Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](/[CH:5]1[CH2:10][O:9][CH:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].[CH:18](=O)[CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:19]([C@H:18]1[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]2[O:7][CH2:6][C@H:5](/[CH:1]=[CH:2]/[CH2:3][CH3:4])[CH2:10][O:9]2)[CH2:16][O:17]1)[CH2:20][CH3:21]
Reactant: CCCC=O
Reactant: CC/C=C/C1COC(CCC(CO)CO)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC/C=C/[C@H]1CO[C@H](CC[C@H]2CO[C@H](CCC)OC2)OC1
Temperature: 68 °C
Reaction time: 0.67 h

Procedure:
A solution of 1.50 g of (E)-2-[2-(5-but-1-enyl-1,3-dioxan-2-yl)ethyl]-1,3-propanediol and 2 ml of butyraldehyde in 40 ml of benzene was treated with 28.5 mg of p-toluenesulfonic acid monohydrate and stirred at 68° C. for 40 minutes. The reaction mixture was neutralized with a few drops of triethylamine and, after cooling, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product (2.15 g) was chromatographed on 40 g of silica gel with hexane/ethyl acetate 5% (v/v). 1.40 g of isomer mixture having a 52% trans/trans content were obtained. Two-fold recrystallization from hexane gave 0.41 g of pure (E)-trans-2-propyl-5-[2-(trans-5-but-1-enyl-1,3-dioxan-2-yl)ethyl]-1,3-dioxane, m.p. (C-SB) 42° C., cl.p. (SB -I) 117.8° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12]C[C@@H:10]1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>O1CCCC1>[CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:10]1[NH:15][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: N[C@H]1CCCC[C@@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@H]1CCC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a solution of (1S,2S)-2-benzyloxycyclohexylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in the vacuum oven (50° C.), affording the title compound (1.15 g, 75%). 1H NMR (D2O, 500 MHz) δ ppm 7.34 (m, 5H), 4.62 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 3.40 (m, 1H), 2.97 (m, 2H), 2.90 (m, 1H), 2.76 (t, 2H, J=6.5 Hz), 2.26 (m, 1H), 1.92 (m, 3H), 1.66 (m, 2H), 1.18 (m, 4H). 13C NMR (D2O, 125 MHz) δ ppm 137.22, 129.34, 129.11, 128.84, 76.74, 70.26, 60.84, 48.02, 42.74, 29.49, 26.43, 23.57, 23.02, 21.53. [α]D=+74.8° (c=0.00207 in water). ES-MS 326 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]Br)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+].O>CS(C)=O>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:28][C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][N:18]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]3)=[CH:24][CH:23]=2)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.1 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (50 mg) and 4-bromomethylpiperidine-1-carboxylic acid benzyl ester (120 mg) in dimethyl sulfoxide (1 ml) was added 4N aqueous sodium hydroxide solution (0.13 ml), and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=O.Cl.[OH:19][NH2:20].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:19][N:20]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.9 %

Procedure:
In a solution of 0.8 g of 4-formyl-2-methyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.3 g of hydroxyamine hydrochloride and 0.4 g of anhydrous sodium acetate were added with stirring at room temperature, and stirred at the same temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and precipitated crystal was filtered off, washed with water and dried to obtain 0.5 g of the aimed product as white crystal.
Reaction SMILES: [OH:1][N:2]([CH3:27])[C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:1][N:2]([CH3:27])[C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4])(=[O:30])[CH3:29]
Reactant: CN(O)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON(C)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 1-(N-hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-6) (222 mg, 0.6 mmole) dissolved into pyridine (3 ml), 1.8 ml of acetic anhydride was added and the mixture was stirred at room temperature for 5 hours, then the resulting mixture was evaporated. Hydrochloric acid (0.5N) was added thereto, and the mixture was subjected to extraction with dichloromethane. The organic layer was washed with water, sodium bicarbonate, and water in order, dried over magnesium sulfate, and evaporated. The obtained residue was recrystallized from dichloromethane/ether, whereby 211 mg of the objective compound (Ia-16) was obtained in 84% yield.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.C([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)C.N#N.CO.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:40](C=O)=[C:39]([CH:43]([CH3:45])[CH3:44])[CH:38]=[C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:36]=2)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:40](/[CH:2]=[CH:3]/[CH:4]=[O:8])=[C:39]([CH:43]([CH3:44])[CH3:45])[CH:38]=[C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:36]=2)=[CH:31][CH:30]=1
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: [Li]CCCC
Agent: N#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
n-BuLi (1.6M in hexane, 554 ul, 0.83 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (333 mg, 0.92 mmol) in dry THF (4 ml) at -78° C. The mixture was stirred at -78° C. for one hour, then cooled to -100° C. (liquid N2 /MeOH) and treated with a solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (221 mg, 0.69 mmol) in THF (2 ml). One hour after the addition, the temperature was raised to -78° C. and the solution was stirred for an additional one hour. TLC analysis indicated that the reaction was incomplete so an additional amount of the vinyl anion reagent (generated from 317 mg vinyl tin reagent, 370 ul of 1.6M n-BuLi and 4 ml THF) was added via canula at -78° C. the resulting solution stirred an additional 45 minutes. The mixture was warmed to 0° C., stirred for 15 minutes, then quenched with H2O (6 ml) and 10% HCl (6 ml). After one hour of vigorous mixing, the solution was made basic with 10% NaOH (12 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2SO4), filtered and stripped to yield a yellow oil. Chromatographic purification (flash, Merck SiO2, 40% hexane in CH2Cl2 followed by straight CH2Cl2 afforded (E)-3-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal (141 mg, 59%) as a light yellow foam.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:29][CH2:30][O:31][CH3:32])=[CH:6][C:7]([O:25][CH2:26][O:27][CH3:28])=[C:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:13](SC)=[N:12][N:11]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl[C:34]1C=CC=C(C(OO)=O)C=1.[S:44]([O-:47])([O-])=[O:45].[K+].[K+]>C(Cl)Cl>[CH:1]([C:4]1[C:5]([O:29][CH2:30][O:31][CH3:32])=[CH:6][C:7]([O:25][CH2:26][O:27][CH3:28])=[C:8]([C:10]2[N:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:13]([S:44]([CH3:34])(=[O:47])=[O:45])=[N:12][N:11]=2)[CH:9]=1)([CH3:2])[CH3:3]
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(OC)cc1
Agent: [K+]
Solvent: ClCCl
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1-c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 9.5 h
Yield: 87 %

Procedure:
3-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-(4-methoxy-phenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F60-01: 2.87 g, 6.3 mmol) and methylene chloride (60 mL) were placed in a 200 mL eggplant shaped flask, cooled to 0° C., and methylene chloride solution of metachloroperbenzoic acid (3.77 g, 21.9 mmol) was gradually added in 4 portions, and the mixture was stirred for 9.5 hours. After completing the reaction, 10% aqueous potassium sulfite (100 mL) was added and stirring was continued for 10 minutes. After that, the organic layer was extracted, washed twice with 1 N sodium hydroxide (50 mL), dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F60-02: 2.67 g, 87%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:29]=[CH:28][C:17]4[N:18]=[C:19]([NH:21][C@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)[S:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>CN1C(=O)CCC1>[CH:39]1([S:42]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:22]([NH:21][C:19]3[S:20][C:16]4[CH:15]=[C:14]([O:13][C:11]5[CH:10]=[CH:9][N:8]=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[CH:12]=5)[CH:29]=[CH:28][C:17]=4[N:18]=3)[CH2:23]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCNC5)sc4c3)ccn2)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCN(S(=O)(=O)C6CC6)C5)sc4c3)ccn2)cn1
Reaction time: 16 h

Procedure:
To the solution of (S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine (7.6 mg, 18 μmol) and DIPEA (35 μL, 200 μmol) in 400 μL of NMP was added cyclopropanesulfonyl chloride (10 mg, 98 μmol). The reaction solution was stirred at 55 for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine (6.2 mg, 12 μmol as white powder. ES/MS m/z 511.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([NH:1][S:30]([CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:32])=[O:31])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: O=S(=O)(Cc1ccccc1)Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with benzenemethanesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:1].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:10])=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCBr
Solvent: CC#N
Product: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 63.6 g. of 7-bromoheptanoic acid 80 g. of triphenylphosphine, and 300 ml. of acetonitrile is refluxed for 68 hours. Then 200 ml. of acetonitrile is removed by distillation. After the remaining solution has cooled to room temperature, 300 ml. of benzene is added with stirring. After forming a crystal, the mixture is allowed to stand overnight. The solid which separates is collected by filtration giving 134.1 g. of the product as white prisms, melting point 185°-187° C. A portion is recrystallized from methanol-ether affording white prisms, melting point 185°-187°. The infrared spectrum shows absorptions at 2850, 2570, 2480, 1710, 1585, 1485, 1235, 1200, 1185, 1160, 1115, 1000, 755, 725, and 695 cm.-1NMR peaks are observed at 1.2-1.9, 2.1-2.6, 3.3-4.0, and 7.7-8.0 δ.
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38]>C(Cl)(Cl)Cl>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH3:34])=[O:26])[CH2:22][CH2:23]1
Reactant: COc1ccccc1N
Reactant: O=C(O)C1CCN(CC2COc3ccccc3O2)CC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Ethyl chloroformate (0.1 g) was added dropwise to a stirred solution of 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid (0.28 g) and triethylamine (0.12 g) in chloroform (10 ml) at 0° C. After 30 minutes a solution of 2-methoxyaniline (0.12 g) in chloroform (5 ml) was added and the mixture stirred at ambient temperature for 16 hours. The reaction mixture was then washed sequentially with water, aqueous sodium hydroxide solution (1M), hydrochloric acid (1M) and water. The solution was dried over magnesium sulphate, the solvent was removed in vacuo, and the residue was eluted through a silica column using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluant. The solvent was removed in vacuo to yield 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide as a solid (50 mg). This procedure was repeated on 9X scale with the following changes. The reaction was heated to 50° C. for 1 hour after being stirred at ambient temperature for 16 hours. The solvent was then removed in vacuo and the residue was eluted through a silica column as previously described. Further desired product (1.05 g) was obtained.
Reaction SMILES: O1CCN([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)CC1.C(N(CC)CC)C.[CH3:19][C:20]1([CH3:31])[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([CH2:27][C:28](Cl)=[O:29])[CH2:21]1.Cl.[OH2:33]>C(Cl)(Cl)Cl>[CH3:19][C:20]1([CH3:31])[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([CH2:27][C:28]([CH:7]2[CH2:8][CH2:9][CH2:10][C:11]2=[O:33])=[O:29])[CH2:21]1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: CC1CC(CC(=O)Cl)CC(C)(C)C1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CC(CC(=O)C2CCCC2=O)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
111 g of freshly distilled morpholinocyclopentene, 71.7 g of triethylamine and 900 ml of chloroform are added to a round flask which is fitted with a thermometer, stirrer, reflux condenser and dropping funnel and the mixture is cooled to 0° C. Under a nitrogen atmosphere there are slowly added dropwise thereto 128 g of crude 3,3,5-trimethyl-cyclohexylacetyl chloride in 200 ml of chloroform. The flask content is stirred until it has reached a temperature of 20° C. and it is then warmed at 40° C. for a further 7 hours. After 12 hours, 76.2 of concentrated hydrochloric acid in 190 ml of water are added thereto and the flask content is held at reflux temperature for 21/2 hours. Thereafter, the organic phase is separated, the aqueous phase is extracted twice with chloroform and the combined chloroform extracts are washed as follows: three times with 10% hydrochloric acid, once with water, once with bicarbonate solution and finally with sodium chloride solution until neutral. Now it is concentrated in a rotary evaporator and the crude product (212 g) is distilled in vacuo. There are obtained 90 g (yield: 58%) of 2-(3,3,5-trimethylcyclohexylacetyl)-cyclopentanone.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:59](=[O:60])[N:34]2[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([NH:31][CH:32]2[C:59](=[O:60])[N:34]3[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]4[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=4)[CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Yield: 22.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid (syn isomer, 2.6 g.), N,N-dimethylformamide (0.6 g.), phosphoryl chloride (1.2 g.), 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (3.2 g.), trimethylsilylacetamide (5.5 g.) and ethyl acetate (65 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].O>C1COCC1>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][C:23]2[NH:24][C:1](=[O:2])[NH:13][C:14]=2[CH:15]=1)=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1′-carbonyldiimidazole (5 g) in THF (20 ml) was added to a solution of methyl 3,4-diaminobenzoate (CAS Reg. No. 36692-49-6, 5 g) in THF (50 ml). The mixture was stirred at room temperature for 2 h. Water (150 ml) was added. The mixture was filtered and the residue dried to give the title compound (5.6 g) as a light yellow powder. MS (m/e, ISP neg. ion)=191.2 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[CH3:40][C:41]1[S:42][C:43]([C:47](=O)[CH3:48])=[C:44]([CH3:46])[N:45]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:43]3[S:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CC(=O)c1cnccn1
Product: Cc1nc(C)c(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)s1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([CH3:14])[N:5]=1>CCCCCC>[NH2:2][C:1]1[N:7]([CH3:8])[CH:6]([CH3:14])[N:5]=[C:4]([Cl:3])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCCCCC
Product: CC1N=C(Cl)C([N+](=O)[O-])=C(N)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Methylamine (15.4 mL 1M in THF, diluted with 10 mL of hexane) is added dropwise to a solution of 4,6-Dichloro-2-methyl-5-nitropyrimidine (3.2 g, 15.4 mmol) in Hexane (30 mL). After addition, the reaction mixture is stirred at room temperature for one hour, and concentrated in vacuo to a solid. After the solid is dissolved in 50 mL of CH2Cl2, the resultant solution is washed with 0.1 N HCl (20 mL) and water (20 mL), dried over Na2SO4 and concentrated to a yellow solid. 1H NMR (CDCl3): δ 7.7 (bs, 1H), 3.10 (d, 3H), 2.55 (s, 3H).