Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([CH2:22][C:23]([O:25]CC)=[O:24])=[N:12]3)=[N:7][C:6]=2[CH:28]=1.O1CCOCC1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([CH2:22][C:23]([OH:25])=[O:24])=[N:12]3)=[N:7][C:6]=2[CH:28]=1
Reactant: CCOC(=O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(5-bromobenzothiazol-2yl- methyl)-4-oxo-3-H-phthalazin-1-ylacetate (15.0 g) and dioxane (150 ml) was brought to solution by warming on a steam bath and to this solution was added a solution of 10% potassium hydroxide (20 ml) in ethanol (50 ml.). The resulting dark purple solution was stirred at room temperature for 2 hours and concentrated to remove excess dioxane and ethanol. The concentrate was diluted with water (100 ml) and the resulting solution was washed with ether (2×100 ml). The aqueous layer was collected and acidified to pH 2.0 by addition of concentrated HCl. The precipitated solid was crystallized from methylene chloride/ethanol (400 ml/40 ml) to obtain the product (Yield 7.65 g; m.p. 214° C.).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21]>>[CH3:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples 65 and 66 to yield 2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>C(O)(C)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[N:29][CH:28]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2nccn12
Yield: 86.3 %

Procedure:
In the same way as described in the general procedure for amine displacement using 4-(2-morpholin-4-yl-ethoxy)-phenylamine (600 mg, 2.7 mmol), N,N-diisopropylethylamine (0.470 mL, 2.7 mmol) and a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.500 g, 1.80 mmol) in isopropanol (6 mL). Purification by silica gel column chromatography eluting with a mixture 97:3 DCM:MeOH affords the title compound as a pale yellow solid (650 mg, 86%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.51-2.62 (4H, m), 2.75-2.83 (2H, t), 3.71-3.78 (4H, m), 4.09-4.18 (2H, m), 6.90 (2H, d), 7.51 (1H, s), 7.61 (1H, s), 7.64 (2H, d), 7.70 (1H, s), 7.90 (1H, s). LCMS: Rt 2.09 min (97%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].O>C(#N)C>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])[CH:13]=[CH2:14]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: C=CCNCC=C
Solvent: CC#N
Solvent: O
Product: C=CCN(CC=C)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
2-Chloro-1-(4-fluorophenyl)ethanone (10 g, 57.4 mmol) is dissolved in acetonitrile (400 mL). The solution is cooled to 0° C. and diallylamine (15.6 mL, 126.2 mmol) is added. After 1 hour, the mixture is poured into water (500 mL) and extracted twice with ethyl acetate (400 mL). The organic extracts are combined, washed with brine (1×200 mL), dried over sodium sulfate, filtered, and concentrated to give the crude title compound (15.84 g, 118%). ES/MS (m/e): 234 (M+H).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])=[N:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:66]([O:69][CH2:70][CH3:71])(=[O:68])[CH3:67]>O>[CH2:70]([O:69][C:66](=[O:68])[CH2:67][O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[N:27][C:26]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:13][CH2:14]1)[CH3:71]
Reactant: CCOC(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile (0.42 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (20 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.31 g) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), sodium borohydride (0.016 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution (10 mL) of the obtained residue in toluene was added dropwise ethyl diazoacetate (0.14 mL) in the presence of rhodium(I) acetate (0.0012 g) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.06 g, 15%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.7 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), isobutyl bromide (0.64 g, 4.6 mmol) and potassium carbonate (0.57 g, 4.1 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.08 g, 19%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.6 g. (0.019 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-ureidoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3][C:2]=1[CH3:1]
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(Br)s1
Reaction time: 2 h

Procedure:
To N-(4-methylthiazol-2-yl)acetamide (39.48 g) in acetic acid (200 ml) under a water-ice bath was added dropwise bromine (16 ml). After 2 h, water (500 ml) was added. Filtration, washing with water (3×) and drying gave N-(5-bromo-4-methylthiazol-2-yl) acetamide as off-white solid (52.13 g). H1-NMR (300 MHz, d6-DMSO) 12.27 (s, 1 H), 2.22 (s, 3 H), 2.13 (s, 3 H) ppm.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8]>C(#N)C>[N:1]([CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CCl)cc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Sodium azide (1.79 g, 27.48 mmol) was added in one portion to a solution of J.30 (5)-tert-butyl 2-(6-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (10.0 g, 27.48 mmol) in acetonitrile (200 mL) and stirred at 60° C. for 16 h. The reaction mixture was concentrated to ⅕ volume, diluted with ethyl acetate, and washed with water and brine prior to being dried (Na2SO4). Concentration gave J.31 (S)-tert-butyl 2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate 6.8 g (48%) as a golden orange foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.22/8.03 (s, 1H), 7.80-7.75 (m, 1H), 7.65/7.56 (d, J=8.5 Hz, 1H), 4.99-4.93 (m, 3H), 3.60 (br. s, 1H), 3.46-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.89 (m, 3H), 1.40/1.06 (s, 9H). LC (Cond.-D2): 1.97 min; LC/MS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.19; found: 371.32. HRMS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.1832; found: 371.1825.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][NH2:13].[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][NH:13][C:32]([NH:31][C:23]1[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=1[CH:28]([CH3:30])[CH3:29])=[O:33]
Reactant: CCCCCC(CN)c1cccc(OC)c1OC
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Product: CCCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccc(OC)c1OC
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To 0.65 g (2.6 mmol) of (+)-2-(2,3-dimethoxyphenyl)-heptylamine was added dropwise a 5.2 ml of 0.502M toluene solution of 2,6-diisopropylphenyl isocyanate at room temperature and the whole was stirred overnight. The reaction mixture was concentrated and the resulting residue was crystallized from methanol. The crystals were collected by filtration and washed with n-hexane to give 0.512 g (43.5% yield) of (+)-1-(2-(2,3-dimethoxyphenyl)heptyl)-3-(2,6-diisopropylpheyl)urea.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH:5]1([N:15]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCc2ccccc21
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C=NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a stirred solution of 242.4 grams (2.46 moles) of phosgene in 200 ml of toluene and 600 ml of benzene is slowly added a solution of 119.9 grams (0.814 mole) of 1,2,3,4-tetrahydro-1-naphthylamine, while maintaining the reaction temperature at 10°C. to 15°C. The mixture is stirred overnight at room temperature and then heated to reflux under a nitrogen atmosphere. After 4 hours reflux, most of the solvent is distilled from the reaction at atmospheric pressure. The residual solvent is evaporated at reduced pressure. The crude product is distilled to give 121.4 grams of product with boiling point 90°C. to 96°C. (0.3 mm).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([OH:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K].CCN(C(C)C)C(C)C.[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH2:51])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH:51][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in the Example 1, step (d), 33.6 mg, 0.110 mmol), DIEA (34 μL, 0.20 mmol), 2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenylamine (as prepared in the previous step, 33.6 mg, 0.110 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with satd aq NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (20-40% EtOAc/hexane) to afford 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenyl]-amide (56 mg, 95%). Mass spectrum (ESI, m/z): Calcd. for C28H39N5O5SSi, 586.2 (M+H). found 586.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[C:6]1[C:13]([O:15][CH3:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>C(Cl)Cl.O>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:11]2[S:10][C:9]3[S:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=3[CH:12]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc2ccsc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
Anhydrous aluminium chloride (136 g) is added in small portions, over a period of 30 minutes, to a mixture of methyl thieno[2,3-b]thiophene-2-carboxylate (40.3 g) and 4-fluorobenzoyl chloride (32.3 g) in methylene chloride (1000 cc) at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then hydrolysed, with care, by the addition over a period of 30 minutes of 0.5N aqueous hydrochloric acid (500 cc), the internal temperature being maintained at about 20° C. by external cooling with a bath of cold water. The methylene chloride solution is diluted with methylene chloride (5000 cc), decanted off, washed three times with distilled water (total 3000 cc), three times with a saturated aqueous sodium bicarbonate solution (total 1000 cc), and again three times with distilled water (total 3000 cc), then dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (1 g), filtered and evaporated. The residue is triturated in diethyl ether (250 cc), the resulting crystals are filtered off, washed three times with diethyl ether (total 375 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. Methyl 5-(4-fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylate (51.8 g), melting at 220° C., is thus obtained.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([CH2:19][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]2=[O:9])=[CH:21][CH:22]=1
Reactant: O=C1CCCCCCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCCCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirring solution of cyclooctanone (1.76 g, 14.0 mmol) in THF (30 mL) at −78° C. was added LDA (8.54 mL, 15.4 mmol, 1.8 M in heptane/THF/ethylbenzene). After 1 h, a solution of methyl 4-bromomethylbenzoate (3.53 g, 15.4 mmol) in THF (10 mL) was added and the reaction mixture was allowed to warm to rt. After 30 min, the reaction was quenched with H2O (10 mL) and the THF was removed on a rotary evaporator. The residue was diluted with EtOAc (100 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Chromatography of the crude product (50:1 to 9:1 hexanes/EtOAc) yielded the desired product as a colorless oil (3.08 g, 80%, Rf=0.30, 9:1 hexanes/EtOAc). IR: 3426, 2929, 2856, 1721, 1700, 1657, 1611 cm−1. 1H NMR (CDCl3, 300 MHz): δ 1.10-1.28 (m, 1H), 1.28-1.42 (m, 1H), 1.42-1.80 (m, 6H), 1.80-1.90 (m, 1H), 1.90-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.22-2.35 (m, 1H), 2.64 (dd, 1H, J=12.6, 6.0 Hz), 3.01 (m, 2H), 3.89 (s, 3H), 7.20 (d, 2H, J=8.1 Hz), 7.93 (d, 2H, J=8.4 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.5, 24.6, 25.1, 27.7, 32.9, 38.1, 43.2, 51.5, 52.0, 128.1, 129.0, 129.7, 145.6, 167.0, 218.9. FAB-HRMS: Calcd. for C17H23O3+ [M+H]+: 275.1647, found: 275.1648.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:27][CH2:28][CH2:29][CH2:30][C:31]([N:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:32]
Reactant: O=C(Cl)CCCCl
Reactant: O=C(O)CNc1csc2ccccc12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CN(C(=O)CCCCl)c1csc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 621 mg (3 mM) of 3-benzothienylglycine in 15 ml of dichloromethane containing 0.92 ml (6.6 mM) of triethylamine and 717 mg of chlorotrimethylsilane was heated at 50° C. and stirred for thirty minutes and then cooled to 5° C. A solution of 0.336 ml (3 mM) of 4-chlorobutyryl chloride in 5 ml of dichloromethane was added dropwise to the reaction mixture and stirring was continued at 5° C. for one hour following the addition. The reaction mixture was warmed to 25° C. and stirred for an additional hour. The reaction mixture was next washed twice with 10 ml portions of water, dried, and the solvent was removed by evaporation to give an oil. The oil was crystallized from 0.7 ml of acetone and 2.7 ml of water, and recrystallized from ethyl acetate to afford 150 mg of N-(3-chloropropylcarbonyl)-3-benzothienylglycine. m.p. 167°-168° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:13][CH3:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[CH2:13]([N:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CCCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)CCCc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Benzoylchloride (6.33 g, 45 mmol) in pyridine (50 mL) was added over a 15-minute period to a solution of N,N-diethyl-3-(p-nitrophenyl)-propylamine (9.4 g, 45 mmol) in pyridine (50 mL). The solution was refluxed for 1.5 hours. The solvent was evaporated, giving a brown oil. The oil was dissolved in dichloromethane (300 mL) and washed with 1N NaOH (200 mL). The dichloromethane layer was dried and evaporated. Toluene (100 mL) was added to the resulting oil and re-evaporated. The semi-solid residue was washed with pentane, then recrystalized from cyclohexane (125 mL) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:13]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CN1CCC(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carbonyl chloride (1 eq) in anhydrous methylene chloride was added to the flask and brought to 0° C. To this was added the solution containing 4-chloropyridin-2-amine (1 eq), and diisopropylethylamine (5 eq) in anhydrous methylene chloride, which was stirred for 1 hour at 0° C. Reaction concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on silica gel, 10% methanol in methylene chloride to yield N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide as a slightly yellow crystal solid. HPLC=2.39 min; MS: MH+=254.