mixture was filtered, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The organic layers were washed with ammonium hydroxide (50 mL×3) and brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1) to give 310 mg (42%) of the title compound as a yellow oil. [M+H] Calc'd for C8H10FN, 140. Found, 140.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:17])[CH2:15][CH3:16]>>[CH2:14]([O:17][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH3:16]
Reactant: CCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (650 mg, 3.3 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 700 mg (96%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:17])[CH2:13]S(C)=O.[CH:18]([CH:20]1[CH2:22][CH:21]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O.N1CCCCC1>C1(C)C=CC=CC=1>[O:17]=[C:12]1[CH:13]=[C:18]([CH:20]2[CH2:22][CH:21]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:1][C:2]2[C:11]3[C:6]([CH:5]=[CH:4][C:3]1=2)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CS(=O)CC(=O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)C1CC1C=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C1CC1c1cc(=O)c2ccc3ccccc3c2o1

Procedure:
A mixture of 12.4g of 1'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone, 7.1g of ethyl 2-formyl-1-cyclopropane carboxylate, 250ml of toluene and 0.5ml of piperidine was refluxed for 8 hrs. The toluene was then removed under reduced pressure, and the oily residue was recrystallized from Skelly B with the aid of charcoal, mp. 106°-07.5°; yield 6.5g (42%); λ max mμ (ε) 219 (50,000), 259 (36,800), 327 (3,990), 341 (4,100); ν max 760 (m), 825 (ms), 1195 (s), 1640 (s), 1650 (s), 1730 (s) cm-1.