Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[NH:16][C:15]2=[O:22])=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH2:26][CH2:25][CH2:24][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][S:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[C:15]2=[O:22])=[CH:30][CH:31]=1
Reactant: CC1(C)NC(=O)N(CCCCSc2ccncc2)C1=O
Reactant: ClCCCCSc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCCSc2ccncc2)C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a suspension of 96 mg (2.4 mmol) of 60% sodium hydride (oily) in 15 ml of dimethylformamide, 587 mg (2.0 mmol) of 3-[4-(4-pyridylthio)butyl]-5,5-dimethylhydantoin was added, and the mixture was stirred at room temperature for 10 minutes. To this reaction mixture, 807 mg (4.0 mmol) of 4-(4-chlorobutylthio)pyridine was added with stirring under ice-cooling, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the-solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to give 0.74 g of the desired product (80.7% yield, yellow oil).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:3]=1.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C(COC)OC>[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[N:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: COc1cccc(-c2cccc(Cl)n2)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-(3-methoxyphenyl)pyridine (3.5 g, 16 mmol), dibenzothiophene-4-boronic acid (4 g, 17.5 mmol), potassium phosphate (10.2 g, 48 mmol), dimethoxyethane 500 mL and water 50 mL was prepared. Nitrogen was bubbled directly in the mixture for 15 minutes. Next tris dibenzylideneacetone dipalladium (147 mg, 0.16 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (263 mg, 0.64 mmol) were added, and then nitrogen was bubbled in the mixture for another 15 minutes. The reaction mixture was heated to reflux overnight under nitrogen. The next day the reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 3.8 g yellow solid (65%).
Reaction SMILES: [ClH:1].NCCSC1SC=C(C(NC2S[C:16]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:17]=3C=2)=O)N=1.Cl.[NH2:25][CH2:26][CH2:27][S:28][C:29]1[S:30][CH:31]=[C:32]([C:34]([NH:36][CH:37]2[N:41](C)[C:40]3[CH:43]=[C:44](F)[CH:45]=[CH:46][C:39]=3[S:38]2)=[O:35])[N:33]=1>>[ClH:1].[NH2:25][CH2:26][CH2:27][S:28][C:29]1[S:30][CH:31]=[C:32]([C:34]([NH:36][C:37]2[S:38][C:39]3[CH:46]=[C:45]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:17]=4)[CH:44]=[CH:43][C:40]=3[N:41]=2)=[O:35])[N:33]=1
Reactant: NCCSc1nc(C(=O)Nc2cc3cc(F)ccc3s2)cs1
Reactant: CN1c2cc(F)ccc2SC1NC(=O)c1csc(SCCN)n1
Agent: Cl
Product: NCCSc1nc(C(=O)Nc2nc3ccc(-c4ccccc4)cc3s2)cs1

Procedure:
In a similar manner were prepared: 2-(aminoethylthio)-N-(5-fluorobenzothiol-2-yl) thiazole-4-carboxamide hydrochloride, m.p. 261-263° C. dec. and 2-(aminoethylthio)-N-(3-methyl-5-fluorobenzothiazol-2-yl)thiazole-4-carboxamide hydrochloride, m.p. 276-277° C. dec.
Reaction SMILES: [O:1]1[C@@H:25]2[C@:2]31[C@H:11]([C@H:12]1[C@:23]([CH3:26])([CH2:24]2)[C@@:15]([O:27][C:28](=[O:30])[CH3:29])([C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1)[CH2:10][CH:9]=[C:8]1[C@:3]3([CH3:35])[CH2:4][CH2:5][C:6]([O:31]C(=O)C)=[CH:7]1.Cl([F:40])(=O)(=O)=O>O1CCOCC1.O.N1C=CC=CC=1>[O:1]1[C@@H:25]2[C@:2]31[C@H:11]([C@H:12]1[C@:23]([CH3:26])([CH2:24]2)[C@@:15]([O:27][C:28](=[O:30])[CH3:29])([C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1)[CH2:10][C@H:9]([F:40])[C:8]1[C@:3]3([CH3:35])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CC=C4C=C(OC(C)=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: -10 °C
Yield: 96.2 %

Procedure:
17,5 g of 9β,11β-epoxy-3,17,21-triacetoxy-pregna 3,5-diene-20-one, prepared as described in Example I were dissolved in a mixture of 200 ml dioxane, 90 ml water, 10 ml pyridine, with the temperature being maintained at -10° C. Next a total quantity of approximately 4 g perchlorylfluoride was introduced at this temperature over a period of 4 hours. The further procedure was as described in Example IX; 16 g 9β,11β-epoxy-6α-fluoro-17α,21-diacetoxy-4-pregnen-3,20-dione were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[CH2:38][NH:39][CH3:40].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:43]=[CH:42][CH:41]=[C:37]([CH2:38][NH:39][CH3:40])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: CNCc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CNCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (89.7 mg, 0.20 mmol), (3-bromo-benzyl)-methyl-amine (43.4 mg, 0.22 mmol), and Pd[P(Ph)3]4 (15.4 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. The product was then converted to the HCl salt. After dissolving the product in a minimum amount of acetonitrile and cooling the solution in dry ice, 2.0M HCl in diethyl ether was added until precipitate crashed out of solution. The mixture was centrifuged, and the liquid was decanted. Additional cold diethyl ether was added, and the mixture was again centrifuged and the liquid decanted. The resulting solid was dried to give the HCl salt of the desired product. Yield 5.9 mg. MS: 444.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.80-2.02 (m, 3H), 2.17-2.35 (m, 1H), 2.53-2.64 (t, 3H), 3.39-3.57 (m, 2H), 4.15-4.23 (t, 2H), 4.33-4.44 (m, 1H), 4.60-5.12 (m, 2H), 7.02-7.76 (m, 12H), 8.06-8.12 (m, 1H), 8.78-8.93 (s, 1H), 10.10-10.25 (s, 1H).
Reaction SMILES: N[CH:2]([OH:5])[CH2:3][CH3:4].[N:6]1C=CC=CC=1.[C:12](Cl)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:5][CH2:2][CH2:3][CH2:4][NH:6][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: c1ccncc1
Reactant: CCC(N)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCO
Reaction time: 2 h

Procedure:
To a solution of 1-aminopropanol (4.04 ml, 52.8 mmol) and pyridine (4.27 ml, 52.8 mmol) in methylene chloride was slowly added oleoyl chloride (5 ml, 15.1 mmol). After 2 hours, the mixture was diluted with chloroform and washed with ammonium chloride (3×), brine (3×) and dried over sodium sulfate. Column chromatography (15% acetone/chloroform to 50% acetone/chloroform) provided the product as white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (95 mg, 75%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1C(C)=CC(C)=CC=1C(=O)CC>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:4]([C:1](=[O:3])[CH2:2][CH3:32])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[CH3:11])=[O:14])(=[O:21])=[O:22]
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reactant: CCC(=O)c1cc(C)cc(C)c1N
Product: CCC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that 2′-amino-3′,5′-dimethylpropiophenone was used instead of 2-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH3:8][C:9](C)([O-:11])[CH3:10].[K+].C([OH:18])(C)(C)C>>[CH2:8]([O:7][CH2:1][CH:6]1[O:18][CH2:5]1)[CH:9]1[O:11][CH2:10]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)O
Reactant: Oc1ccccc1
Agent: [K+]
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A phenol derivative (5.28 g) of the following formula: ##STR21## S-(+)-epichlorohydrin (11.55 g), potassium t-butoxide (3.00 g) and t-butyl alcohol (45 ml) are mixed, the mixture is stirred at 60° C. for 3 hours. The reaction mixture is distilled under reduced pressure to remove the solvent and the residue is extracted with chloroform. The extract is distilled under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography to give R isomer of glycidyl ether (5.82 g) of the following formula: ##STR22##
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:38])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:39])=[O:4])[CH2:12][CH2:11]2)=[CH:18][CH:17]=1)=[O:38])=[O:25]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4)oc3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1C(=O)NCCC(=O)Nc1ccc([C@H]2CC[C@H](CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (59.6 mg, 1.5 mmol) was added to trans-[4-(4-{3-[(5-methyl-2-phenyloxazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (75 mg, 0.15 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered, then eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Therefore, the desired compound as a white solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].CN(C)CCN(C)C.[Li]CCCC.C([O:28][C:29]1[C:30](=[O:35])[CH2:31][CH2:32][CH2:33][CH:34]=1)C>C1COCC1>[OH:35][C:30]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=2[O:9][CH3:10])[CH2:31][CH2:32][CH2:33][CH2:34][C:29]1=[O:28]
Reactant: COc1cccc(OC)c1OC
Reactant: CCOC1=CCCCC1=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCCC2=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
A stirred solution of 8.70 g (51.8 mmol) of 1,2,3-trimethoxybenzene and 8.25 mL (54.7 mmol) of tetramethylethylenediamine in 40 mL of THF was cooled in an ice bath and 24.0 mL of 2.5 molar n-BuLi in hexanes (60.0 mmol) was added dropwise over 20 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The mixture was cooled to -70° C. and a solution of 6.95 g (49.6 mmol) of 2-ethoxycyclohex-2-en-1-one in 30 mL of THF was added dropwise over 45 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 days. The mixture was poured into 150 mL of 5% aqueous HCl and allowed to stand for 2 h. The mixture was extracted with two 80 mL portions of ether. The combined ether extracts were washed with 50 mL of saturated aqueous NaHCO3, and dried over MgSO4. Removal of the solvent left 13.56 g of an oil which was purified by flash chromatography on a column of 100 g of silica gel eluted successively with 250 mL portions of 0, 8, 16, 24, 40, 60, 80 and 100% ether in hexanes to furnish 7.08 g of 2-hydroxy-2-(2,3,4-trimethoxyphenyl)cyclohexanone as a solid, mp 88°-91° C. 1H-NMR (CDCl3) d 1.5-1.8 (4H), 2.0 (m, 1H), 2.5 (m, 2H), 2.9 (m, 1H), 3.7 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.6 (s, 1H), 6.75 (d, 1H), 7.25 (d, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].ClC(F)C(N(CC)CC)(F)[F:36]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([F:36])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(F)CS[C@H]12

Procedure:
To a solution of 325 mg. (0.7 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 10 ml. of methylene chloride was slowly added an equivalent amount of N-(2-chloro-1,1,2-trifluoroethyl) diethylamine. The reaction mixture was heated for 30 minutes under gentle reflux and was then evaporated to dryness in vacuo. The residue was dissolved in a mixture of ethyl acetate-water and the organic layer was separated. The organic layer was washed with 5% hydrochloric acid, water and brine and was then dried. The dried reaction product solution was concentrated to a small volume and n-hexane was added to precipitate, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[NH:6][C:5]2([CH2:26][N+:27]([O-:29])=[O:28])[C:22]([F:25])([F:24])[F:23].[H-].[Na+].CI.[C:34](OCC)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:7](=[O:21])[N:6]([CH3:34])[C:5]2([CH2:26][N+:27]([O-:29])=[O:28])[C:22]([F:23])([F:25])[F:24]
Reactant: CCOC(C)=O
Reactant: COc1ccc(CN2C(=O)NC(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(CN2C(=O)N(C)C(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (192.1 mg, 0.405 mmol) was dissolved in DMF (2.0 mL), and sodium hydride (40.5 mg, 1.013 mmol) and methyl iodide (76 μL, 215 mmol)were sequentially added to the reaction solution at room temperature. The reaction solution was stirred overnight at 50° C. and then cooled to room temperature. Ethyl acetate and water were added thereto and the solution was stirred at room temperature for 10 minutes. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (ethyl acetate/hexane), whereby the objective 6-bromo-1-(4-methoxybenzyl)-3-methyl-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (44.3 mg, 22.4%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:21])[CH2:17][NH:18][CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3].O1CCCC1.[O-:37][C:38]#[N:39].[K+]>O>[CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)=[O:21])[CH2:17][N:18]([C:38]([NH2:39])=[O:37])[CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: N#C[O-]
Reactant: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CNC)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CN(C)C(N)=O)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Temperature: 50 °C
Yield: 87 %

Procedure:
To a solution of N-(propylsulfonyl)-D-isoleucyl-3-(methylamino)-N1-(4-cyanobenzyl)-L-alaninamide (500 mg, 1.0 mmol) in water (1.3 ml)/tetrahydrofuran (3 ml), potassium cyanate (243 mg, 3 mmol) was added under stirring at 50° C. and then further stirred under the same conditions. After stirring for 3 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give N-(propylsulfonyl)-D-isoleucyl-3-[(aminocarbonyl)(methyl)amino]-N1-(4-cyanobenzyl)-L-alaninamide (430 mg, 0.87 mmol; yield 87%).
Reaction SMILES: C1([Si:7]2([CH:20](C)[CH2:21][CH2:22][CH3:23])[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Cl)[CH:29]=[CH:30][C:31]=1[F:32].F[C:36]1C=C(C2CCC([Si]3(CCC(C)C)CCCCC3)CC2)C=CC=1F>>[F:25][C:26]1[CH:27]=[C:28]([CH:16]2[CH2:15][CH2:14][CH:13]([C@H:10]3[CH2:9][CH2:8][Si@H:7]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:36])[CH2:12][CH2:11]3)[CH2:18][CH2:17]2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: CCCC(C)[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Cl)cc1F
Reactant: CC(C)CC[Si]1(C2CCC(c3ccc(F)c(F)c3)CC2)CCCCC1
Product: CC(C)CC[Si@H]1CC[C@H](C2CCC(c3ccc(F)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 6 was repeated using 4-(4-phenyl-4-(methylbutyl)-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium chloride, thereby obtaining trans, trans-4-(4-(3,4-difluorophenyl)cyclohexyl-1-(3-methylbutyl)-1-silacyclohexane. The results of NMR and IR analyses are shown below.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.ClC1C=CN=CC=1.[NH2:18][C:19]1[C:24]2[O:25][C:26]3[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][C:27]=3[S:28](=[O:31])(=[O:30])[CH2:29][C:23]=2[CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[O:30]=[S:28]1(=[O:31])[C:27]2[CH:32]=[C:33]([C:36]([OH:38])=[O:37])[CH:34]=[CH:35][C:26]=2[O:25][C:24]2[C:19]([N:18]3[CH:3]=[CH:7][CH:6]=[CH:5]3)=[CH:20][CH:21]=[CH:22][C:23]=2[CH2:29]1
Reactant: Nc1cccc2c1Oc1ccc(C(=O)O)cc1S(=O)(=O)C2
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)Cc1cccc(-n3cccc3)c1O2
Reaction time: 1 h
Yield: 73.7 %

Procedure:
2,5-Dimethoxy tetrahydrofuran (0.053 g, 0.40 mmol) and 4-chloropyridine hydrochloride (0.0047 g, 0.03 mmol) were added to a solution of the methyl ester of Example 10k (0.1 g, 0.31 mmol) in dry dioxan (15 mL). The reaction mixture was refluxed with stirring for 1 h, concentrated and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to obtain a product which was subsequently hydrolysed as described in the synthesis of Example 11 to obtain the title compound. Yield: 73.7%; 1H NMR (DMSO-d6): δ 5.40 (s, 2H, CH2), 6.40 (s, 2H, pyrrolyl), 6.80 (d, 1H, Ar), 7.10 (s, 2H, pyrrolyl) 7.50-7.70 (m, 3H, Ar), 8.05 (d, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 355 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][CH2:14][C:15]1[C:16]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:14][C:15]2[C:16]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][CH2:14][C:15]2[C:16]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Product: CN(c1ncccc1CNc1ncc(C(F)(F)F)c(Cl)n1)S(C)(=O)=O

Procedure:
Reaction of 2,4-dichloro-5-(trifluoromethyl)pyrimidine XL with N-[3-(aminomethyl)pyridin-2-yl]-N-methylmethanesulfonamide (WO2007/072158, WO2008/115369) in the presence of diisopropylethylamine affords a solution of N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa and its regioisomer N-[3-({[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIb. On larger scales stirring at 0° C., precipitation of the pure 4-substituted isomer XLIa occurs. Reaction of a sample of the pure mixture of N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide with anilines such as 4-[(diethylphosphoryl)methyl]aniline in the presence of TFA and TFE under microwave irradiation yields 2-substituted N-methyl-N-[3-({[5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]methanesulfonamides (e.g. N-[3-({[2-({4-[(diethylphosphoryl)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide, Example 10).