Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[O-].[Na+]>CO.[Cu]>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CCOC(=O)C(Br)C#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 2 h

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (15.1 parts), copper-containing catalyst in amount indicated in the table below and methanol (32 parts) is heated to reflux and ethyl bromocyanoacetate (19.2 parts) in methanol (14 parts) is then added at a uniform rate during 6 hours, and the acid-base balance ("pH" as indicated by a pH meter) is maintained at a predetermined value by the addition of a 13% solution of sodium methoxide in methanol. On completion of the ethyl bromocyanoacetate addition, heating at reflux temperature is continued for a further 2 hours, maintaining the desired acid-base balance as necessary. The resulting solution is evaporated under reduced pressure to remove the solvent and the product is isolated as described in Examples 2-6 above. The yield, strength and composition of the ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate obtained are given in the following table together with other reaction details:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@H:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 84.1 %

Procedure:
NaH (60% in oil, prewashed with hexane; 2.76 g, 69.0 mmol) was suspended in anhydrous THF (100 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of (S)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (5.00 g, 23.0 mmol) in THF (100 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 10.0 g, 29.0 mmol) was added and the reaction mixture was stirred overnight at room temperature before standing for 24 h. The reaction mixture was cooled to 5-10° C. A 10% aqueous solution of NaHCO3 (22 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated before drying in vacuo to give (3S)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (8.19 g, 84%) as an orange gum.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:42])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (96 mg) in tetrahydrofuran (10 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.33 ml), followed by stirring at room temperature for 2.5 hrs. A solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 0.800 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to provide the titled compound (64.5 mg, 48%) as pale yellow powder.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH:11]=[CH:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3]>O1CCOCC1>[CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH:11]=[CH:10][C:9]1=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]2)[C:2]#[CH:3]
Reactant: C#CC[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1COCCO1
Product: C#CC[C@]12C=CC(=O)C=C1C=C[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]12

Procedure:
A mixture of 190 mg of 10-(2-propynyl)estra-4,6-diene-3,17-dione, 168 mg of dichlorodicyanoquinone and 10 ml of dioxane is heated at reflux for 5 hours. The mixture is cooled and filtered and the filtrate is diluted with ether, washed with aqueous 1 N sodium hydroxide solution and brine, dried and then concentrated. The resulting residue is chromatographed on silica gel using 50% ethyl acetate/hexane to give 10-(2-propynyl)estra-1,4,6-triene-3,17-dione. This compound melts at about 185°-189° C. after recrystallization from ethyl acetate/hexane and it has the following structural formula ##STR12##
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:34][CH2:33][CH2:32][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][CH:15]=3)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(Cl)nc21
Reactant: NCCN1CCCCC1
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCCCC3)nc21
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 31 supra) (1.0 g, 2.3 mmol), 2-(piperidin-1-yl)ethanamine (324 mg, 2.53 mmol) and TEA (256 mg, 2.53 mmol) in IPA (30 mL) was stirred at reflux for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (a silica gel, MeOH:dichloromethane, 1:100) to give [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine as a white solid. (Yield 285 mg, 23.3%).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C([O-])([O-])=O.[K+].[K+].Cl.[NH:22]=[C:23]1[NH:28][CH2:27][CH:26]([OH:29])[CH2:25][NH:24]1>CCO>[OH:29][CH:26]1[CH2:27][N:28]2[C:4](=[O:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:22]=[C:23]2[NH:24][CH2:25]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C1NCC(O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccccc2)nc2n1CC(O)CN2
Temperature: 90 °C
Reaction time: 17 h

Procedure:
In a 250 mL RBF with a stirrer bar, a mixture of 3-oxo-3-phenyl-propionic acid ethyl ester (15 g, 78 mmol), K2CO3 (11.0 g, 80 mmol) and 2-imino-hexahydro-pyrimidin-5-ol hydrochloride (11.8 g, 78 mmol) in EtOH (150 mL) was heated at 90° C. under nitrogen overnight. After 17 h, the mixture was cooled to room temperature, and filtered. The mother liquid was concentrated to a sludge that was then diluted with H2O. The resulting slurry was filtered and the solid was washed first with MeOH, then a mixture of EtOAc-MeOH (2:1) to give the first batch of product. The solid residue from the crude reaction was washed first with H2O (3×10 mL), then MeOH, and finally a mixture of EtOAc-MeOH (2: 1) to yield a second batch of product. The combined products were the dried in air to provide a white solid. 1H NMR (400 MHz, DMSO6): 7.94 (m, 2 H), 7.44 (bt, J 3.2, 0.5 H), 6.10 (s, 1H), 5.35 (d, J 3.2, 0.5 H), 4.22 (m, 1 H), 4.12 (d, J 14,1H), 3.54 (dd, J 14, 2.0,1 H), 3.39 (d, 12.4, 1H), 3.18 (m, 1H). M+1: 244.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:11]=1[C:12]#[N:13].C(O)(C(F)(F)F)=O>>[Br:8][C:15]1[C:14]([CH3:18])=[C:11]([C:10]([F:9])=[CH:17][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (265 g, 1490 mmol) was added portion wise to a stirred, cooled room temperature mixture of 2-Fluoro-6-methylbenzonitrile (191.8 g, 1419 mmol) in TFA (553 mL, 8500 mmol) and then the mixture was heated at reflux for 48 hours. The reaction was poured into 1 L of ice, diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organic layers were washed with 1N NaOH twice and with water. The organic layers were dried over Na2SO4, concentrated, and then stored in a −10° C. freezer overnight. The resulting crystals were filtered and washed with 5% EtOAc/Hexanes to yield the title product.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl.O>[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:12][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][F:1])=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCCCC(O)CF
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)OC(CF)CCCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of optically active 1-monofluoro-2-decyl alcohol (0.1 g) and triethylamine (0.06 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of 4-n-octyloxybiphenyl-4'-carboxylic acid chloride (0.22 g) in methylene chloride (10 ml). The mixture was left to stand until it reached room temperature and stirred overnight. The mixture was poured in water and extracted with methylene chloride. The solution extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, purification was made by silica-gel column chromatography to obtain the titled compound (0.16 g).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1)=O.Cl>C1COCC1>[OH:4][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of LiBH4 (1.53 g, 70 mmol) in THF (30 ml) was slowly added to a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester (2.5 g, 14 mmol) in dry THF (30 ml) at 0° C. and under an argon atmosphere. The reaction mixture was stirred for a further 2 h at r.t., then chilled to 0° C. and treated with 2 N HCl (40 ml). The reaction mixture was filtered, concentrated under reduced pressure and crystallized from MeOH: 340 mg;
Reaction SMILES: [Cl:1][C:2]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].Cl.[NH2:19][CH2:20][C:21]#[C:22][CH2:23][OH:24].C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:24][CH2:23][C:22]#[C:21][CH2:20][NH:19][C:3](=[O:4])[C:2]([Cl:1])([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(Cl)(c1ccccc1)C1CCCCC1
Reactant: NCC#CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC#CCO)C(Cl)(c1ccccc1)C1CCCCC1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of 2-chloro-2-cyclohexyl-2-phenylacetyl chloride (9.0 g) in methylene chloride (50 ml) was added dropwise to a solution of 4-amino-2-butyn-1-ol hydrochloride (5.38 g) and triethylamine (30.8 ml) in methylene chloride (120 ml) at 0° C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for an additional 3.5 hours and 1N hydrochloric acid was added thereto. The organic layer was separated, washed with saturated sodium bicarbonate, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (6:1) as an eluent to give N-(4-hydroxy-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide (7.32 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC2CCN(S(=O)(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 157B (84 mg), benzenesulfonyl chloride (46 mg), and triethylamine (101 mg) in CH2Cl2 (2 mL) was stirred for 1 hours. The product was chromatographed on silica gel with 25% ethyl acetate/hexanes.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:6]([C:8](OC)=[O:9])[CH2:5]1)#[N:2].O1CCCC1.[BH4-].[Li+]>CO>[OH:9][CH2:8][CH:6]1[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:5]1
Reactant: COC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
To a mixture of methyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarboxylate (7.0 g, 0.015 mol) in tetrahydrofuran (100 mL, 1 mol) was added lithium tetrahydroborate (0.327 g, 0.0150 mol) at 0° C. The reaction was then heated at 50° C. for 3 h. To the reaction was added 60 mL of methanol. The resulting mixture was heated at 50° C. for another 15 min, then evaporated to dryness. The residue was treated with 1 N HCl, then neutralized with solid sodium bicarbonate, extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 100% EtOAc, to give the desired product as cis- and trans-mixture (5.85 g, 88.91%). LCMS calculated for C22H31N6O2Si(M+H)+: 439.2; Found: 439.4.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([OH:7])=O.[NH2:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:7]
Reactant: C[Si](C)(C)CCOCOC(=O)C1=C(CSc2cnns2)CS[C@@H]2C(N)C(=O)N12
Reactant: CO/N=C(\C(=O)O)C(=O)CCl
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CO/N=C(/C(=O)CCl)C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOCC[Si](C)(C)C)=C(CSc3cnns3)CS[C@H]12
Yield: 20.7 %

Procedure:
A solution of 4-chloro-2-(Z)-methoxyimino-3-oxo-butanoic acid (2.17 g, 4.77 mmol.), 2-(trimethylsilyl)ethoxymethyl 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate (0.85 g, 4.77 mmol.), and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1.18 g, 4.77 mmol.) in 40 ml of methylene chloride was stirred at room temperature for 3 hours then worked up as described in Example 6 to afford 0.615 g of the ester. NMR (CDCl3) δ0.03 [S, 9H, --Si(CH3)3 ], 0.97 (t, 2H, J=7.5 Hz, --CH2Si--), 3.62 (pair of d, 2H, J=18 Hz, endocyclic --CH2S--), 3.75 (m, 2H, --OCH2 --), 4.17 (pair of d, 2H, J=3 Hz, exocyclic --CH2S), 4.18 (S, 3H, --OCH3), 4.63 (S, 2H, --ClCH2 --), 5.07 (d, 1H, J=4.9, 6H of 7ACA), 5.38 (pair of d, 2H, J=6.0 Hz, --OCH2O), 5.87 (dd, 1H, J=4.9 and 8.5 Hz, 7H of 7ACA), 7.22 (d, 1H, J=8.5 Hz, --NH--), 8.52 (S, 1H, thiadiazole H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][Cl:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:38].[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:37][C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(OCc5ccncc5)cc4)cc3)ccn2c1=O
Yield: 83.6 %

Procedure:
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)-benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (126 mg), 4-picolyl chloride hydrochloride (154 mg) and potassium carbonate (274 mg) in DMF (7 ml) was stirred at room temperature for 17 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol =19:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (140 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:21](=[O:22])[C:20]1[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=1
Reactant: CNc1cnccc1-c1ncccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cccnc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 55, from methyl-(3-methyl-[2,4]bipyridinyl-3′-yl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (20%). MS (ESI): m/z=440.4 [M+H]+.
Reaction SMILES: [H-].[Na+].CC1C=CC(S([CH2:13][N+:14]#[C-:15])(=O)=O)=CC=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CCOC(C)=O.CCCCCC>CCOCC.CS(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:13][NH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)cc1Cl
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1c[nH]cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 60 %

Procedure:
Dry ether was added to NaH (1.5 eq as the oil dispersion) under argon. After decanting off the ether via syringe, the NaH was suspended again with fresh ether under argon. A solution of TOSMIC (1.1 eq) and 2 (1 eq) dissolved in a mixture of ether and DMSO was added dropwise to the stirred suspension of NaH at 0° C. over 20-30 min. The addition was mildly exothermic and evolved gas. After the addition, the reaction was allowed to warm to ambient rt. The progress of the reaction was followed by TLC (25% EtOAc/Hexane, the UV active product was at Rf=0.4) and LCMS until done (−2-3 h). Upon completion, the reaction was carefully quenched with sat. aq. NH4Cl (added slowly to avoid strong gas evolution and exotherm) and diluted with ether. The layers were separated and the organic phase was washed with sat. aq. NaHCO3, water, and brine. The crude dark solid can be purified by recrystallization. Best results were achieved either through recrystallization directly from a mixture of hot EtOAc/hexane (1:3 v/v) or by dissolving the crude product in minimal hot EtOAc followed by addition of hexane (−2 volumes of hexane based on the volume of EtOAc). The hot solutions were allowed to cool to room temperature and age over night. The crystals were first filtered and then washed with hexane giving 99% pure product in 60-70% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[CH:17](O)=[O:18]>O>[CH:17]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16])=[O:18]
Reactant: O=CO
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Solvent: O
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1NC=O

Procedure:
A mixture comprising 0.11 mole (26.6 g) of 2-amino-4-nitro-1,3,5-trimethoxybenzene and 55 ml of formic acid are refluxed during three hours. The reaction mixture is cooled and diluted with iced water. The expected product precipitates and is separated by filtration. After drying it is recrystallized from ethanol. It melts at 98° C.