Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>[OH-].[Na+]>[S:22]([NH:1][CH2:2][C:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)NCC2(N3CCN(C)CC3)CCCCC2)cc1
Yield: 46.3 %

Procedure:
1-(1-Aminomethylcyclohexyl)-4-methylpiperazine (0.5 g) was added to 10% sodium hydroxide solution (10 ml) and p-toluene sulphonyl chloride (0.5 g), and the mixture shaken vigorously. The solid was filtered, washed with water and recrystallised from 95% ethanol to give colourless needles (0.4 g, 46.2%) of 1-(1-tosylaminomethylcyclohexyl)-4-methyl piperazine, m.p. 128°-130°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1nnnc1-c1ccc(O)cc1

Procedure:
Feed materials: 5-(4-hydroxyphenyl)tetrazole and ethyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:35]([OH:36])[C:34]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:33]=1[CH3:32])(=[O:9])=[O:10]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc(C)cc2C)sc2ncccc12
Yield: 73.3 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)thieno[2,3-b]pyridine-3-sulfonamide (0.18 g, 0.42 mmoles)[Example 4(A)], t-BuLi (1.7 M, 0.32 ml, 0.55 mmoles), THF (5 ml) and 2,4-dimethylbenzaldehyde (0.12 ml, 0.84 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.17 g (73%) of the title compound.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([CH2:39][CH3:40])/[CH:34]=[CH:35]/[C:36]([OH:38])=O)=[O:31])([CH3:28])[CH3:27].[NH:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl>[N:41]1([C:36](=[O:38])/[CH:35]=[CH:34]/[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:26]([CH3:25])([CH3:27])[CH3:28])[CH2:39][CH3:40])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42]1
Reactant: CC[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 50 wt % ®T3P in EtOAc (22.00 mL, 37.0 mmol) was added dropwise via addition funnel to a solution of (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}-amino)-2-hexenoic acid (5.65 g, 24.64 mmol), 2,3-dihydro-1H-indole (2.76 mL, 24.64 mmol), and Et3N (11 mL, 79 mmol) in CH2Cl2 (90 mL) at 0° C. (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 30 min, the reaction was quenched by dropwise addition of saturated aq. NaHCO3 (50 mL). The layers were separated, and the reaction was washed with 10% citric acid (1×50 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 7.21 g (89%) of the title compound. LC-MS m/z 331 (M+H)+, 1.05 (ret time).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[C:31]([CH3:39])[C:28]=1[CH:29]=[O:30]>O.C1(C)C=CC=CC=1.C(OCC)C>[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[C:31]([CH3:39])[C:28]=1[CH:29]([C:18]1[C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=1[Cl:20])[OH:30]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(C)c(C(O)c2c(C(F)(F)F)cnc(Cl)c2Cl)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
70.0 ml (106 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added to a diethyl ether 120 ml solution of 15.0 ml (107 mmol) of diisopropylamine at 0° C., followed by stirring for 1 hour. The solution was cooled to −78° C., a diethyl ether 10 ml solution of 22.1 g (102 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added thereto, followed by stirring for 30 minutes, and then a toluene 40 ml solution of 21.0 g (100 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was added thereto, followed by stirring for 2 hours. 30 ml of water was added to the mixture to terminate the reaction, the aqueous layer was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 24.8 g (yield 58%) of (2,3,4-trimethoxy-6-methylphenyl)(2,3-dichloro-5-trifluoromethyl-4-pyridyl)methanol (m.p. 95-98° C.).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)N)=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:13][O:12][C:10](=[O:11])[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]1[N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:28]2[C:27]([C:6]=1[S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 39 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in a mixture of 300 mL of toluene and 150 mL of glacial acetic acid was added 15 g of NaOAc and 50 g of 1-(4-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine hydrochloride. The reaction was maintained with stirring at room temperature for 3 days under argon in the dark. The mixture was poured into 3 L of H2O and extracted with 3×500 mL of EtOAc. The ethyl acetate was washed with 3×500 mL of water then solid NaHCO3 was added. The mixture was filtered and the filtrate washed twice with water. The organic phase was dried over MgSO4 and evaporated to dryness to provide the title compound. m.p. 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 10 h
Yield: 46.7 %

Procedure:
To a solution of 48 (150 mg, 0.33 mmol) and DMAP (4 mg, 0.033 mmol) in pyridine (1.0 ml) was added pivaloyl chloride (57 μl, 0.46 mmol) as dropwise at room temperature and stirred for 10 h. The crude product was purified by prep HPLC (C18) to provide the titled compound (83 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH3:20])=[O:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:15][CH2:14][C:11]1([C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 45.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (6 g, 21 mmol) and DIEA (7.3 mL, 42 mmol, 2.0 equiv.) in THF (60 mL) was added methyl chloroformate (1.94 mL, 25 mmol, 1.2 equiv.) at 0° C. The mixture was stirred at 0° C. until the reaction was complete. NaBH4 (3.16 g, 84 mmol, 4.0 equiv.) was added at 0° C. MeOH (10 mL) was then added. The mixture was stirred at 0° C. for 90 min. The reaction mixture was then quenched by saturated NaHCO3 and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give 1-tert-butyl 4-methyl 4-(hydroxymethyl)piperidine-1,4-dicarboxylate (2.6 g, 46%). LRMS (M-Boc+H+) m/z 174.1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@H:19]([C:21]2[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH3:20])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl.[CH:33](OCC)(OCC)OCC>CCO>[F:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:33][N:11]([C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:18][C@H:19]([C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1)[CH3:20]
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)c(F)cc2[N+](=O)[O-])n[nH]1
Reactant: CCOC(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2cnc3cc(F)c(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N6-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 42, 3.05 mmol) in EtOH (5 ml) were added SnCl2.2H2O (1.74 g, 9.18 mmol) and triethyl orthoformate (0.652 ml). The resulting solution was heated to 70° C. overnight. The mixture was allowed to cool to room temperature and filtered through Celite® and washed with EtOAc. Evaporation of the volatiles under reduced pressure gave a colored residue that was purified by Gilson (5%→95% MeCN/H2O) to give the title compound. LC-MS: 357 [M+1]. 1H NMR δ 2.01 (d, 3H) 2.34 (s, 3H) 6.46-6.55 (m, 1H) 8.20 (s, 1H) 8.72 (s, 1H) 8.87 (s, 2H) 9.72 (s, 1H) 9.86 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:11])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O.O>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:6]([C:5](=[O:11])[CH2:4][CH3:3])[C:7](=[O:10])[CH2:8][CH3:9])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CCC(=O)CC(=O)CC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil, 0.17 g) was added portionwise to a stirred solution of heptane-3,5-dione (0.54 mL) in N,N-dimethylformamide (4.0 mL) at 0-10° C. The resulting mixture was stirred at 0-10° C. for 10 minutes and then a solution of 1-bromomethyl-4-methanesulfonylbenzene (1.2 g) in N,N-dimethylformamide (2.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 by volume) gave title compound as a white solid, 0.61 g.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Br[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23]>CCOCC.O>[CH:1]1([S:7][CH:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: O=C1c2ccccc2CC1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2CC1SC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.6 %

Procedure:
After 5.5 g of cyclohexylmercaptan was dissolved into 50 ml of ethanol, 1.97 g of sodium hydroxide was added thereto and refluxed under heating. After the complete dissolving of the sodium hydroxide, the solution was cooled on standing. After 10 g of 2-bromo-1-indanone (available from Aldrich Corporation) dissolved in 10 ml of ether was added dropwise to the cooled solution and stirred for three hours at room temperature, the reaction mixture was poured into 300 ml of cold water. After 200 ml of ether was added thereto for extracting an organic phase, the ether layer was sequentially washed with an aqueous sodium chloride solution and water. After the ether layer was dried with magnesium sulfate, the ether was evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=9/1) to provide 2.4 g of 2-(cyclohexylthio)-1-indanone (yield: 23%). Then, 2 g of the 2-(cyclohexylthio)-1-indanone was dissolved into 6 ml of nitromethane, and 10.7 g of methyl iodide was added thereto and stirred at room temperature. After an hour, 40 ml of nitromethane dissolving 2.09 g of silver trifluoromethanesulfonate was added dropwise thereto. After the stirring for 18 hours at room temperature, precipitated silver iodide was filtrated and a filtrate was concentrated to about one-third under vacuum. After the residue was added dropwise to 250 ml of ether, a precipitated sulfonium salt was filtered. The precipitated sulfonium salt was recrystalized from ethyl acetate-ethanol to provide 2.42 g of the sulfonium salt having the above structure (yield: 73%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
A solution of 3.88 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-formylindole in 40 ml of THF is added dropwise, under N2 and with stirring, to a suspension of 0.57 g of lithium aluminum hydride in 20 ml of THF. The mixture is stirred for a further hour at 20° and is decomposed with dilute sodium hydroxide solution and then with water and is filtered and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-hydroxymethylindole, m.p. 178°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:24](=[O:27])[NH:25][CH:26]=1.I[CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>>[CH2:35]([N:25]1[C:24](=[O:27])[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:22][C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:26]1)[CH3:36]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c[nH]c(=O)c(N2CCOCC2)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1cc(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)nc(N2CCOCC2)c1=O

Procedure:
Method 1 was followed using N-(4-methyl-3-(6-morpholino-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.), iodoethane (1.2 equiv.) and potassium carbonate (2.0 equiv.) at room temperature. 1H NMR (400 MHz, <cd3od>) δ ppm 1.38 (t, J=7.24 Hz, 3H) 2.39 (s, 3H) 3.80 (s, 8H) 4.02 (q, J=7.30 Hz, 2H) 7.02-7.31 (m, 2H) 7.57 (dd, J=8.22, 1.96 Hz, 1H) 7.65-7.81 (m, 2H) 7.89 (d, J=7.83 Hz, 1H) 8.13-8.38 (m, 1H). LCMS (m/z) (M+H)=487.4, Rt=1.02 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:26])[N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:13]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:26]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCN(C)C)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Yield: 98.8 %

Procedure:
A solution of 12 (1.15 g, 2.92 mmole) in 40% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 4 h. The solvent was removed by rotary evaporation, and the resulting organic residue was carefully partitioned between dichloromethane and a saturated solution of sodium bicarbonate (30 mL each). The organic extract was dried over anhydrous sodium sufate, filtered, and concentrated to give 13 (0.80 g, 95%) as a light brown oil. This amine was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1.CCCCCC.O>[C:27]([C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1)(=[O:29])[CH3:28]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Temperature: -78 °C

Procedure:
Di-isopropylamine (44.7 ml) was dissolved in dry tetrahydrofuran (400 ml) and cooled to -78° C. under nitrogen with mechanical stirring. A solution of n-butyllithium in hexane (1.6M, 197 ml) was added. After stirring at -78° C. for 10 minutes a solution of dimethyl cyclohexane-1,4-dicarboxylate (56.6 g, Lancaster) in tetrahydrofuran (200 ml) was added. After stirring for a further 30 minutes at -78° C. a solution of acetyl chloride (22.5 ml) in tetrahydrofuran (200 ml) was added. The reaction mixture was allowed to warm up to room temperature over a period of 3 hours. Water was then added and the mixture extracted with ether. The ethereal extracts were washed with water, saturated sodium bicarbonate solution, dilute hydrochloric acid and brine, and then were dried over anhydrous magenesium sulphate. Evaporation under reduced pressure gave a colourless oil which was slowly distilled to yield dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (23.3 g, b.pt. 114°-120° C. at 0.4 mmHg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[C:14](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>>[CH3:14][N:4]([CH2:3][C:2]([F:12])([F:13])[F:1])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: O=C([O-])O
Reactant: Cc1cccc(NCC(F)(F)F)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cc1cccc(N(C)CC(F)(F)F)c1

Procedure:
The same method as in Example 2 is carried out using 56.7 parts of N-(2,2,2-trifluoroethyl)-m-toluidine, 53 parts of sodium bicarbonate and 75 parts of dimethyl sulphate. 52.8 parts, i.e. a yield equal to 86.7% of the theoretical yield, of N-methyl N-(2,2,2-trifluoroethyl)-m-toluidine are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].[N-:27]=[C:28]=[O:29].C([O-])(O)=O.[Na+].CCOCC>O1CCOCC1>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:28]([NH2:27])=[O:29])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.12 h

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4carboxylic acid (3.8 g) in dioxan (35 ml) was added to the above isocyanate reagent in one portion and the resulting solution was stirred at ca 22° for 7 minutes. The reaction mixture was poured into 3% aqueous NaHCO3 solution (170 ml) and the pH was adjusted to 5 by the addition of more aqueous NaHCO3 solution. After heating to 40° for 2 hours and allowing to cool to 22° over 14 hours, the reaction mixture was washed (at pH 5.9) with ethyl acetate (2×200 ml), the aqueous layer was separated, layered with ethyl acetate (200 ml), and acidified with concentrated hydrochloric acid to pH 1.9. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (200 ml). The organic extracts were combined, washed with brine (2×400 ml), dried (MgSO4) and evaporated to give a white solid which, on trituration with ether (100 ml) afforded the title compound (3.18 g, 75% m.p. (MSO2) 175°; [α]D +42° (c 1.02, DMSO).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][C:15]1[N:16]=[CH:17][O:18][C:19]=1[CH:20]=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:14][C:15]1[N:16]=[CH:17][O:18][C:19]=1[CH:20]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[OH:21]
Reactant: Cc1ncoc1C=O
Reactant: Cc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2ocnc2C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.5 solution in hexanes, 3.9 ml) was added dropwise to a stirred solution of 3-bromotoluene (1.1 ml) in dry tetrahydrofuran (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 20 minutes, 4-methyl-5-oxazolecarbaldehyde (1.15 g) in tetrahydrofuran (10 ml) was added. After 1 hour the mixture was allowed to warm to room temperature and was then heated under reflux for 1 hour. The cooled solution was poured into saturated aqueous sodium hydrogen carbonate. Extraction with ethyl acetate and flash chromatography then gave the title compound. M.p. 76.5°-77.5° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][N:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Yield: 58.5 %

Procedure:
Compound B (36.8 g) was dissolved in ethanol (270 ml) and catalytically hydrogenated at atmospheric pressure over platinum oxide (300 mg). The catalyst was removed by filtration through diatomaceous earth. The solvent was removed by evaporation and the residue triturated with hexane to give 5-amino-2-[2-(trimethylsilyl)ethoxy]pyridine (C) (20.0 g), as dark crystals, m.p. 59°-61° C.; NMR: 0.0(s,9H), 0.95-1.05(m,2H), 3.1-3.3(br s, 2H), 4.2-4.3(m,2H), 6.5(d,1H), 6.95(dd,1H), 7.6(d,1H).