Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH2:33]C)=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cc2cc(F)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 5-fluorobenzofuran-2-ylboronic acid (258.0 mg, 1.43 mmol) in dioxane (5.5 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160.0 mg, 81%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].CO>C(Cl)Cl.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>[O:21]=[C:18]1[NH:8][CH:7]=[C:6]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:5]=[CH:4]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 90 °C
Yield: 117.1 %

Procedure:
IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl 4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boronoic acid (25.0 g, 163 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO4) and concentrated to give a brown solid. The crude residue was subject to column chromatography (0 to 1.5% MeOH in DCM) to give a white solid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (20.95 g, 63.8 mmol, 58% yield).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH2:22]([Al](CC)CC)[CH3:23].O>O1CCOCC1.CCCCCC.[Cu]Br>[CH2:22]([C@@H:14]1[C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])=[CH:11][C:12](=[O:20])[CH2:13]1)[CH3:23]
Reactant: CC[Al](CC)CC
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cu]Br
Solvent: CCCCCC
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C

Procedure:
2.84 g (10 mmol) of androsta-1,4-diene-3,17-dione is dissolved under nitrogen atmosphere in 20 ml of anhydrous dioxane. 143 mg (1 mmol) of copper(I) bromide is added, and the solution is heated to 25° C. Then, 10 ml (10 mmol) of a 1 molar solution of triethylaluminum in hexane is added to the reaction, so that the temperature does not rise above 30° C. Then, it is stirred for 1.5 more hours at 30° C. For hydrolysis, 1 ml of water mixed with 5 ml of dioxane is added to the reaction, and the solution is stirred for 15 more minutes. The inorganic solid is suctioned off and rewashed with 30 ml of dioxane. After concentration by evaporation of the dioxane solution, 3 g of crude product is obtained, which is chromatographed on silica gel with a hexane/ethyl acetate mixture with an increasing portion of ethyl acetate as eluent. After concentration by evaporation of the fractions, 2.67 g of 1α-ethylandrost-4-ene-3,17-dione (85% of theory) of melting point 168° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+].Cl>CO>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(C(=O)OC)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of the ester 32 (0.058 g, 0.16 mmol) in 75% aqueous methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The mixture was stirred at 70° C. for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSo4, filtered, and concentrated to afford a white solid. Recrystallization from dichloromethane/hexane afforded the desired acid 33 as a white, crystalline solid (42 mg, 91%): m.p. 230°-231° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:16]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:19]=1[CH2:20]Cl)[CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(Cl)Cl.CC(C)=O>[CH3:14][C:12]1[N:13]=[C:3]2[C:2]([NH:1][CH2:20][C:19]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:18]=3[CH2:16][CH3:17])=[CH:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][N:4]2[C:11]=1[CH3:15]
Reactant: CCc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 51.4 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (3.3 g, 16.2 mmol), 2-ethyl-6-methylbenzylchloride (2.73 g, 16.2 mmol), potassium carbonate (8.0 g, 58 mmol) and potassium iodide (1.1 g, 6.6 mmol) were added to acetone (150 ml) and refluxed for 20 h. An additional amount of 2-ethyl-6-methylbenzylchloride (1.0 g, 5.9 mmol) was added and the reaction mixture was refluxed for 7 h. Methylene chloride (60 ml) and methanol (30 ml) were added. The reaction mixture was filtered and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:7) as eluent. Crystallization from ethyl acetate gave 2.8 g (50%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH2:12].C(N(C(C)C)CC)(C)C>C(O)CCC>[CH3:6][CH2:5][CH2:4][CH:10]([CH3:16])[CH3:11].[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccc(F)cc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)C
Product: Fc1ccc(Nc2ccnc(Cl)n2)c(F)c1

Procedure:
2,4-Dichloropyrimidine (200 mg, 1.34 mmol), 2,4-difluoroaniline (173 mg, 1.34 mmol) and diisopropylethylamine (0.26 ml, 1.48 mmol) were dissolved in n-butanol (5 ml). The reaction mixture was heated at reflux for 12 hours, cooled and evaporated onto silica (5 ml). The residue was purified by column chromatography and eluted with EtOAc (30%): isohexane to give the title product as a solid on evaporation (174 mg, 54%). NMR (300 MHz): 6.70 (d, 1H), 7.12 (t, 1H), 7.38 (t, 1H), 7.70 (dd, 1H), 8.14 (d, 1H), 9.74 (brs, 1H); m/z: (ES+) 242.1 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:30]2=[O:57])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[C:30]2=[O:57])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3S(=O)C2)cc1

Procedure:
A solution of 85% strength m-chloroperbenzoic acid (55.22 g) in methylene chloride (600 cc) is added dropwise, in the course of 2 hours, to a solution, cooled to -10° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (or -3-ene) (mixture of the E and Z forms) (180.56 g) in methylene chloride (1.4 liters). The mixture is washed with a 5% strength solution of sodium bicarbonate (1.5 liters) and with water (2×1.5 liters), dried over sodium sulphate and concentrated at 20° C. under reduced pressure (20 mm Hg) to a volume of 300 cc. This solution is chromatographed on a column of Merck silica gel (0.05-0.2 mm) (3 kg) (diameter of the column: 9.2 cm, height: 145 cm). Elution is carried out successively with the following mixtures of cyclohexane/ethyl acetate: 80/20 (by volume) (15 liters) and 70/30 (by volume) (32 liters), 600 cc fractions being collected. Fractions 27 and 28 are collected and concentrated to dryness and this yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5.56 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.Cl>C(OCC)C.C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH2:7][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ncccn2)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: c1cnc(CC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 3-(pyrimidin-2-ylmethyl)piperidine-1-carboxylate (Preparation 70, 27.3 g, 98.4 mmol, 1 eq) in diethyl ether (160 mL) and DCM (50 mL) was added dropwise a 2M solution of hydrogen chloride in diethyl ether (246 mL, 492 mmol, 5 eq) while maintaining the internal temperature below 30° C. The reaction mixture was stirred at room temperature for 20 h. The solvent was decanted and fresh diethyl ether (300 mL) added. The solid was collected by filtration and washed with diethyl ether (3×100 mL) then dissolved in water (150 mL). The aqueous layer was washed with DCM (2×150 mL), basified with sodium hydroxide pellets to pH 13-14 and extracted with DCM (5×200 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford title compound (15 g, 84.6 mmol, 86%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][CH2:40][N:39]2[CH2:43][CH2:44][CH2:45][C@H:38]12.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[CH2:43][CH2:44][CH2:45][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 44.7 %

Procedure:
The title compound was prepared starting from 100 mg (0.187 mmole) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl) -3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 70 mg (0.554 mmol) of (8aR) -octahydropyrrolo[1,2-a]pyrazine, 52.2 mg of potassium carbonate (0.377 mmol); the reagents were dissolved in 0.6 ml of DMSO and the reaction mixture was heated at 150° C. overnight. Obtained after flash chromatography 52 mg of the desired compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>>[C:26]1([S:32]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH2:11][CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CCn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Yield: 36 %

Procedure:
The product of step A was coupled with sodium benzenesulfinate following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 4:1 to 1:1 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (0.12 g, 36%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 7.94-7.99 (m, 2H), 7.40-7.53 (m, 4H), 7.31 (d, J=8.7 Hz, 1H), 5.20-5.33 (m, 1H), 4.55-4.81 (m, 1H), 3.95-4.11 (m, 2H), 3.19-3.50 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.15-2.38 (m, 2H), 1.91-2.01 (m, 1H), 1.53-1.62 (m, 1H), 1.34 (s, 9H), 1.25-1.31 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[CH2:5].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[C:9]([O:8][C:7](=[O:13])[N:6]([CH2:3][CH:4]=[CH2:5])[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCN(CC=C)C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 116.2 %

Procedure:
To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in DMF (30 mL) was added tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40° C. for approximately 2 hours whereupon the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water (2×'s), brine, dried (MgSO4), filtered and concentrated to give 10 grams of the title compound as an oil: MS(EI) 226 (M+H+).
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+]C2CCCCC2)CCCCC1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:38][N:7]([CH3:1])[CH:8]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:13]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Temperature: 50 °C
Yield: 89.1 %

Procedure:
To 1.20 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 20 ml methylene chloride and 2.1 ml solution of dimethylamioethyl-chloride in the amount of 0.5 g, which stoichiometrically corresponds to two times molar volume, in toluene were added to be subjected to reflux in oil bath at 50° C. for 35 hrs. After cooling down to the room temperature, the reaction mixture was similarly treated as in Step Example 1 to obtain N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 842 mg (yield; 89.1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O

Procedure:
1 mol of 6-hydroxy-1-tetralone, 1.2 mols of methyl chloroacetate, 2 mols of potassium carbonate and 0.1 mol of potassium iodide are boiled under reflux in 2 l of butanone for 6 hours. The mixture is filtered, the residue is rinsed with acetone and the filtrate is evaporated. The residue is taken up in methylene chloride, and the mixture is washed 3 times with 0.5N NaOH solution, dried over sodium sulphate and evaporated.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][CH:36]([CH2:38][C:39](O)=[S:40])[F:37].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:39](=[S:40])[CH2:38][CH:36]([F:37])[F:35])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(=S)CC(F)F
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Temperature: -30 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 7β-amino-3-(1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (550 mg : 1.08 mMol.) and difluoromethylthioacetic acid (160 mg : 1.13 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml : 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous saline, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene : ethyl acetate=1:1) to give 7β-difluoromethylthioacetamido-3-(1,2,3-triazol-4-ylthiomethyl- thio) -3-cephem-4-carboxylic acid diphenylmethyl ester (475 mg) as pale yellow foam. Yield : 69%.
Reaction SMILES: CO[C:3]1([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([O:22]C)([O:20]C)OC)[CH:7]=[CH:6][CH:5]([O:8]C)O1.O.P([O-])(O)(O)=[O:26].[Na+].O1CCOCC1.S(=O)(=O)(O)O>P([O-])([O-])(O)=O.[Na+].[Na+].O>[OH:26][CH:7]1[CH2:6][C:5](=[O:8])[C:10]([CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([OH:20])=[O:22])=[CH:3]1
Reactant: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Reactant: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 112.5 %

Procedure:
A stirred mixture of 7.1 g of 2,5-dihydro-2,5-di- methoxy-2-(8,8,8-trimethoxy-3-octynyl)furan, 2.76 g of sodium dihydrogen phosphate monohydrate, 140 mg of disodium hydrogen phosphate, 60 ml of dioxane and 40 ml of water was boiled under reflux for 19 hours, then cooled to 50° C. and treated dropwise with 4.1 ml of concentrated sulfuric acid. The resulting solution was boiled under reflux for 12 hours, cooled and partitioned with ether and brine. The ether layer was separated, washed with brine, dried and concentrated, giving 5.0 g of crude 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid. This crude product was dissolved in 40 ml of pyridine and the stirred solution treated at 0° to 10° C. with 10.5 ml of hexamethyldisilizane followed by 6.3 ml of chlorotrimethylsilane. The resulting mixture was stirred at 25° C. for 3 hours and then concentrated to dryness at 30° C. The residue was extracted with hexane, the extract filtered through diatomaceous earth and concentrated. The residue was distilled at 0.11 mm on a Kugelrohr at 155°-170° C., giving 1.66 g of the desired compound as an oil.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][OH:44])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)=[O:17])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:45])([CH3:46])[CH2:42][CH2:43][O:44][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23]1)=[O:17])=[O:9]
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)CCO[Si](C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
TMSCl (0.08 mL, 0.596 mmol) was added dropwise to a solution of 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (300 mg, 0.497 mmol) and triethylamine (0.11 mL, 0.745 mmol) in dichloromethane at 0° C. After stirring for 1 h, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The solution was washed with water, brine, dried and concentrated to give crude 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-5-trimethylsilanyloxy-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (330 mg) which was carried to next step without further purification.