Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:31](Cl)(Cl)[C:32](Cl)=[O:33].P(Cl)(Cl)(Cl)=O>[Cu].[Zn].C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][C:32](=[O:33])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCCCCCCCCCCCCCCCCC)COCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture containing 7.18 g (18 mmol) of the compound prepared in (a) above, 75 ml of anhydrous diethyl ether and 1.4 g of zinc-copper couple was blanketed with nitrogen and treated dropwise at room temperature with a solution containing 3.63 g (20 mmol) of trichloroacetyl chloride and 3.06 g (20 mmol) of phosphorus oxychloride. After stirring the mixture at room temperature for 48 hours, the salts were filtered off and the filtrate concentrated in vacuo. The residue was then chromatographed on silica gel employing a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 9:1 as the eluent to yield a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Product: CCOC(=O)COc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 62 %

Procedure:
The same procedure as in Example 48 was repeated, using 3.90 g (7.13 mmol) of Compound 47 obtained in Example 47, except that ethyl bromoacetate was used in place of methyl iodide, to give 2.81 g (yield: 62%) of Compound 54 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][C:7]=1[CH2:8]Cl.[CH3:12][N:13]=[C:14]=[S:15].O.C[N:18](C)C=O>>[CH3:12][NH:13][C:14]([NH:18][CH2:8][C:7]1[NH:6][C:5](=[O:10])[NH:4][C:3](=[O:11])[C:2]=1[Cl:1])=[S:15]
Reactant: CN=C=S
Reactant: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Reactant: CN(C)C=O
Solvent: O
Product: CNC(=S)NCc1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: 70 °C
Yield: 61 %

Procedure:
A suspension of 0.50 g of 5-chloro-6-chloromethyluracil and 0.22 g of methyl isothiocyanate in N,N-dimethylformamide (3 ml) was heated at 70° C. for 4 hours under stirring. Water (50 ml) was added to the reaction mixture. A crystallized matter was collected by filtration and then washed with water and methanol, whereby 435 mg of the title compound were obtained (yield: 61%).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:12]([OH:29])[CH2:13][CH:14]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][CH:11]([CH:12]([OH:29])[CH2:13][CH:14]([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCC(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
To a solution of (4-benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octyl)-carbamic acid benzyl ester in ethanol is added 10 mole % palladium hydroxide on carbon. The mixture is then shaken on a Parr shaker under 50 psi of hydrogen for approximately 18 h. The catalyst is filtered off and the solution concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[C:8]2[C:9]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]=3[CH:17]=[CH:18][CH:19]=2)(=[O:6])=[O:5].[CH3:20]I>CN(C)C=O>[CH3:20][N:12]1[C:13]2[C:9]3[C:8](=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]1=[O:16])[C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=2
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
To 25 ml of N,N-dimethylformamide is added 0.6 g of 60% sodium hydride under argon, followed by the rapid dropwise addition of a solution of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) dissolved in 50 ml of N,N-dimethylformamide. The mixture is stirred for 20 minutes then heated at 50° C. for minutes followed by cooling to room temperature. While stirring, a solution of 2.14 g of methyl iodide in 25 ml of N,N-dimethylformamide is added dropwise. The stirring is continued at room temperature for 2 hours. The reaction mixture is poured over 200 ml of crushed ice and the resulting solid collected, washed with water and dried to afford 2.54 g of the desired product, m.p. 216°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (15.0 g, 67.2 mmol) in DMF (150 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 3.90 g, 97.5 mmol). The mixture was stirred at 0° C. for 1 hour and (2-(chloromethoxy)ethyl)trimethylsilane (14.8 mL, 84.0 mmol) was added. The resulting solution was allowed to warm from 0° C. to ambient temperature while stirring over 24 hours. The reaction mixture was diluted with 1:1 brine:H2O (500 mL), extracted with EtOAc (3×200 mL), dried over sodium sulfate, filtered and concentrated to an oil. Purification of the oil by column chromatography, eluting with 10-50% EtOAc/Hexane, afforded 2-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a light orange oil, (17.1 g, 70%). LCMS (APCI+) m/z 353, 355 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])=[O:14])=[N:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.CN1C2C(=CC=CC=2)C(=O)C(S(C)(=O)=O)=N1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])(=[O:25])=[O:14])=[N:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(S(C)=O)c(=O)c2ccc(Cl)cc21
Agent: Cn1nc(S(C)(=O)=O)c(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)(=O)=O)c(=O)c2ccc(Cl)cc21

Procedure:
This was prepared by oxidizing a solution of 10 g of 7-chloro-1-methyl-3-(methylsulfinyl)-4(1H)-cinnolinone in 500 ml of CHCl3 with 7.5 g of m-chloroperbenzoic acid in analogous fashion to 1-methyl-3-(methylsulfonyl)-4(1H)-cinnolinone. The material was recrystallized from CH3CN, m.p. 270°-72°; yield 7.5 g (71%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:22]([C:5]1[C:4]2[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:23]
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Temperature: 110 °C
Yield: 57.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (310 mg, 0.745 mmol) and CuCN (200 mg, 2.24 mmol) were added to 5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 136 mg of the title compound. MS: (+) m/z 316.29 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1ccc(Cl)nc1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=328.1 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-5-fluoro-pyridine.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (39.0 g, 110 mmol) in ethanol (100 mL) was added a solution of sodium hydroxide (5.73 g, 143 mmol) in water (100 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure, the residue taken up in water (200 mL), the solution washed with dichloromethane (3×75 mL) and then acidified to about pH 6. The aqueous mixture was extracted with dichloromethane (3×75 mL), and then the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (31.0 g) as a solid that was used directly in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].O.[Cl-].[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([C:33]([O:35][CH3:36])=[O:34])[C:19]2[CH2:20][N:21]([CH:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:22](=[O:25])[C:23]=2[CH:24]=1>ClCCl>[CH3:7][S:8]([NH:15][C:16]1[CH:17]=[C:18]([C:33]([O:35][CH3:36])=[O:34])[C:19]2[CH2:20][N:21]([CH:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:22](=[O:25])[C:23]=2[CH:24]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(CCC)N1Cc2c(C(=O)OC)cc(N)cc2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(CCC)N1Cc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
In a three-necked flask, 500 mg of methyl 6-amino-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are dissolved in 5 cm3 of dichloromethane. 150 μl of pyridine are added and the reaction mixture is cooled to a temperature in the vicinity of 0° C. 188 mg of methanesulfonyl chloride are added over 15 min, then the mixture is left to return to a temperature in the vicinity of 25° C. and stirred for 12 h. 5 cm3 of distilled water and 20 cm3 of a saturated solution of sodium chloride are added successively and left stirring for 1 h at a temperature in the vicinity of 25° C. 10 cm3 of dichloromethane are added. The organic phase is separated, dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow solid is triturated with 15 cm3 of hot diisopropyl ether. The mixture is left to return to a temperature in the vicinity of 25° C. The residual solid is filtered, then rinsed with 2×5 cm3 of diisopropyl ether. 574 mg of methyl 6-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are obtained in the form of a beige solid.
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 94 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed in 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate [1.1], 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. (10.5 mmole) of p-toluenesulfonic acid monohydrate. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94% yield) of benzyl oximino-acetoacetate ethylene ketal [2.1] as a light yellow oil! Its NMR spectrum was consistent with the assigned structure. Generally, the product was used as such in subsequent reactions but one of the isomers can be crystallized2 from toluene-petroleum either (b.p. 30°-60° C.); m.p. 52° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]([CH2:11][CH:12]2[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)[S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC1CCC(C(=O)O)CC1
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)CC2CCC(C(=O)O)CC2)cc1

Procedure:
Prepared as in example 5-11 from 1-(bromomethyl)-4-fluorobenzene, 4-(aminomethyl)cyclohexanecarboxylic acid and 4-methylbenzene-1-sulfonylchloride. MS (M+H, 420); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 0.71 (m, 2H)), 0.95 (m, 2H), 1.15 (br, s, 1H), 1.51 (d, 2H), 1.76(d, 2H), 2.0(1H), 2.40 (s, 3H), 2.85 (m, 2H), 4.22(s, 2H), 7.14(m, 2H), 7.32(m, 2H), 7.40(m, 2H), 7.69(m, 2H), 11.93(br, s, 1H).
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:21]([CH3:22])([C@@H:2]12)[C@@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@H:13]([C@H:14]([OH:16])[CH3:15])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.O.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:21]([CH3:22])([C@@H:2]12)[C@@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@H:13]([C@H:14]([O:16][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH3:15])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H](OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2.67 g (8.1 mmol) of (20R)-1α,2α-epoxy-20-hydroxy-pregna-4,6-dien-3-one in 120 ml of benzene is concentrated to 60 ml in a water-jet vacuum at 40° C., cooled to room temperature and to the suspension are added 1.6 ml of 3,4-dihydro-2H-pyran as well as 16 mg of anhydrous p-toluenesulphonic acid. The mixture is stirred at room temperature for 2.5 hours. The resulting solution is diluted with ether, washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There are obtained 3.3 g of crystalline (20R)-1α,2α-epoxy-20-[(tetrahydro-2H-pyran-2-yl)oxy]-pregna-4,6-dien-3-one. Recrystallisation from ether containing 0.1% triethylamine yields colourless prisms of melting point 139°-140° C.; [α]D25 =+233.6° (c=0.5 in chloroform), UV (ethanol): λmax 291 nm (ε=20940).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[N:20]1([C:26]([CH2:28][CH2:29][NH2:30])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:30][CH2:29][CH2:28][C:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])[N:6]=1)[CH:2]=[CH2:3]
Reactant: NCCC(=O)N1CCCCC1
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCCC(=O)N2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Yield: 87.2 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and then 220 mg (1.14 mmol) of 2-piperidinocarbonylethylamine hydrochloride and 0.40 ml (2.85 mmol) of triethylamine were added thereto, followed by heating under reflux overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 191 mg (87.7%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39](Cl)=[O:40])[N:37]=1)=[O:31].Cl>O.O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:40])[N:37]=1)=[O:31]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1

Procedure:
7β-Amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, 157 g, is suspended in a mixture consisting of 500 ml of tetrahydrofuran and 500 ml of water, and to this, 141 g of sodium hydrogen carbonate is added in small portions with stirring. With stirring at 5° C., 150 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetylchloride hydrochloride is added over 20 minutes, and the reaction mixture is stirred for further 1 hour at the same temperature. After completion of the reaction, the pH is adjusted to 3.0 with 10% hydrochloric acid, and the reaction mixture is extracted twice with 1 liter each of a mixture of ethyl acetate-tetrahydrofuran (1:1). The extract is dried over anhydrous magnesium sulfate, the solvent is evaporated off under reduced pressure to leave colorless powder, which is washed with 200 ml of ethyl acetate and filtered, to give 253 g of the desired compound.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1[CH:92]=[CH:91][N:90]=[CH:89][C:88]=1[CH2:93][C:94](O)=[O:95]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][C:88]1[CH:89]=[N:90][CH:91]=[CH:92][N:87]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)Cc1cnccn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3cnccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-pyrazine acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 650.6 (M+H)+, 2.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.68-8.50 (m, 3H), 7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 3H), 5.29 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 3.79 (q, J=14.3 Hz, 2H), 2.66-2.53 (m, 2H), 2.42-2.31 (m, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.91-1.74 (m, 3H), 1.72 (br. s., 1H), 1.71 (s, 2H), 1.67 (d, J=11.9 Hz, 2H), 1.57-1.18 (m, 13H), 1.17-1.02 (m, 3H), 1.00 (br. s., 3H), 1.00 (br. s., 3H), 0.94 (s, 3H), 0.92 (br. s., 3H), 0.92 (br. s., 3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:10]=O)=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.[H-].[Na+].[N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][CH:29]=1>O.CN(C)C=O>[N:28]1([C:2]2[S:3][C:4](/[CH:10]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([CH:7]([CH3:8])[CH3:9])[N:6]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[CH:29]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)c1nc(Cl)sc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of 2-chloro-4-isopropyl-5-thiazolecarbaldehyde (2.0 g), ethyl diethylphosphonoacetate (2.47 g), sodium hydride (0.44 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. Benzimidazole (1.54 g) and sodium hydride (0.44 g) were added to the reaction mixture and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into water, the precipitated crystals were collected by filtration and washed with water. Recrystallization from acetone-hexane gave ethyl (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (3.01 g, 84%) as a pale-yellow prism crystal. melting point: 229–230° C.