Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@H:8]2[C@@H:10]([C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)[O:9]2)=[O:5])[CH3:2].CCOCC.[Mg+2].[Br-].[Br-].[CH2:27]([NH2:30])[CH:28]=[CH2:29].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>COC(C)(C)C.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@@H:8]([NH:30][CH2:27][CH:28]=[CH2:29])[C@H:10]([OH:9])[C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H]2O[C@H]2C1
Reactant: C=CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: CC#N
Product: C=CCN[C@@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@H]1O
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
In a 2.5 l 4-necked round bottom flask equipped with a reflux condenser, a thermometer, a mechanical stirrer and an inert gas supply 254.3 g (1.0 mol) of (1S,5R,6S)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester were dissolved under argon with stirring in 900 ml tert.-butyl methyl ether and 100 ml acetonitrile whereby the temperature dropped to about 10° C. To the clear, yellowish solution 51.7 g (0.2 mol) of magnesium bromide diethyl etherate were added followed by 150 ml (2.0 mol) of allylamine whereby the temperature rose to about 20° C. The yellow suspension was heated to 55° C. whereby complete dissolution occurred after about 1.5 h. The clear yellow solution was refluxed for 15 h. The yellowish, turbid solution was cooled to about 30° C. and stirred vigorously with 1000 ml of 1M aqueous ammonium sulfate for 15 min whereby a clear two-phase mixture evolved after initial cloudiness. The organic phase was separated, filtered and evaporated in a rotary evaporator at 48° C./340 mbar to a volume of about 580 ml. The solid particles were filtered and the brown solution was evaporated at 48° C./340 to 15 mbar for 2 h to yield as the crude product 312.8 g (97%) of (3R,4S,5R)-5-allylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester as a brown-yellow oil containing about 7.0% of the 4-allylamino-5-hydroxy isomer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:11]=[C:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2ccc(Cl)nc2)C(=O)O1
Yield: 91 %

Procedure:
The mixture of 6-chloropyridin-3-amine (5.0 g, 38.8 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.2 g, 38.8 mmol) in i-PrOH (60 mL) was stirred at reflux for 2 h, and the solvent was removed to afford 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a solid in 91% yield (10.0 g). m/z 283 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12][C:11](N(N=O)C)=[N:10]2)=[CH:5][CH:4]=1.CN(C)C=O.CC(C)([O-])C.[K+].[N+:31]([CH3:34])([O-:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:34]/[N+:31]([O-:33])=[O:32])/[NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COCC(N(C)N=O)=N2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 mmol of [5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine, 200 ml of N,N-dimethylformamide, 50 ml of nitromethane and 115 mmol of potassium tert-butoxide is stirred at room temperature for 15 minutes. It is quenched by adding 20 ml of glacial acetic acid and diluted with dichloromethane and water. The organic phase is separated off, washed with water, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([OH:27])(=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:28]O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:1]([O:27][CH3:28])(=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-pentacosadiynoic acid (10 gm, GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MePDA) was dried using a rotovap and the material stored in a chloroform solution. The solid form of MePDA was very unstable to polymerization and therefore kept dissolved in organic solutions.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[C:20]([N:24]1[CH:29]=[CH:28]C(=O)N=C1)([CH3:23])([CH3:22])[CH3:21].[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O.CCCCCC>[C:20]([N:24]1[CH2:29][CH2:28][CH:34]([CH:35]=[O:31])[CH2:33][CH2:32]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)n1ccc(=O)nc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)N1CCC(C=O)CC1
Reaction time: 0.5 h

Procedure:
6.52 g of diisopropylamine was dissolved in 24 mL of tetrahydrofuran, and the solution was cooled on ice. Then, 2.91 mL of n-butyl lithium (a 2.66 M hexane solution) was added thereto. After stirring at the same temperature for 30 minutes, the mixture was kept at −78° C. To the reaction mixture, 3.87 mL of trimethylsilyldiazomethane (a 2 M hexane solution) was added at the same temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a solution prepared by dissolving 1 g of 1-tert-butylpyrimidin-4-one (synthesized by the method as described in J. Org. Chem., 2005, 70, 1930) in 6 mL of tetrahydrofuran was added at the same temperature, and the mixture was stirred at the same temperature for 1.5 hours, and heated overnight under reflux. To the reaction mixture, water was added, and the mixture was extracted with 200 mL of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. Then, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 120 mL of ethyl acetate, and 24 g of silica gel was added thereto at room temperature. The mixture was stirred at the same temperature for 1.5 hours. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain 830 mg of 1-tert-butylpiperidin-4-carboaldehyde [87-1] (hereinafter, referred to as the compound [87-1]).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([OH:14])[CH3:13]>CO>[CH2:12]([O:14][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Cl:1])[CH3:13]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: CCO
Solvent: CO
Product: CCOC(=O)c1ccccc1CCl
Reaction time: 10 h
Yield: 90 %

Procedure:
To a double-neck 500 ml flask equipped with cooler, thermometer and dropping funnel was added 180 g of o-(chloromethyl)benzoic acid chloride, and then 60 ml of ethanol was further added dropwise, while maintaining the internal temperature of reactor at 40˜50° C. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 40˜50° C. After a distiller was equipped immediately, the residue was subjected to fractional distillation under reduced pressure to afford 179 g of desired compound (yield 90%) as oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1.[CH3:16]I>[Ag]=O.O1CCCC1>[CH3:16][O:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Reactant: CI
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CO[C@@H]1CC[C@@H](NC(C)=O)c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of racemic N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide (3.9 g) and 150 ml. tetrahydrofuran (THF) is stirred and 17 ml. of methyl iodide and 24.4 g. of freshly prepared silver oxide are added over a 4-hour period, under a nitrogen atmosphere. After 16 hours, an additional 10 ml. of methyl iodide and 11.4 g. of silver oxide are added over a 4-hour period and stirring is continued for 2 days. The mixture is filtered through a layer of celite and the filter cake washed with THF (2 × 75 ml.). The filtrate and wash solution are combined and evaporated to dryness in vacuo to afford 4.3 g. of solid. The solid is recrystallized from hexane/ether to afford 2.4 g. of title compound, melting point 97°-100° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[NH3:14]>>[NH2:13][C:7]1[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1
Reactant: N
Reactant: COC(=O)c1cc(OC)cc(N)n1
Product: COc1cc(N)nc(C(N)=O)c1

Procedure:
In analogy to example 103b, by replacing 2,6-diaminoisonicotinic acid ethyl ester with 6-amino-4-methoxy-pyridine-2-carboxylic acid methyl ester and using 25% aqueous ammonia instead of methylamine, the title compound was obtained as white solid. MS (ISP) M+H+=168.4
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH:44][CH2:45][CH3:46]>CN(C=O)C>[CH2:45]([N:44]([CH2:43][CH:39]1[CH2:40][CH2:41][CH2:42][O:38]1)[C:15]1[C:16]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1)[CH3:46]
Reactant: CCNCC1CCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CN(C)C=O
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). N-((tetrahydrofuran-2-yl)methyl)ethanamine (84 mg, 0.65 mmol) was added and the reaction was stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>CN(C)C=O.CO.C(Cl)(Cl)Cl>[CH3:13][C:8]1[C:9]([CH3:12])=[CH:10][C:11]2[C:2]3[N:3]([C:17](=[O:16])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:1]=3)[CH:4]=[N:5][C:6]=2[CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc2ncnc(N)c2cc1C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(C)c(C)cc3ncn2c1=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
A mixture of 4-amino-6,7-dimethylquinazoline (11.3 g) and diethyl ethoxymethylenepropanedioate (15.55 g) in N,N-dimethylformamide (45 ml) was stirred for 4 hours at 110° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water to give crystals, which were separated by filtration, washed with water and dried under reduced pressure to give crude crystals (18.5 g). The crude crustals were dissolved in 1% methanol-chloroform solution (500 ml) and concentrated under reduced pressure after insoluble materials were removed by filtration. The residue was recrystallized from chloroform to give crystalline ethyl 9,10-dimethyl-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (3.57 g).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12.[CH2:15]([CH2:17][NH2:18])[OH:16]>C1(C)C(C)=CC=CC=1>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12
Reactant: NCCO
Reactant: Clc1c2c(nc3cn[nH]c13)CCCC2
Solvent: Cc1ccccc1C
Product: OCCNc1c2c(nc3cn[nH]c13)CCCC2
Yield: 19.7 %

Procedure:
9-Chloro-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinoline (2.45 g, 0.012 mole) and ethanolamine (2.2 ml, 0.036 mole) were heated under reflux in dry xylene (25 ml) for 24 hours. The solvent was evaporated off and the residue dissolved in water/methanol. The pH of the solution was adjusted to 9 by the addition of 10% sodium carbonate solution. The precipitate which formed was filtered off, washed with water, dried and recrystallised from ethyl acetate to give the title compound as a beige solid (0.55 g, 20%), m.p. 205°-210° C. Found: C, 62.05; H, 6.95; N, 24.00% C12H16N4O requires C, 62.05; H, 6.95; N, 24.10%
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (295 mg).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)#[N:2].CC([O-])(C)C.[K+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:9]2=[O:14])=[CH:15][CH:16]=1)#[N:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: N#Cc1ccc(C=C2NC(=O)NC2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=C2NC(=O)N(CC(=O)OCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
6.4 g (0.03 mol) of (5-(4-cyanobenzylidene)-2,4-dioxoimidazolidine and 3.5 g (0.031 mol) of potassium tert-butylate are dissolved in 30 ml of dimethylformamide. After addition of 7.1 g (0.031 mol) of benzyl bromoacetate, the mixture is stirred at room temperature for 7 hours, heated briefly to 100° C. and concentrated. Water is added to the residue, and the mixture is extracted with ethyl acetate. The product crystallises out of the ethyl acetate phase, or can be precipitated by addition of heptane.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[N:6]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1csc(Br)n1
Product: CC(C)(C)NC(=O)c1csc(Br)n1

Procedure:
Similarly, 2-bromo-4-t-butylaminocarbonylthiazole is prepared by following the same procedure but using 2-bromo-4-carboxythiazole in place of the 5-position isomer. Similarly, by replacing t-butylamine with the amine reagents set forth in Preparation 2, the corresponding 2-bromo-4- and 5-substituted aminocarbonylthiazoles are respectively prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cnccn3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cnccn3)CS[C@H]12
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 147 mg of benzhydryl 3-(2-pyrazinylvinyl)-7β-(2-thienylacetamido)-3-cephem-4-carboxylate in 1.5 ml anisole at 0° was added 3 ml of cold trifluoroacetic acid. The solution was kept 10 minutes at 0° and then placed directly on a vacuum pump and evaporated. The residue was flushed with 1 ml anisole and reevaporated. The residue was triturated with 4 ml boiling ether and the ether was cooled and siphoned off. This procedure was repeated twice more. The remaining insoluble material weighed 116 mg yield 87% (calculated as mono--CF3COOH salt) and was characterized by n.m.r. and electrophoresis.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[NH4+:12].C(O)C.O>C(O)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: CCO
Solvent: O
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10 ml) was added a solution (6.8 M, 15 ml) of ammonium/ethanol at room temperature, and the mixture was stirred at room temperature for 19 hr in a sealed container. Water (25 ml) was added to the reaction mixture, and the precipitate was collected by filtration and washed with ethanol. This was suspended in ethanol (55 ml), heated, and allowed to cool. The precipitate was collected by filtration to give 2-amino-6-bromo-3-nitropyridine as a yellow powder (3.19 g).
Reaction SMILES: [Li]CCCC.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[O:16]1[CH2:19][C:18](=O)[CH2:17]1>C1COCC1>[C:10]1([S:7]([CH:6]=[C:18]2[CH2:19][O:16][CH2:17]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1COC1
Reactant: CS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(C=C1COC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of BuLi (2.5 M in hexanes, 22.5 mL, 56.3 mmol) was added over 10 min to a solution of methylphenylsulfone (4.00 g, 25.6 mmol) in THF (70 mL) at 0° C. The solution went from clear to light green to a heterogeneous yellow suspension. The mixture was stirred for 30 min at 0° C. and then chlorodiethylphosphonate (4.46 mL, 30.7 mmol) was added dropwise and the stirring was continued for 30 min, at which point the solution turned clear orange. The reaction mixture was then cooled to −78° C. and oxetan-3-one (1.85 g, 25.6 mmol) was added in THF (3 mL). The reaction mixture turned pale brown/yellow in color. After stirring for another 1.5 h, the reaction mixture was filtered through a plug of silica gel. The filtrate was triturated with solid NH4Cl until pH reached 7. The mixture was then filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/heptane) to provide 3-((phenylsulfonyl)methylene)oxetane. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.86-7.99 (m, 2 H) 7.68-7.77 (m, 1 H) 7.57-7.68 (m, 2 H) 6.18 (t, J=2.40 Hz, 1 H) 5.59-5.70 (m, 2 H) 5.30 (td, J=3.41, 2.27 Hz, 2 H)
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O[CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:1]([O:18][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCC(O)CC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCC)CC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
Hexadecanoic acid (1.92 g) and tert-butyl 3-hydroxyoctanoate (324 mg) was reacted to afford an oil of tert-butyl 3-hexadecanoyloxyoctanoate (620 mg) in the similar method to that of Preparation 1-(2).
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:4]1([SiH:2]([Cl:3])[Cl:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1=CCCCC1
Reactant: Cl[SiH2]Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[SiH](Cl)C1CCCCC1
Temperature: 100 °C

Procedure:
Dichlorosilane in an amount of 83.5 g (0.827 mol), 82.3 g of cyclohexene (1.00 mol), 0.05 mol % of chloroplatinic acid (relative to dichlorosilane) were charged in a 500 ml pressure-proof stainless steel reactor and after sealing, reaction was carried out by heating in an oil bath at 100° C. for 30 hours. After reaction, the seal of the reactor was broken and the reacted liquid was discharged and subjected to vacuum distillation to obtain 139.3 g (0.761 mol) of cyclohexyldichlorosilane having a boiling point of 110°~112° C./155 mmHg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:18][CH2:17]4)=[N:13][CH:12]=[N:11][C:10]=3[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:8]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O.O>CO.C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10]([NH:11][CH:12]=[N:13][C:14]=3[N:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncnc(N4CCC(NC(=O)c5ccccc5)CC4)c23)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3[nH]cnc(N4CCC(NC(=O)c5ccccc5)CC4)c2-3)cn1

Procedure:
N-{1-[5-(1-methyl-1H-pyrazol-4-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D27 (160 mg) and cesium carbonate (285 mg, 0.88 mmol) in MeOH (2 ml) and THF (4 ml) was stirred under nitrogen at room temperature for 1 hour. EtOAc was added followed by water and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and concentrated to give crude product. This was purified by TLC preparation eluting with EtOAc to give 50 mg of desired product E40. LCMS [MH+] 402.2@1.44 min (5 min run)