Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].C([CH2:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])=[O:31])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:29]/[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:31])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCCCC#CCCOc1cc(C=O)ccc1OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 83.7 %

Procedure:
Piperidine (190 μL, 1.9 mmol) was added to a suspension of 4-methoxy-3-(oct-3-ynyloxy)benzaldehyde (0.50 g, 1.9 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.39 g, 1.7 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-methoxy-3-(oct-3-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.60 g, 82%) as a colourless crystalline solid; mp 157-158° C.; δH (400 MHz, DMSO-d6) 0.85 (t, J=7.2 Hz, 3H, CH3), 1.32-1.42 (m, 4H, CH3CH2CH2), 2.14 (t, J=7.2 Hz, 2H, CH2), 2.62 (t, J=7.2 Hz, 2H, CH2CH2O), 3.80 (s, 3H, OCH3), 4.10 (t, J=7.2 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 13.4, 17.8, 19.3, 21.3, 30.5, 55.6, 67.1, 76.9, 81.5, 111.9, 112.1, 116.6, 120.0, 120.3, 122.6, 122.9, 127.3, 131.1, 134.0, 141.0, 141.5, 147.9, 150.8, 164.2, 169.4; HRMS (ESI) calculated for C25H27NO5 [M+H]+ 421.1962. found 421.1962; vmax 757, 1131, 1259, 1515, 1582, 1671, 2954, 3335 cm−1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:43])[CH2:41]Br)=[CH:36][CH:35]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[O:43])[CH2:41][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:38][CH:39]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Yield: 48.8 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 4'-benzoyloxy-2-bromoacetophenone (302 mg, 0.95 mmol, 1.5 eq) provided 171 mg of L-isoleucine, N-[1-(2-(4-benzoyloxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a foam.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:23]([O-:25])=[O:24])=[C:12]([CH:22]=1)[O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[N:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([O:13][C:12]2[CH:22]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[N+:23]([O-:25])=[O:24])[CH2:19][CH2:18]1)[CH3:21]
Reactant: COC(=O)Cl
Reactant: CN[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
129 μl methyl chloroformate were added to an ice-cooled mixture of 0.305 g [trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexyl]-methyl-amine hydrochloride and 417 μl triethylamine in 5 ml methylene chloride. After 10 minutes the coolant was removed and the mixture was stirred at rt overnight. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium hydrogen sulfate solution and 10% aq.potassium carbonate solution. The organic phase was passed through a hydrophobic frit.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[Br:1][C:2]1[S:14][C:5]2[N:6]([CH3:17])[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2cc(Br)sc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)sc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To solution of ethyl 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (6.35 g, 23.16 mmol) in DMF (80 mL) at 0° C. was added NaH (60%, 1.54 g, 38.50 mmol) in portions. Reaction mixture was stirred at 0° C. for 15 min before MeI (2.90 mL, 46.58 mmol) was added. It was then allowed to warm to room temperature and was stirred 1.5 h. Reaction mixture was cooled to 0° C. and was quenched with solution of NH4Cl (aqueous saturated, 50 mL). It was then diluted with H2O (˜200 mL) and product was extracted with EtOAc (3×100 mL). Combined organics were washed with NaCl (aqueous saturated, 80 mL) and dried over Na2SO4. After concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-10% gradient) to yield ethyl 2-bromo-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylate (5.47 g) in 82% yield.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10]C(C)C(=O)[N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](Cl)(C)C.[F:31][C:32]([F:51])([F:50])[S+]1C2C=CC=CC=2C2C=CC(S([O-])(=O)=O)=CC1=2.[CH2:52]1[CH2:56][O:55]C[CH2:53]1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:52]([CH3:53])([C:32]([F:51])([F:50])[F:31])[C:56](=[O:55])[N:13]=1
Reactant: O=S(=O)([O-])c1ccc2c3ccccc3[s+](C(F)(F)F)c2c1
Reactant: C1CCOC1
Reactant: CC1SC(NC2CC3CCC2C3)=NC1=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC1(C(F)(F)F)SC(NC2CC3CCC2C3)=NC1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar under an atmosphere of N2 was charged with 528 mg (2.35 mmol) of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one in 5 mL of anhydrous THF. The reaction was cooled to −20° C. and 5.0 mL (5.0 mmol) of NaHMDS (11.0M in THF) were added drop-wise via syringe. The resulting reaction mixture was stirred at −20° C. for 30 min then 0.86 mL (6.78 mmol) of TMSCl was added drop-wise via syringe. The reaction mixture was held at −20° C. for 15 min, and then the mixture was allowed to warm to ambient temperature. After stirring the reaction mixture for an additional 1 h, the mixture was concentrated in vacuo. The reaction flask was again equipped with a magnetic stir bar and placed under an N2 atmosphere. Anhydrous CH3CN was added, and 978 mg (2.58 mmol) of S-(trifluoromethyl)dibenzothiophenium-3-sulfonate C2 H5OH was added to the reaction mixture in one portion, and the resulting suspension was stirred at ambient temperature for 19 h. The solids were then removed by filtration through a Celite pad, and the reaction flask and pad were rinsed with CH2Cl2. The organic layer was washed with 20 mL of 1:1 H2O/sat'd NH4Cl, and the aqueous layer was extracted with an additional portion of CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography (SiO2, CH2Cl2 to 5% MeOH/CH2Cl2) provided the desired compound. MS (ESI, pos. ion) m/z: 293.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H].ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, to a solution of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (400 mg, 996 μmol) in ethyl acetate (20 mL) was added Palladium/charcoal activated (10% Pd) (80.0 mg) at room temperature. The atmosphere in the reaction flask was replaced with hydrogen gas and the mixture was stirred at room temperature for 3 hours. After replacing the atmosphere of the reaction system again with argon, to the mixture was added dichloromethane (15 mL) and stirred at room temperature for an hour. The catalyst was removed by filtration. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel 40 g, n-hexane/ethyl acetate=2/1) to give Compound 7r (403 mg, 994 μmol, 99.8%) as a brown oily substance. Rf=0.48 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.93 (s, 9H), 2.92 (t, 3H, J=8.0 Hz), 3.05 (t, 3H, J=8.0 Hz), 6.25 (s, 2H), 6.81-6.90 (AA′BB′, 2H), 7.10-7.18 (m, 1H), 7.18-7.35 (m, 4H), 7.75-7.85 (AA′BB′, 2H), 8.27 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), 18.0, 25.6 (3C), 31.7, 34.0, 120.0 (2C), 125.7, 126.1 (2C), 128.2 (2C), 128.5 (2C), 130.9, 135.6, 138.5, 140.1, 141.9, 152.3, 154.6; IR (KBr, cm−1) 507, 635, 677, 698, 750, 781, 841, 914, 1009, 1103, 1146, 1167, 1213, 1254, 1389, 1420, 1454, 1512, 1605, 2857, 2928, 2955, 3061, 3318.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:22]=[O:23])CCC.C(Cl)(Cl)=O>>[N:1]([S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])=[C:22]=[O:23]
Reactant: COC(=O)c1ccc(SC)cc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C(Cl)Cl
Product: COC(=O)c1ccc(SC)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-(methylthio)benzoate (5.23 g, 20.0 mmol), n-butyl isocyanate (2.25 mL, 20.0 mmol). and 1,4-diaza[2.2 2]bicyclooctane (0.09 g. 0.8 mmol) in mixed Xylenes (50 mL) was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 2-(isocyanatosulfonyl)-4-(methylthio)benzoate as a yellow oil (6.4 g). This was used immediately without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][Cl:12].[C:14](O)(=[O:16])[CH3:15]>>[Cl:12][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:14](=[O:16])[CH3:15])=[O:13]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCl)c(N)c1
Product: COc1ccc(C(=O)CCl)c(NC(C)=O)c1
Yield: 100 %

Procedure:
A solution of 1-(2-amino-4-methoxyphenyl)-2-chloroethanone (9.93 g, 49.74 mmol) (Example 10) in acetic acid (100 mL) was heated at 85° C. for 4 h. The solvent was evaporated under reduced pressure to yield a yellow solid (12.00 g, 100%). LC/MS m/z 242 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.45 (d, 1H), 7.73 (d, 1H), 6.63 (dd, 1H), 4.71 (s, 2H), 3.89 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH2:5]SC.O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][S:22]([CH3:26])(=[O:24])=[O:21])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of Example 287d (1.38 g, 4.00 mmol) in methanol (15 mL) was added oxone (5.16 g, 8.40 mmol) in water (15 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 to 40% ethyl acetate in heptanes) to provide the title compound (1.49 g, 98%).
Reaction SMILES: [N-]=[C:2]=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)O[C:15](=O)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:15]1([C:14]2([CH:2]=[O:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: [N-]=C=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC1(c2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 150.3 %

Procedure:
To compound 2 (5.0 g, 26.3 mmol) in CH2Cl2 (50 mL) was added 13.4 g (31.6 mmol) of Dess-Martin periodinane. After 2 h, sodium thiosulfate (58 g) followed by sat. NaHCO3 (200 mL) was added. After stirring for 1 h, the reaction mixture was diluted with EtOAc then washed with H2O, brine and dried over anhydrous sodium sulfate. Purification by flash chromatography (3:1, hexane-EtOAc) gave 1-phenyl-cyclohexanecarbaldehyde (4.47 g, 90%) as a colorless oil. Mass Spec [M+H]+=189.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH2:31])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]>O=S(Cl)Cl.C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH:31][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:13])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After concentration under reduced pressure, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., and was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (180 mg, 38%). 1H-NMR (CDCL3): 8.24 (s, 1H), 8.21 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J=7.2 H), 3.04 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.43 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Reaction SMILES: [CH2:1]([C:3]([N:10]=C=O)([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6])[CH3:2].C(#N)CC.C([Mg]Br)C=C.CCOCC.[NH4+].[Cl-]>CCOCC>[CH2:1]([C:3]([NH2:10])([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6])[CH3:2]
Reactant: C=CCC(CC)(CC=C)N=C=O
Agent: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCC#N
Solvent: CCOCC
Product: C=CCC(N)(CC)CC=C
Yield: 34 %

Procedure:
1-Ethyl-1-(2-propenyl)-3-butenyl isocyanate: A solution of propionitrile (14.5 g, 264 mmol) in dry Et2O (40 mL) was added dropwise to 1.0M allyl magnesium bromide/Et2O (880 mL). The reaction mixture was mechanically stirred at reflux for 2 h, after which time it was cooled to 0°. A saturated aqueous solution of NH4Cl (320 mL) was added cautiously to the cooled reaction mixture. The organic phase was separated, dried (MgSO4), cooled to 0° and then mixed at the same temperature with 1M HCl/Et2O (200 mL). The resulting solid was collected and dried under reduced pressure (ca 27 g). The latter material dissolved in CH2Cl2 (200 mL). The solution was washed with a 10% (w/v) aqueous solution of Na2CO3 (2×) and then brine, dried (MgSO4) and concentrated to dryness to afford a yellow oil. The oil was distilled (82°-85°/20 Torr) to give 1-ethyl-1-(2-propenyl)-3-butenylamine as a colorless liquid (11.6 g, 34%); 1H NMR(CDCl3), 400 MHz) δ 0.89 (t, J=7 Hz, 3H), 1.39 (q, J=7 Hz, 2H), 2.11 (d, J=7 Hz, 2H), 5.06-5.14 (m, 4H), 5.80-5.89 (m, 2H ).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28](Cl)[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[NH2:36][C:37](N)=[S:38].S1(CCCC1)(=O)=[O:41].Cl>COCCO.O>[OH:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH:28]3[S:38][C:37](=[O:41])[NH:36][C:29]3=[O:30])=[CH:25][CH:26]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCOc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
1.6 g of ethyl 3-{4-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)ethoxy]phenyl}-2-chloropropionate, 300 mg of thiourea and 2 ml of sulfolane were heated at 110°-115° C. for 3 hours under a nitrogen stream. A mixture of 4 ml of water, 2 ml of ethylene glycol monomethyl ether and 1 ml of concentrated hydrochloric acid was then added and the whole mixture was heated at 95°-97° C. for 4.5 hours. The mixture was then treated as described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to give the title compound, melting at 152°-154° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][C:11]=12)(=[O:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].P([O-])([O-])([O-])=O>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[C:13]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:12][C:11]=12)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(CNS(C)(=O)=O)c2s1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A solution of 231 mg of 7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazole dissolved in a mixed solution composed of 10 ml of dry THF and 1 ml of dry HMPA was cooled to −50° C. with stirring. A 1.6 N n-butyllithium/n-hexane solution (2.0 ml) was added dropwise to the mixed solution in an argon atmosphere at −51 to −49° C. over a period of 15 min. The mixture was stirred at the same temperature for 15 min. Further, 0.34 ml of tri-n-butylstannyl chloride was added dropwise thereto at −50 to −48° C. over a period of 10 min. The mixture was stirred at −50 to −40° C. for 140 min. Tri-n-butylstannyl chloride (0.07 ml) was additionally added to the reaction solution at −42° C. The mixture was stirred for 30 min. 0.38 M phosphate buffer (pH 6.0) (15 ml) was added thereto. The mixed solution was extracted with 30 ml of ethyl acetate. The organic layer was washed with 0.38 M phosphate buffer (pH 6.0) and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous magnesium sulfate was removed by filtration. The solvent was removed by distillation. The brown oil thus obtained was purified by column chromatography on silica gel (eluting with dichloromethane:ethyl acetate 1:1 and then with ethyl acetate only) to give 160 mg of the title compound as a yellow crystal.
Reaction SMILES: [OH:1][C:2]([C:5]1([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]([C:5]1([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:23][CH2:24]4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)C1(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C1(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-amide (207 mg, 0.45 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoroacetic acid (1.7 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (5 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (2.5 mL) and ethylenediamine (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h then H2O and EtOAc were added. The aqueous layer was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography over 12 g of SiO2 using EtOAc/hexanes (gradient: 0-90% EtOAc) to afford 79 mg (53%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-amide as a white solid. MS: (M+H)+=329; mp=232.0-234.0.
Reaction SMILES: [C:1]([Cu])#[N:2].N[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=[O:15])=[C:10]2[S:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:19])=[O:18].N(OC(C)(C)C)=O>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=[O:15])=[C:10]2[S:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:19])=[O:18])#[N:2]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: N#Cc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 18 h

Procedure:
To a stirring suspension of CuCN (35 mg, 0.39 mmol, 1.25 equiv) and 7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (100 mg, 0.31 mmol, 1.0 equiv) in 3 mL of DMSO was added dropwise tert-butyl nitrite (110 μL, 0.92 mmol, 3.0 equiv). After stirring for 18 hours, the title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 335.3 [M+H]+.
Reaction SMILES: C([C:3]1(C(C2C=CC(OCC(OC)=O)=CC=2)=O)CC2C=CC=CC=2[O:4]1)C.[CH2:26]([C:28]1[O:29][C:30]2[CH:49]=[CH:48][CH:47]=[CH:46][C:31]=2[C:32]=1[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](N)=[O:42])=[CH:37][CH:36]=1)=[O:34])[CH3:27]>>[CH2:26]([C:28]1[O:29][C:30]2[CH:49]=[CH:48][CH:47]=[CH:46][C:31]=2[C:32]=1[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([O:4][CH3:3])=[O:42])=[CH:37][CH:36]=1)=[O:34])[CH3:27]
Reactant: CCC1(C(=O)c2ccc(OCC(=O)OC)cc2)Cc2ccccc2O1
Reactant: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(N)=O)cc1
Product: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(=O)OC)cc1

Procedure:
Compound 11 was the intermediate of Example 7.