Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)CCCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1

Procedure:
A suspension of 2.9 g (7.76 mmol) ethyl 4-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-butanoate and 300 mg 10% Pd/C in 60 mL MeOH was hydrogenated at RT and 50 psi hydrogen pressure for 24 h. The catalyst was filtered off, the mixture was evaporated down i.vac., the residue was taken up in a little DIPE and isopropanol and combined with 4 M HCl in 1,4-dioxane. The precipitated bis-hydrochloride salt was separated off and dried.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH:10]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:27]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH:10]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:36][CH2:35]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Reactant: CC(C)(C(=O)O)C(C=Cc1ccccc1)NC(=O)c1ccc(C#N)cc1
Product: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(C=Cc2ccccc2)NC(=O)c2ccc(C#N)cc2)CC1
Yield: 30.3 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-styryl-α,α-dimethyl-β-alanine (100 mg, 0.287 mmol) using 4-piperidineacetic acid t-butyl ester (203 mg, 0.86 mmol) to yield an oil of N-4-cyanobenzoyl-β-styryl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (46 mg, 30.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH2:5]2.C1C[O:17][CH2:16]C1.[Li]CCCC.CN(C=O)C>CCOC(C)=O>[CH3:12][C:7]1([CH3:13])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:16]=[O:17])[CH:3]=2)[O:8]1
Reactant: C1CCOC1
Reactant: CC1(C)CCc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCc2cc(C=O)ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen flushed 100 mL round bottom flask were added 6-bromo-2,2-dimethyl-3,4-dihydro-2H-chromene (0.41 g, 1.7 mmol) and THF (6 mL). A solution of n-BuLi in hexanes (0.69 mL, 2.6 M, 1.79 mmol) was added at −78° C. The resulting reaction mixture was stirred at −78° C. for 10 minutes when DMF (0.20 mL, 2.55 mmol) was added. The reaction mixture was allowed to warm to room temperature and was diluted with EtOAc (25 mL). It was stirred over wet silica gel (10 g silica gel/0.5 mL water) for 10 minutes and was filtered. The solid was rinsed with EtOAc and the filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 20% EtOAc/hexanes to give the title intermediate (0.25 g) as a light yellow oil.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:39])[C@H:6]([O:14][C:15]1[C:20]([Br:21])=[CH:19][C:18]([C:22]2[C:34]3[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=3[C:29]([Br:37])=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]3)=[CH:17][C:16]=1[Br:38])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1COCC1>[Br:21][C:20]1[CH:19]=[C:18]([C:22]2[C:34]3[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=3[C:29]([Br:37])=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]3)[CH:17]=[C:16]([Br:38])[C:15]=1[O:14][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:39])=[O:4]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C
Yield: 94.5 %

Procedure:
Aqueous potassium hydroxide (1 N, 2.00 mL, 2.00 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionic acid methyl ester (0.699 g, 0.99 mmol) in THF (12 mL)/methanol (7 mL). After 3 h the solution was concentrated, diluted with water (100 mL) and acidified with 10% aqueous HCl. The solid was filtered, washed with water and triturated with petroleum ether and dried in vacuo to provide the title compound as a white solid (0.645 g, 94%): [a]D25=+14.29° (8.75 mg/mL CHCl3); NMR (DMSO-d6); δ8.19 (d, J=8 Hz, 1H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.61 (s, 2H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.38-7.20 (m, 5H), 5.27 (t, J=7 Hz, 1H), 3.37 (dd, 14, 6 Hz, 1H), 3.28 (dd, 14, 7 Hz, 1H), 2.43 (s, 3H), 1.59 (s,3H); MS (+FAB): 3 bromine isotope pattern 686 (20%), 688 (75%), 690 (75%), 692 (25%); Anal. Calc. for C29H21Br3O3S: C, 50,53; H, 3.07; N, 0.00. Found: C, 50.04; H, 3.11; N, 0.05.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH:5]/[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A solution of nickel(II) chloride hexahydrate (7.8 mg, 0.033 mmol) and (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (111 mg, 0.33 mmol) in methanol (3 mL) was cooled to 0° C. and then treated with sodium borohydride (25 mg, 0.66 mmol) in two portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with water (25 mL) and ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (101 mg, 91%) as a colorless oil: EI-HRMS m/e calcd for C18H26O4S (M+) 338.1552, found 338.1555.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH2:46]([O:45][C:43]([N:36]1[CH2:37][CH2:38][N:33]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=4)[CH:14]=[C:13]([CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:41])[CH:22]=3)=[O:39])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C(=O)OCC)CC3)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
Triethylamine (0.19 mL, 1.34 mmol) was added slowly at 0° C. to a stirred reaction mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.200 g, 0.33 mmol, prepared as described above) in dichloromethane (7 mL). The reaction mixture was stirred at room temperature for 15 minutes. Ethyl chloroformate (0.07 mL, 0.73 mmol) was added slowly to the reaction mixture and stirring was continued for an additional 3 hours at room temperature. The mixture was diluted with dichloromethane (10 mL), then washed with a saturated solution of sodium bicarbonate (5 mL) and water (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (1:3 ethyl acetate -hexane) to give 0.077 g (41.4%) of 4-[4-(3-ethoxycarbonylmethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester as a viscous yellow solid. MS cald. for C28H29FN2O7S ([M+H]+) 556, obsd. 557.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH2:34][CH2:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCc1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCCc2ccccc2)=C(C)N1

Procedure:
259 mg (0.718 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.122 ml (0.79 mmol) of 4-phenylbutyl alcohol, 193 mg (1.01 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 17.5 mg (0.144 mmol) of 4-dimethylaminopyridine were stirred together in 7.2 ml of dichloromethane at room temperature overnight. Water was added to the reaction liquid. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[NH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1.[OH-].[Na+]>ClCCl.O>[NH2:7][C:8]1[C:12]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N:10]([CH3:13])[N:9]=1
Reactant: FC(F)(F)SCl
Reactant: Cn1ccc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(SC(F)(F)F)c(N)n1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfenyl chloride (11.6 g, 85.0 mmol) was added to a solution of 3-amino-1-methylpyrazole (8.0 g, 82.4 mmol) in 150 mL of dichloromethane with stirring at a rate such that the temperature did not rise above 5° C. when the addition was complete the mixture was allowed to warm to ambient temperature and stir for 18 hours and was then purged with nitrogen gas for 1 hour to remove any unreacted trifluoromethanesulfenyl chloride. The solid that formed during the reaction was collected by filtration and the filtrate was concentrated by evaporation under reduced pressure to obtain additional solids. The combined solids were dissolved in water and the solution as basified with 1N aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2×100 mL) and the extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a solid residue that appeared to be a mixture of two compounds. This solid was recrystalized from methylcyclohexane to obtain 16.2 g (40 percent of theory) of the title compound as a yellow solid melting at 138°-140° C. The impurity was identified as 1-methyl-3-((trifluoromethanesulfenyl)amino)-4-(trifluoromethylthio)pyrazole.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].CO.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1>[C:1]([CH2:2][CH2:3][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29])#[N:4]
Reactant: C=CC#N
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc2ccccc2n1CCC#N
Temperature: 55 °C
Yield: 99.7 %

Procedure:
After 3.63 g (68.4 mmol) of acrylonitrile and 2.2 ml of 40% methanol solution of N-benzyltrimethylammonium hydroxide was added to a solution of 10.0 g (57.1 mmol) of methyl 2-indolecarboxylate in 150 ml of 1,4-dioxane, the mixture was stirred at 55° C. for an hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to a mixture of 5 ml of acetic acid and 500 ml of water. The aqueous layer was extracted twice with methylene chloride and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 13.0 g of methyl 1-(2-cyano-ethyl)-2-indolecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([S@@:38]([CH3:40])=[O:39])[C@@H:26]([CH3:41])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@H:28]1[C@@H:27]([S@@:38]([CH3:40])=[O:39])[C@@H:26]([CH3:41])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:42])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1[S@@](C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1[S@@](C)=O
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-((R)-methylsulfinyl)cyclohexylcarbamate in DCM (0.10 M) was added TFA (30.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo; the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-((R)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 54% yield. LC/MS (m/z)=503.2 (MH+), Rt=0.57 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.48 (s, 1H), 8.58 (d, J=4.0, 1H), 8.50 (d, J=4.0, 1H), 8.34 (dd, J=8.0, 4.0, 1H), 8.20 (dd, J=8.0, 8.0, 1H), 8.20 (dd, J=16.0, 4.0, 1H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (dd, J=8.0, 8.0, 2H), 3.40-3.42 (m, 1H), 3.06-3.20 (m, 1H), 2.92 (s, 3H), 2.06-2.20 (m, 1H), 1.95-2.04 (m, 2H), 1.70-1.80 (m, 1H), 1.56-1.70 (m, 1H), 0.86 (d, J=8.0, 3H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH2:58])=[CH:52][CH:51]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:58][CH2:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: COc1ccc(CCN)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCc2ccc(OC)cc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(4-methoxy-phenyl)-ethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H53Cl2N6O4 [(M+H)+] 799.35, observed 799.3501.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29](=O)[CH2:30]Br)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]>O1CCCC1.O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29]3[N:1]=[C:2]([NH2:4])[S:3][CH:30]=3)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of thiourea (0.103 g.) and sodium bicarbonate (0.11 g.) in a mixture of tetrahydrofuran (1.3 ml.) and water (1.3 ml.) was gradually added 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (0.55 g.) with stirring at room temperature, and then the resulting solution was stirred for 40 minutes at room temperature. After the reaction, the precipitated crystals were collected by filtration with suction, washed with water, tetrahydrofuran and water in turn, and then dried over phosphorus pentoxide to give 3-carbamoyloxymethyl-7-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (0.48 g.).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14]Cl)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14][S:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CCl)n2C
Reactant: N#Cc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C

Procedure:
A mixture of 1.5 g (4.1 mmol) of 2-chloromethyl-1-methylbenzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide and 0.65 g (4.8 mmol) of p-cyanothiophenol was heated in 10 mL of dimethylformamide and 10 mL of diisopropylethylamine for 1 hour to 100° C. The solvent was distilled off in vacuo, the crude product was dissolved in 30 mL ethyl acetate, washed with 30 mL water, and after concentration purified by flash chromatography (silica gel; methylene chloride/ethanol (49:1 to 19:1). Yield: 1.5 g (79% of theory) of brown oil; Rf value: 0.65 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[C:6]2[C:16]#[N:17].P(Br)(Br)([Br:20])=O.C(Cl)Cl>C1(OC)C=CC=CC=1>[Br:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[C:6]([C:16]#[N:17])=[CH:7][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COc1cc2c(C#N)cnc(Br)c2cc1OC
Temperature: 80 °C
Yield: 73.1 %

Procedure:
The mixture of 6,7-Dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile (8 g, 35 mmol) and phosphorus oxybromide (70 g, 244 mmol) in anisole (30 mL) was heated to 80° C. for 12 h. The solvent and excess POBr3 were removed by rotary evaporator. The resulting solid was washed with hexane and dried. The solid was slowly added to ice and the product was extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution, saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown solid. Flash chromatography (Merck Silica gel 60, 70–230 mesh, methylenechloride) afforded 1-Bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (7.5 g, 75%) as a brown solid. LC-MS m/e calcd for C12H9BrN2O2 (MH+) 293, found 293.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C(OCC)C.CCCCCC>[Br:9][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc(Cl)cc(Br)c1
Temperature: -30 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH:24]=[CH2:25]>>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[CH:24]=[CH2:23]
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Reactant: C=CCBr
Product: C=CCOc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (100 mg, 0.45 mmol) and 3-bromoprop-1-ene (133 mg, 0.96 mmol) according to the general procedure IV to give 101 mg (70%) of a pale yellow oily product. Rf=0.55 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.45 (d, J=8.0 Hz, 2H), 7.24 (t, J=1.3 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.06 (t, J=1.9 Hz, 1H) 6.90 (dd, J=8.3 Hz, 2.5 Hz, 1H), 6.10-6.00 (m, 1H), 5.42 (dd, J=17.3 Hz, 1.5 Hz, 1H), 5.30 (dd, J=10.5 Hz, 1.3 Hz, 1H), 4.55 (dt, J=5.3 Hz, 1.3 Hz, 2H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.1, 158.3, 140.9, 133.0, 131.7, 129.4, 128.3, 124.3, 124.3, 121.1, 117.7, 117.2, 115.6, 89.1, 89.0, 68.8, 51.6, 35.4, 30.8; MALDI-MS m/z 343.4 (M+Na+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=1)=O>O1CCOCC1.C(OCC)(=O)C>[CH3:20][O:19][C:15]1[N:14]=[C:13]([NH:12][CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:8]=2[OH:7])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(NC(=O)c2cccc(C)c2O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(NCc2cccc(C)c2O)n1
Temperature: 80 °C

Procedure:
80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added in small fractions to a mixture of 90 mg (0.35 mmol) of 2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide in 10 ml of dioxane. The reaction medium is heated at 80° C. for 16 h. 80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added again and the medium is heated at 80° C. for 4 h. The reaction medium is diluted with 50 ml of ethyl acetate and washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-[(6-methoxypyridin-2-ylamino)methyl]-6-methylphenol is obtained in the form of a white solid.