Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].[N:10]1[CH:11]=[CH:12][N:13]2[C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=12>C(#N)C>[N:10]1[CH:11]=[CH:12][N:13]2[C:18]([C:19]([NH:9][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[C:7]#[N:8])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: N#CC(N)c1ccco1
Reactant: O=C(Cl)c1cccc2nccn12
Solvent: CC#N
Product: N#CC(NC(=O)c1cccc2nccn12)c1ccco1
Yield: 61 %

Procedure:
α-(2-Furyl)-α-aminoacetonitrile (0.7 g, 5.5 m moles) was dissolved in acetonitrile (20 ml), and imidazo[1,2-a]pyridine-5-carboxylic acid chloride (1.0 g, 5.5 m moles) was added thereto and reacted at room temperature for 2 hours. After completion of the reaction, the solvent was removed from the reaction mixture. To the residue were added water (20 ml), saturated aqueous solution of sodium bicarbonate (50 ml) and chloroform (50 ml), and the mixture was stirred. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography on silica gel (eluent: methanol/chloroform=1/9) to give the object compound (0.9 g, yield 64%) as amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22]>O1CCCC1>[F:10][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[C:4]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C=O
Temperature: -55 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1,2-difluoro-4-methoxy-benzene (Aldrich; 10.0 g, 69.4 mmol) in dry tetrahydrofuran (500 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 40 mL, 72.9 mmol) was added dropwise by syringe. The reaction mixture was warmed to −55° C. and held at this temperature for 1 h. The mixture was then cooled again to −78° C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to −10° C. and quenched by the addition of ice flakes (˜200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30% ethyl acetate/hexanes to give 2,3-difluoro-6-methoxy-benzaldehyde (7.0 g, 59% yield) as an oil that solidified upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]=[CH:19][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CNc2cc(Br)ccc2N)cc1
Solvent: O
Solvent: COC(OC)OC
Product: COc1ccc(Cn2cnc3ccc(Br)cc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 886.7 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)benzene-1,2-diamine (550 mg, crude) in HC(OMe)3 (20 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was then concentrated and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the desired product (450 mg, 79% yield) and the crude product used in next step without further purification. LCMS (m/z): 318.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH2:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([O:29]O)(C)(C)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[O:29][CH2:16]2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OO
Reactant: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1
Solvent: c1ccccc1
Product: OC(Cn1cncn1)(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Yield: 62 %

Procedure:
2,3-Bis(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-butene-2-ol (1.0 g) was dissolved in 50 ml of anhydrous benzene and stirred under nitrogen. To this solution was added 0.012 g of vanadium acetonyl-acetonate. The solution was then refluxed and tert-butyl hydroperoxide (0.44 g dissolved in 5 ml of anhydrous benzene) was added dropwise over 10 minutes. The reaction was refluxed for one additional hour and then cooled to ambient temperature. The benzene was removed in vacuo and the residue chromatographed on silica gel (2% MeOH/CH2Cl2). This yielded a total of 650 mg of diastereomeric products in a 3:1 ratio. Further chromatography resulted in the separation of the diastereomers. The major isomer was a waxy white solid. NMR (CDCl3 /TMS) δ 2.60 (d, J=6 Hz, 1H); 3.48 (d, J=6 Hz, 1H); 4.70 (q, J=7 Hz, 2H); 5.25 (s, 1H); 6.8-7.3 (m, 8H); 7.55 (s, 1H); 7.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=O)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[NH:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc2nc(Cl)[nH]c12

Procedure:
To a round bottomed flask was added 4-methoxy-1H-benzo[d]imidazol-2(3H)-one (1.8163 g, 11.06 mmol). POCl3 (1.031 mL, 11.06 mmol) was added and the reaction was brought to reflux. Upon completion, POCL3 was evaporated off. The residue was taken up in DCM. The reaction mixture was diluted with water and saturated sodium bicarbonate and extracted with DCM. The organic extract was washed with sat. sodium bicarbonate solution, water, brine, dried with magnesium sulfate, filtered, and concentrated to provide 2-Chloro-7-methoxy-1H-benzo[d]imidazole. MS (ESI, pos. ion) m/z: 182.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[CH:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-butyllithium (n-BuLi, 1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]−).
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>>[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16]([O:5][C@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][I:1])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)c2c1SCC2
Reactant: O[C@H](CCI)c1ccccc1
Product: Fc1ccc(O[C@@H](CCI)c2ccccc2)c2c1CCS2

Procedure:
using (R)-1-iodo-3-phenyl-3-propanol with 4-fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 242 mg of the title compound as a colorless solid: δH (300 MHz, CDCl3) 7.32-7.12 (5H, m, 3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H, m, CH2CH2HI and SCH2CH2), 2.50-2.31 (1H, m, CHHCH2I) and 2.27-2.09 (1H, m, CHHCH2I).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:11]1[C:12](=[O:24])[N:13]([CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20])[C:14](=[O:17])[C:15]=1C.[CH2:25](O)C>>[C:19]([C:18]([N:13]1[C:12](=[O:24])[CH:11]=[C:15]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[C:14]1=[O:17])([CH3:25])[CH:21]([CH3:22])[CH3:23])#[N:20]
Reactant: CC1=C(Br)C(=O)N(C(C#N)C(C)C)C1=O
Reactant: CCO
Reactant: Nc1ccccc1CO
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2CO)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To o-aminobenzyl alcohol, (2 g, 0.0125 mol) and 3-bromo- -isopropyl- -methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.7 g, 0.01 mol) is added absolute ethanol (100 ml) containing 3 g of 5 A pulverized sieves. The mixture is stirred for 20 hours at room temperature. The solvent is removed and the residue is purified through a silica gel dry column, eluant ether-hexane (2:1). Starting bromomaleimide is first recovered, followed by a bright yellow solid 1.89 g (60%), mp 39°-45° C. Anal. calcd. for C17H19N3O3:C, 65.16; H, 6.11; N, 13.41. Found: C, 65.94; H, 6.21; N, 12.87.
Reaction SMILES: [OH:1]I(C1C=CC=CC=1)OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH2:27][CH2:26]2.[C:33](#N)[CH3:34]>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH:27]([O:1][CH2:33][CH3:34])[CH2:26]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CC#N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Product: CCOC1Cc2cc(Br)ccc2C1=O
Temperature: 25 °C

Procedure:
310 mg of [hydroxy (p-nitrobenzenesulfonyloxy]iodo]benzene was added at room temperature to 20 ml solution of acetonitrile with 130 mg of 5-bromo-1-indanone, and the mixture was heated under reflux for 3 hours. The reaction solution was cooled down to room temperature, the solvents were distilled outunder reduced pressure. The obtained residues were dissolved in 20 ml of ethanol, and refluxed all night. The reaction solution was cooled down to room temperature, the solvents were distilled outunder reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were purified by silicagel column chromatography (hexane:ethyl acetate=95:5) to obtain 84 mg of the above compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=NNS(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.[Cl-].[NH4+]>COC(C)(C)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C(=NNS(=O)(=O)c3ccc(C)cc3)CC[C@@H]12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C=CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
2.43 g (5.37 mmol) of 3-methoxy-17-tosylhydrazono-13α-estra-1,3,5(10)-triene is suspended in 20 ml of anhydrous methyl-tert-butylether. 1.61 ml of a 10 M n-butyllithium solution in hexane is slowly added in drops to this suspension. It is stirred for 1 hour at room temperature. While being cooled, 50 ml of saturated ammonium chloride solution is added in drops. After the organic phase is separated, it is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried (MgSO4). The crude product (2.1 g of brown oil) is chromatographed on silica gel, whereby 0.81 g of 3-methoxy-13α-estra-1,3,5(10),16-tetraene is obtained as a colorless oil; [α]D=−6° (chloroform; c=0.94).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([NH:11][C:12]2[C:13]3[C:17]([CH:18]=[C:19](B4OC(C)(C)CC(C)(C)O4)[CH:20]=2)=[N:16][N:15](C2CCCCO2)[CH:14]=3)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[CH2:48][C:49](=[O:55])[NH:50]2.O1CCOCC1>O>[CH3:3][CH:2]([N:4]1[C:8]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:46]3[CH:54]=[CH:53][CH:52]=[C:51]4[C:47]=3[CH2:48][C:49](=[O:55])[NH:50]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:1]
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3c2CC(=O)N3)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg), Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-bromo-1,3-dihydro-2H-indol-2-one (available from Apollo, 33 mg), 1,4-dioxane (0.5 ml) and water (0.1 ml). The reaction was heated under microwave irradiation for a total of 30 min at 120° C.). Further tripotassium phosphate (60 mg) and Solvias catalyst (8 mg) were added and the reaction was heated under microwave irradiation for 10 min at 120° C. The reaction was passed through a silica cartridge, dried, then extracted with DCM and water before drying the DCM under a stream of nitrogen. The residue was purified as follows:
Reaction SMILES: N1CCCCC1.C(O)=O.CC1(C)[O:18][C:16](=[O:17])[CH2:15][C:13](=O)O1.C(=O)[C:21]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[C:23]([O:24][CH3:25])[CH:22]=1>>[CH3:25][O:24][C:23]1[CH:22]=[C:21]([CH2:13][CH2:15][C:16]([OH:18])=[O:17])[CH:30]=[CH:29][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: C1CCNCC1
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropping 20.4 g (23.7 ml, 0.24 mol) of piperidine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][C:29]1([CH3:41])[O:33][C@@H:32]([C:34]2[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:31][O:30]1.N1C=CC=CC=1.Cl>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 6.29 g, 19.01 mmol) and N,N-dimethylformamide (2 drops) in methylene chloride (70 mL) was stirred at 2° C. and then treated with oxalyl chloride (4.15 mL, 45.7 mmol). The mixture was stirred at 2° C. for 5 min and at 25° C. for 15 min. The reaction mixture was then concentrated in vacuo. The residue was dissolved in benzene (25 mL), and the evaporation was repeated. The resulting acid chloride was dissolved in methylene chloride (40 mL), cooled to 0° C., and then treated with a solution composed of 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (3.65 g, 18.95 mmol), pyridine (4.6 mL, 56.9 mmol) and methylene chloride (40 mL). The mixture was stirred for 16 h without replenishing the cooling bath. The reaction mixture was then treated with a 1N aqueous hydrochloric acid solution (100 mL). The layers were separated, and the aqueous layer was extracted with methylene chloride (75 mL). The organic layers were washed with a saturated aqueous sodium bicarbonate solution (100 mL) and a saturated aqueous sodium chloride solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (8.9 g, 92%) as a white foam: (ES)+-HRMS m/e calcd for C24H30ClN3O5S (M+H)+ 508.1668, found 508.1671.
Reaction SMILES: [ClH:1].Cl.F[C:4]1C=CC(CCOC2C=CC(C3(O)CCCCC3CCN3CCN(C)CC3)=CC=2)=CC=1.Cl.Cl.[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH:53]([C:61]3([OH:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)[CH2:54][N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:49][CH:48]=2)=[CH:40][CH:39]=1>>[ClH:1].[ClH:1].[F:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][O:46][C:47]2[CH:48]=[CH:49][C:50]([CH:53]([C:61]3([OH:67])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]3)[CH2:54][N:55]3[CH2:60][CH2:59][N:58]([CH3:4])[CH2:57][CH2:56]3)=[CH:51][CH:52]=2)=[CH:42][CH:43]=1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCCc3ccc(F)cc3)cc2)CC1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCCc3ccc(F)cc3)cc2)CCCCC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCCc3ccc(F)cc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-{4-[2-(4-fluorophenyl)ethoxy]phenyl}-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-(1-{4-[2-(4-fluorophenyl)ethoxy]phenyl}-2-piperazin-1-ylethyl)cyclohexanol (see Example 462). MS (ESI) m/z 441.
Reaction SMILES: N[C@@H](C[S:6][CH2:7][CH:8]1[CH2:10][CH2:9]1)CO.CN1CCOCC1.FC(F)(F)C(OS(C(F)(F)F)(=O)=O)C1C=CC=CC=1.C1C(C[C@:41]([NH:46][CH:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48]([F:51])([F:50])[F:49])([CH3:45])[CH:42](S)[OH:43])C1>C1COCC1>[CH2:9]1[CH:8]([CH2:7][S:6][C@:41]([NH:46][CH:47]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:48]([F:49])([F:50])[F:51])([CH3:45])[CH2:42][OH:43])[CH2:10]1
Reactant: C[C@](CC1CC1)(NC(c1ccccc1)C(F)(F)F)C(O)S
Reactant: N[C@H](CO)CSCC1CC1
Agent: O=S(=O)(OC(c1ccccc1)C(F)(F)F)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@](CO)(NC(c1ccccc1)C(F)(F)F)SCC1CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (80.5 mg, 0.5 mmol) in anhydrous THF (3 mL) were added activated 4A molecular sieves (250 mg) and N-methylmorpholine (51 mg, 0.5 mmol). After stirring for 10 min, trifluoromethanesulfonic acid 2,2,2-trifluoro-1-phenylethyl ester (190.5 mg, 0.5 mmol) was added and the reaction was stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography to afford the desired mixture of diastereomers of 2(R)-3-cyclopropylmethyl-sulfanyl-2-(2,2,2-trifluoro-1(RS)-phenylethylamino)-propan-1-ol. LC-MS: 318.3(M−1), 320.8(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].CO.C(OO)(=[O:28])C>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][S@:4](=[O:28])[C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CC(=O)OO
Solvent: CO
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@@](=O)C1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of polymer ester of (6R, 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (5.00g, 4.45 mole, from example 8 in methylene chloride (35 ml.) and methanol (10 ml.) cooled to 0° was added peracetic acid (38% w/v, 1.1 ml., 5.50 m.mole) in one portion. Stirring was continued for 30 minutes at 0° and for a further 15 minutes, after removal of the cooling bath. The reaction mixture was filtered and pulled as dry as possible. The product was washed with methylene chloride (2 × 50 ml.) methanol (2 × 50 ml.), and methylene chloride (2 × 50 ml.). The product was dried to constant weight in vacuo at 30° to give the pale yellow polymer ester of (1S, 6R. 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid 1-oxide (5.00g, which proved to be similar (infra red, nmr., and t.l.c.) with the product obtained in example 9 above.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=CC=C[CH:4]=1.[CH3:9][C:10]12[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]2=[N:19][OH:20].C(Br)C#C>CN(C)C=O.O>[CH2:8]([O:20][N:19]=[C:11]1[CH2:12][CH:13]2[C:16]([CH3:17])([CH3:18])[C:10]1([CH3:9])[CH2:15][CH2:14]2)[C:3]#[CH:4]
Reactant: CC12CCC(CC1=NO)C2(C)C
Reactant: c1ccccc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCON=C1CC2CCC1(C)C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
4.8 g (0.2 mole) of sodium hydride are added to 150 ml of dry benzene, and a solution of 33.4 g (0.2 mole) of (±)-1,7,7-trimethyl-bicyclo[2,2,1]heptane-2-one-oxime in 50 ml of dimethyl formamide is introduced into the mixture at 50° C. within 0.5 hours. When gas evolution ceases, the mixture is cooled to 25° C., and 23.8 g (0.2 mole) of propargyl bromide are added. The reaction is continued for an additional 2 hours. Thereafter the reaction mixture is shaken with water, the phases are separated, the benzene phase is evaporated, and the residue is subjected to fractional distillation in vacuo. 37.0 g (90.5%) of (±)-2-(propargyloxyimino)-1,7,7-trimethyl-bicyclo[2,2,1]heptane are obtained as a light yellow oil; b.p.: 94°-96° C./1.5 mm Hg, nD20 =1.4953.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:26][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:19][C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C=O
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccccc1CNc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 1.64 g of 2-isopropoxybenzaldehyde in 10 ml of methanol was added 1.85 g of 2-aminodiphenyl ether, and then the mixture was stirred at room temperature for 30 minutes and cooled on ice-water. To the cooled reaction solution was gradually added 1.50 g of sodium borohydride, followed by stirring under ice-cooling for 30 minutes and then at room temperature for 30 minutes. An aqueous acetic acid solution (1.5 ml of acetic acid—30 ml of water) was added dropwise to the reaction solution, followed by stirring at room temperature for 10 minutes. After extraction with ethyl acetate, the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:25) to give 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][N:5]=1.[C:21](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([O:16][CH3:21])=[O:15])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccc(C(=O)O)cc1Oc1ccnc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)c(Oc2ccnc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 1.6 ml methyl iodide are added to a mixture of 6.21 g 3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoic acid, 4.88 g potassium carbonate to and 30 ml N,N-dimethylformamide. The mixture is stirred overnight at ambient temperature. Then the mixture is added to ice-cold water, and the precipitate is filtered off and dried at 45° C.