Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:14]=2[CH3:15])[C:5](=[O:35])[CH:4]=1.Cl>C1COCC1>[O:35]=[C:5]1[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][N:6]1[CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15]
Reactant: COC1=CC(=O)N(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CN1CCC(=O)CC1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 5,6-dihydro-4-methoxy-1-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4yl]methyl]-2(1H)-pyridinone (500 mg) in THF (4 ml) was added hydrochloric acid (5M; 1 ml), and the mixture was stirred at 50° for 1 h. The solvent was removed in vacuo, triethylamine (1 ml) was added, and the mixture was again evaporated to dryness. FCC of the residue eluting with ethyl acetate:methanol:triethylamine (8:4:1) gave the title compound (139 mg), m.p. 100°-106° (decomp.).
Reaction SMILES: [Cl:1][CH2:2][CH:3](OC)OC.[CH3:8][C:9]([SH:16])([CH2:11][C:12]([CH3:15])([SH:14])[CH3:13])[CH3:10].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Cl:1][CH2:2][CH:3]1[S:16][C:9]([CH3:10])([CH3:8])[CH2:11][C:12]([CH3:15])([CH3:13])[S:14]1
Reactant: CC(C)(S)CC(C)(C)S
Reactant: COC(CCl)OC
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC1(C)CC(C)(C)SC(CCl)S1
Temperature: 25 °C

Procedure:
2-Chloro-1,1-dimethoxyethane (0.1 mole) and 2,4-dimethyl-2,4-pentanedithiol (0.1 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, Dean Stark trap and reflux condenser. Toluene sulfonic acid (0.1 grams) is added and the reaction mixture is heated and thiol removed. When the thiol evolution ceases, the reaction mixture is then cooled to room temperature, treated with sodium carbonate (5 grams) and filtered. Volatiles are stripped from the filtrate using a rotary evaporator to yield the desired product 2-chloromethyl-4,4,6,6-tetramethyl-1,3-dithiane as the residue.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][O:20][C:21]([CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)=[O:22]>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:21]([O:20][CH3:19])=[O:22])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COC(=O)Cn1nnnc1S
Product: COC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
7-Aminocephalosporanic acid was reacted with 1-methoxycarbonylmethyl-1H-tetrazole-5-thiol in a conventional manner to give 7-amino-3-(1-methoxycarbonylmethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:8]2=[O:33]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: C1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN4CCOCC4)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added morpholine (0.17 ml, 1.94 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)—N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide; hydrochloride as a white solid (200 mg, 68% yield): mp, 198-200° C.; 1H NMR (CDCl3 with D2O added) δ 1.46 (t, J=7.0 Hz, 3H, OCH2CH3), 2.68 (broad, 4H, CH2NCH2 on morpholino ring), 2.99 (s, 3H, SCH3), 3.24 (broad, 2H, CH2NCO), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.87-3.92 (m, 7H, OCH3+OCH2OCH2 on morpholine ring), 4.05-4.23 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.40 (d, J=15 Hz, 1H, CHHN), 5.71-5.77 (m, 1H, NCH), 6.86-6.97 (m, 3H, Ar), 7.40d, J=8 Hz, 1H, Ar), 8.52 (d, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 41.71, 47.09, 51.22, 51.59, 55.09, 56.02, 63.81, 64.10, 64.81, 105.68, 111.67, 112.28, 119.32, 120.0, 120.27, 124.03, 128.81, 133.20, 134.72, 139.41, 149.09, 150.01, 168.55. Anal Calcd for C26H33Cl2N3O7S+0.53H2O: C, 51.02; H, 5.61; N, 6.87. Found: C, 50.70; H, 5.38; N, 6.76; 0.98% H2O.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:7]=[N:8][C:9](=[O:12])[NH:10][CH:11]=1>CN(C)C=O.C(N(CC)CC)C>[CH3:1][NH:2][C:3]([N:10]1[CH:11]=[C:6]([Cl:5])[CH:7]=[N:8][C:9]1=[O:12])=[O:4]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (56.5 ml) was added dropwise over 15 minutes, with cooling, to a stirred solution of 5-chloropyrimidin-2-one (25 g) in N,N-dimethylformamide (290 ml) and triethylamine (30.4 ml). The temperature of the reaction mixture was kept at approximately 22° C. The mixture was stirred at room temperature for a further 40 minutes and then cooled in an ice bath. The solid was collected, washed with cold dichloromethane (4×215 ml), briefly air dried and then dried in vacuo at room temperature to give the title compound as white crystals (33.36 g), m.p. 241°-243° C. decomp. U.V. data: λmaxEtOH 230 nm (ε10,370), 322.5 mm (ε1,700).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([OH:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][O:24][CH2:25]Cl>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([O:22][CH2:23][O:24][CH3:25])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCl
Reactant: NC(=O)CCc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(OCc2ccccc2)ccc1CCC(N)=O
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 5.64 g of 60% sodium hydride in oil in 628 mL of N,N-dimethylformamide was added 34.8 g of 3-(4-benzyloxy-2-hydroxyphenyl)propionamide under ice-cooling, and the mixture was stirred at 50° C. for 40 minutes. To the reaction mixture was added 12.39 g of chloromethyl methyl ether under ice-cooling, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was poured into a mixture of 500 mL of ethyl acetate, 100 mL of toluene, and 200 mL of water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a colorless solid. The solid was triturated in ethyl acetate-diisopropyl ether to collect by filtration of 35.3 g of 3-(4-benzyloxy-2-methoxymethoxy-phenyl)propionamide as a colorless solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C>O1CCCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(OC2C=CCCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: OCc1ccc(OC2C=CCCC2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
4-(Cyclohex-2-enyloxy)benzoic acid (25 g, 115 mmol) was dissolved in 250 mL dry tetrahydrofuran and cooled to -10° C. under an atmosphere of dry nitrogen. N-Methylmorpholine (12.6 mL, 115 mmol) and isobutylchloroformate (15.9 mL, 115 mmol) were added. After 10 minutes at -10° C. the mixture was warmed to room temperature and filtered. The volume was reduced to 50 mL under reduced pressure before cooling to 0° C. and adding diisobutylaluminum hydride (1.5M in toluene, 160 mL) over 10 minutes. After 30 minutes, the reaction was warmed to ambient temperature for 2 hours. The mixture was cooled in an ice bath, diluted with ether, quenched with methanol, and poured into cold Rochelle's salt solution. The crude product was extracted with ether, dried over Na2 SO4, and chromatographed eluting with 20% ethyl acetate in hexane to give 4.24 g (18%) of 4-(cyclohex-2-enyloxy)benzyl alcohol.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([NH2:19])[N:13]=2)[CH2:6]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:10][CH2:9][C@@H:8]([CH3:11])[N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([NH2:19])[N:13]=2)[CH2:6]1
Reactant: C[C@@H]1CO[C@H](CN=[N+]=[N-])CN1c1cc(Cl)nc(N)n1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CO[C@H](CN)CN1c1cc(Cl)nc(N)n1
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
A suspension of 4-[(2S,5R)-2-(azidomethyl)-5-methyl-4-morpholinyl]-6-chloro-2-pyrimidinamine (890 mg, 3.14 mmol) and 10% Pd/C (95 mg, 0.09 mmol) in ethanol (35 mL) was stirred under an atmosphere of hydrogen for 1.5 hours, then filtered through a pad of celite. The filtrate was concentrated in vacuo to give the title compound (778 mg, about 85% purity) as a white solid. LC-MS (ES) m/z=258, 260 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.[Cl-].[NH4+]>COCCOC>[C:12]([O:11][C:10](=[O:16])[NH:9][CH2:8][C:7]1[CH:17]=[CH:18][C:4]([O:3][C:22]2[N:23]=[C:24]([Cl:26])[CH:25]=[C:20]([Cl:19])[N:21]=2)=[CH:5][CH:6]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCc1ccc(O)cc1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2nc(Cl)cc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (394 mg) was suspended in 1,2-dimethoxyethane (20 mL), and tert-butyl 4-hydroxybenzylcarbamate (1 g) and 15-crown-5-ether (1.09 g) were added thereto, followed by stirring at room temperature for 30 minutes. 4,6-Dichloro-2-(methylsulfonyl)pyrimidine was added thereto, followed by stirring at 80° C. overnight. The reaction solution was cooled to room temperature and then an aqueous ammonium chloride solution (50 mL) was added thereto, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to obtain tert-butyl{-4-[(4,6-dichloropyrimidin-2-yl)oxy]benzyl}carbamate (762 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[NH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[O:16]1CC[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+].ClCC(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:16]=[C:17]1[CH2:18][O:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]3=[CH:3][C:2]=2[NH:1]1
Reactant: COC(=O)c1cc2cc(N)c(O)cc2[nH]1
Reactant: C1CCOC1
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: COC(=O)c1cc2cc3c(cc2[nH]1)OCC(=O)N3
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a solution of 2.0 g (9.7 mmol) of methyl 5-amino-6-hydroxy-indole-2-carboxylate (Example 5/c) in 300 ml of tetrahydrofuran 2.45 g (29.2 mmol) of sodium hydrogencarbonate and 1.3 ml (16.3 mmol) of chloroacetyl chloride are added and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and 100 ml of water is added to the residue. The precipitated crystals are filtered off, washed with water and suspended in 120 ml of acetonitrile. 4.05 g (29.3 mmol) of potassium carbonate is added to the suspension and the resulted mixture is stirred at room temperature overnight. The reaction mixture is concentrated and 100 ml of water is added to the residue. The product is filtered off, washed with water and dried to yield 1.7 g (71%) of the title compound. Mp.: 188-196° C. (water).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:31][C:32]#[N:33])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Temperature: 120 °C
Yield: 31.4 %

Procedure:
To a mixture of 9-benzyl-6-methoxy-9H-carbazol-4-ol (1.21 g, 4.0 mmol) in DMF (25 mL) is added potassium carbonate (2.07 g, 15 mmol) and bromoacetonitrile (0.7 mL) 10 mmol). The mixture is heated at 120° C. overnight. The mixture is partitioned between water and Et2O. The organic layer is washed twice with water (100 mL) and dried over anhydrous sodium sulfate. The residue is dissolved in CH2Cl2 and passed through a silica gel plug. The filtrates are concentrated to dryness to give 0.43 g (31%) of the title compound; IR (drift) 1487, 1469, 1449, 1439, 1291, 1275, 1211, 1181, 1170, 1147, 1120, 775, 745, 705, 697 cm−1. 1H NMR (CDCl3) δ3.94, 5.06, 5.48, 6.7, 7.09, 7.24, 7.36, 7.81; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 76.68; H, 5.31; N, 8.08.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=1)(=[O:3])N.Cl.C[O:28]CCO>>[CH2:10]([NH:9][C:7]1[CH:8]=[C:4]([C:1]([OH:28])=[O:3])[S:5][CH:6]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COCCO
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(N)=O)c1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1

Procedure:
A mixture of 4.4 g. of 2-carbamyl-4-hexadecylaminothiophene, 50 ml. of methyl cellosolve, and 50 ml. of 6 N hydrochloric acid is refluxed for 40 hours and then allowed to cool. The solid is filtered and recrystallized from methanol. The solid is then dissolved in hot sodium bicarbonate solution, filtered, and the filtrate is acidified with concentrated hydrochloric acid. The resulting precipitate is collected and recrystallized from isopropanol to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.CC(O[CH2:20][CH3:21])(OCC)OCC>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:20]([CH3:21])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nc2cc(Br)cnc2n1C
Temperature: 80 °C

Procedure:
To a suspension of 5-bromo-N2-methylpyridine-2,3-diamine (510 mg, 2.51 mmol) in AcOH (20 mL) was added MeC(OEt)3 (1 mL) and the solution was warmed to 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-25% THF/CH2Cl2 gradient) to afford the desired product. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][CH:14]=[N:13][C:12]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN(C)[CH:29]=[O:30]>O1CCCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([CH:29]=[O:30])=[N:13][C:12]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncsc1C(=O)NCc1ccccc1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of N-benzyl-4-methylthiazole-5-carboxamide (1.00 g, 4.31 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (9.5 mL of 1.0 M solution in tetrahydrofuran, 9.5 mmol) at −78° C. The reaction mixture was stirred for 5 minutes, and N,N-dimethylformamide (0.35 mL, 4.54 mmol) was added. The reaction mixture was slowly warmed to ambient temperature over 4 hours, quenched with 5% hydrochloric acid (10 mL), extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 98% yield (1.1 g): MS (ES+) m/z 261.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](=O)[CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[N:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:31]=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=12)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1=O)C1CCCCC1
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.3, 2-cyclohexyl-3-oxo-3-(2-oxo-cycloheptyl)-propionic acid ethyl ester was condensed with (4-chloro-phenyl)-hydrazine (CAS Reg. No. 1073-69-4) in ethanol to give the title compound as orange oil. MS: m/e=415.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C@H:16]3[C@@:25]45[CH2:35][CH2:36][C@:22]6([CH2:23][C@@H:24]4[C@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[O:28][CH2:27][O:26]5)[C@@:17]43[CH2:18][CH2:19][N:20]([CH2:38][CH:39]3C[CH2:40]3)[C@@H:21]6[CH2:37][C:12]([C:13]=24)=[CH:11][CH:10]=1)C1C=CC=CC=1.CI.C(Br)C1C=CC=CC=1.C(N1CC[C@@]23C4C5C[C@@H]1[C@]12CC[C@]2(OCO[C@@](C(C)(C)C)(C)[C@H]2C1)[C@@H]3OC=4C(O)=CC=5)C=C.C([C@]1(C)[C@@H]2[C@@]3(CC[C@]4(C2)[C@@]25C6C(=CC=C(O)C=6O[C@@H]32)C[C@H]4N(CC2CC2)CC5)OCO1)(C)(C)C>>[CH2:38]([N:20]1[CH2:19][CH2:18][C@@:17]23[C:13]4[C:12]5[CH2:37][C@@H:21]1[C@:22]12[CH2:36][CH2:35][C@:25]2([O:26][CH2:27][O:28][C@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[C@H:24]2[CH2:23]1)[C@@H:16]3[O:15][C:14]=4[C:9]([O:8][CH3:1])=[CH:10][CH:11]=5)[CH:39]=[CH2:40]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Agent: BrCc1ccccc1
Agent: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@]24CC[C@]3(C[C@@H]2[C@@](C)(C(C)(C)C)OCO4)[C@H]1C5
Agent: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Solvent: CI
Product: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2[C@@]24CC[C@]3(C[C@@H]2[C@@](C)(C(C)(C)C)OCO4)[C@H]1C5
Yield: 58 %

Procedure:
The title compound 18 was synthesized similar to the procedure described in Example 5 for preparing compound 7 using methyl iodide rather than benzyl bromide and compound 17 rather than compound 3. After column chromatography, 300 mg (58% yield) of compound 18 was isolated in a purity of >99% as a white solid.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.[N:41]1([S:46](Cl)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:46]([N:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)(=[O:48])=[O:47])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: O=S(=O)(Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)N6CCCC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.12 g, 0.28 mmol), DIEA (0.48 mL, 2.8 mmol) in DMA (2.75 mL). Pyrrolidine-1-sulfonyl chloride (0.07 g, 0.41 mmol, Matrix) was added dropwise and reaction mixture was stirred at ambient temperature for about 1 h. K2CO3 (0.190 g, 1.37 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide, which was dissolved in NaOH (1 N aqueous, 1.10 mL, 1.10 mmol) and 1,4-dioxane (1 mL) and heated at about 50° C. for about 1 h. The crude material was purified by preparative reverse phase HPLC (Table 2, Method 1) to give N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide (0.042 g, 37%) as a white solid: LC/MS (Table 1, Method a) Rt=1.81 min; MS m/z 416 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:8][C:9](=[O:24])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:23])[C@H:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[C:19]([S:18][CH2:17][C@@H:16]([CH3:22])[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([OH:32])=[O:5])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
1-[(2S)-3-(Acetylthio)-2-methyl-1-oxopropyl]-L-prolyl-L-phenylalanine tert-butyl ester (1.19 g, 0.025 Mol) was dissolved in a solution of trifluoroacetic acid:CH2Cl2 (1:2, 30 ml) and the reaction was stirred at room temperature for 1 hour. Then it was evaporated under reduced pressure affording 1-[(2S)-3-(acetylthio)-2-methyl-1-oxopropyl]-L-prolyl-L-phenylalanine as a clear oil (1.00 g, 100%) that was used in the subsequent reaction without any further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)=[O:8]
Reactant: Cc1oncc1C(=O)Cl
Reactant: C1CSCCN1
Product: Cc1oncc1C(=O)N1CCSCC1

Procedure:
of melting point 64.5° to 65° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and thiomorpholine.