Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCBr
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
62.8 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 7 mg of sodium hydride under cooling with ice. After 15 minutes, 80 μl of decyl bromide was added, and the reaction solution was allowed to react at room temperature under stirring for another 18 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×20 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 85.7 mg of compound (48) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22]Cl>C(#N)C>[CH3:19][C:20]([CH3:24])=[CH:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CC(C)=CCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 95.2 %

Procedure:
Ethyl 4-hydroxybenzoate (1.66 g, 10.0 mmol) and anhydrous potassium carbonate (2.07 g, 15.0 mmol) in acetonitrile (30 ml) was treated with 3-methyl-2-butenyl chloride (1.35 ml, 12.0 mmol) and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organics were separated and the solvent removed in vacuo to afford ethyl 4-(3-methyl-but-2-enyloxy)-benzoate (2.23 g, 95%) as a pale yellow liquid which was used without further purification. 1H NMR (DMSO-d6) 7.89 (2H, d), 7.04 (2H, d), 5.44 (1H, t), 4.62 (2H, d), 4.28 (2H, q), 1.77 (3H, s), 1.73 (3H, s), 1.31 (3H, t). MS: [M+H]+ 235.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(OCC)(=O)C>CC(N(C)C)=O.[Cu]I.O>[N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: c1cnc(-n2cccn2)nc1
Temperature: 140 °C
Yield: 15.7 %

Procedure:
A reaction mixture containing pyrazole (2 g, 29 mmol), 2-bromopyrimidine (3.8 g, 24 mmol), copper (I) iodide (0.91 g, 4.8 mmol) and 1,10-phenanthroline (1.7 g, 9.6 mmol) in DMA was heated at 140° C. in a sealed tube for 6 hours. After the reaction, ethyl acetate (30 mL) was added, followed by water. The aqueous layer was extract three times (20 mL) and the organic layer was collected, dry over sodium sulfate. After concentration under vacuum, the crude product was purified using column chromatography (10% ethyl acetate in dichloromethane) to give 0.55 g of pure product. 15% yield. MS (ESMS, M+H 146).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH:12]S(O)(=O)=O.[C:17](#[N:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][C:17](=[O:12])[CH3:18])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Reactant: CC#N
Product: CC(=O)NC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 21.0 g (97.6 mmol) 2-(4-bromophenyl)-propan-2-ol in 1 L ACN are added 16.1 mL conc. H2SO4 dropwise while keeping the temperature at 20° C. The resulting mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is partitioned between water and diethylether. The organic layer is washed with water (2×), sat. aq. NaHCO3 solution (2×) and water again (1×). The solution is dried with MgSO4 and the solvent is removed in vacuo. The crude product is triturated with PE.
Reaction SMILES: [CH2:1]([C:3]12[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=[C:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=12)[CH:13]=[N:12][N:11]3[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:2]>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[CH2:1]([C@:3]12[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=12)[CH:13]=[N:12][N:11]3[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH3:2].[CH2:1]([C@@:3]12[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=12)[CH:13]=[N:12][N:11]3[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Product: CC[C@]12CCC(=O)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reaction time: 12 h
Yield: 41.4 %

Procedure:
A solution of (12b-ethyl-9-(4-fluorophenyl)-1,2,6,7,9,12b-hexahydro-5H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (8, R1=4-Fluorophenyl, R2=Ethyl) (3.03 g, 8.09 mmol) in toluene (75 mL) containing 20% Pd(OH)2 on carbon (0.290 g, 0.413 mmol) was evacuated and placed under hydrogen. The reaction was shaken under about 55 psi of hydrogen for about 12 h then at about 55° C. for about 6 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated under reduced pressure. The residue was treated with EtOAc (20 mL) and the solids which formed upon standing were collected by filtration and washed with EtOAc (3 mL). The filtrate was retained. The solid was recrystallized from EtOAc (25 mL) to yield (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (10, R1=4-Fluorophenyl, R2=Ethyl) (1.26 g, 41%); LC/MS, method 2, Rt=3.05 min, MS m/z 377 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=0.8 Hz, 1H), 7.86 (s, 1H), 7.83-7.77 (m, 2H), 7.59 (s, 1H), 7.45-7.37 (m, 2H), 3.29-3.24 (m, 1H), 2.99-2.94 (m, 1H), 2.55-2.43 (m, 3H), 2.40-2.11 (m, 3H), 2.09-1.85 (m, 5H), 1.64-1.57 (m, 1H), 1.37-1.28 (m, 1H), 0.49 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:30])[NH:32][CH3:33])=[CH:25][CH:24]=5)[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c2)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (0.97 mmol) in CH2Cl2 (3 mL) at ambient temperature was added a solution of 3′-amino-N-methylbiphenyl-4-sulfonamide (0.25 g, 0.97 mmol), Et3N (0.68 mL, 4.9 mmol), DMAP (0.050 g, 0.058 mmol), and CH2Cl2 (1 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (50 mL). The solution was washed with 1N HCl (2×25 mL), sat. aq. NaHCO3 (2×25 mL), then brine (25 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5-25% EtOAc/hexanes) to provide 1-benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropane-1-carboxamide as a white solid. ESI-MS m/z calc. 450.5. found 451.3 (M+1)+. Retention time of 3.13 minutes.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][OH:16])[CH3:12].[OH-].[K+].C(O)(C)C>O>[CH2:11]([N:13]([CH2:18][CH3:19])[C:14](=[O:17])[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1)[CH3:12]
Reactant: FC(F)(F)c1nsc(Cl)n1
Reactant: CCN(CC)C(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCN(CC)C(=O)COc1nc(C(F)(F)F)ns1
Temperature: -10 °C
Reaction time: 10 h
Yield: 47.1 %

Procedure:
5.6 g (0.03 mol) of 5-chloro-3-trifluoromethyl-1,2,4-thiadiazole are added to a mixture which comprises 4 g (0.03 mol) of hydroxyacetic acid diethylamide, 1.9 g (0.03 mol) of potassium hydroxide powder and 80 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 10 hours at -10° C. and poured into water, and the product is filtered off under suction. 4 g (47% of theory) of (3-trifluoromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid diethylamide are obtained in the form of white crystals of melting point 60° C.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29])[CH2:23][NH2:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:29])([F:30])[F:31])[CH2:23][NH:24][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 3-fluoro-4-(trifluoromethyl)benzylamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].CCN(CC)CC.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[NH:1][C:33]([N:32]([CH3:36])[CH3:31])=[O:34])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a solution of N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of dimethylcarbamoyl chloride (54 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaHCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (50 mg, 23%) as a foam.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10]1)=O)(C)(C)C.[Cl:18]CCl.ClC(OC)=O.C[O:27][C:28](=[O:32])[C@H:29]([CH3:31])[NH2:30]>C(N(CC)CC)C>[ClH:18].[NH2:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([NH:30][C@H:29]([C:28]([OH:32])=[O:27])[CH3:31])=[O:17])=[CH:10]1
Reactant: CC(C)(C)OC(=O)NC1C=C(C(=O)O)C=CC1
Reactant: COC(=O)[C@H](C)N
Reactant: ClCCl
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C1=CC(N)CC=C1)C(=O)O
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 240 mg (1 m mole) of 3-tert-butoxycarbonylamino-1,5-cyclohexadiene carboxylic acid and 5 ml of dichloromethane is treated with 202 mg (2 m mole) of triethylamine and 94 mg (1 mole) of methyl chloroformate. After 30 minutes at 25° C. the solution is treated with 103 mg (1 m mole) of alanine methylester and maintained at 25° C. for 1 hour after which the solution is washed with water, dryed and concentrated. The residue is treated with 3 ml of methanol and 120 mg of sodium hydroxide in 2 ml of water for 3 hours at 25° C. then solidified and extracted with dichloromethane. The organic phase is dryed and concentrated. The residue is treated with 7 ml of methanol containing 5% HCl for 18 hours at 25° C. Evaporation affords N-(3-amino-1,5-cyclohexadienyl)carbonylalanine hydrochloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:61][CH2:62][CH3:63])[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)[CH2:50][CH3:51]>CN(C=O)C>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:58]2[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:52]([CH2:61][CH2:62][CH3:63])[CH2:49][CH2:50][CH3:51])[CH2:56][CH2:57]2)=[O:20])=[CH:17][CH:16]=1)[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)CCN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
The compound (103.8 mg) obtained in Example 2-2 was dissolved in DMF (3.1 ml) and then added with DCC (68.8 mg) and HOBt (45.0 mg), followed by stirring at room temperature for 10 days. The solution was added with 1-(2-dipropylaminoethyl)piperazine (71.1 mg) and further stirred at the same temperature for 4 days. The reaction solvent was distilled off and the residue was then added with 1 mol/l hydrochloric acid, followed by washing with chloroform. The aqueous layer was adjusted to pH 12 with a 1 mol/l sodium hydroxide aqueous solution and then subjected to separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloride acid, thereby obtaining hydrochloride (52.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:4]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)CC#Cc1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1noc(-c2ccccc2)c1CC(C)C
Reaction time: 6 h
Yield: 30.1 %

Procedure:
A solution of (4-methylpent-1-ynyl)benzene (0.247 g, 1.56 mmol), dimethyl 2-nitromalonate (0.421 mL, 3.12 mmol), 1-butyl-3-methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (5 mL) was subjected to the microwave at 170° C. for 150 min. By HPLC, the reaction was ˜40-50% complete and resubjected to the microwave conditions for 360 min. (170° C.). The toluene was decanted off leaving a dark gum which was triturated several times with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-isobutyl-5-phenylisoxazole-3-carboxylate (0.122 g, 0.470 mmol, 30.2% yield) as a clear, colorless oil. The compound had an HPLC ret. time=2.96 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=259.9. 1H NMR (500 MHz, chloroform-d) δ ppm 0.88 (s, 3H), 0.89 (s, 3H), 1.89 (dt, J=13.75, 6.87 Hz, 1H), 2.80 (d, J=7.15 Hz, 2H), 4.00 (s, 3H), 7.45-7.53 (m, 3H), 7.73 (d, J=6.60 Hz, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[C@:12]2([CH2:16][CH2:15][N:14]([C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18])[C:13]2=[O:23])[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl.C(N(C(C)C)CC)(C)C.BrC[CH:42]=[CH:43][CH2:44][OH:45]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:22][O:21][C:19](=[O:20])[CH:17]([N:14]1[CH2:15][CH2:16][C:12]2([N:8]([CH2:6][CH:42]=[CH:43][CH2:44][OH:45])[CH2:9][CH2:10][CH2:11]2)[C:13]1=[O:23])[CH3:18]
Reactant: COC(=O)[C@H](C)N1CC[C@@]2(CCCN2C(=O)OC(C)(C)C)C1=O
Reactant: OCC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)N1CCC2(CCCN2CC=CCO)C1=O

Procedure:
82 mg (0.25 mmol) (S,S)-7-(1-methoxycarbonyl-ethyl)-6-oxo-1,7-diaza-spiro[4.4]nonane-1-carboxylic acid tert-butyl ester are stirred at room temperature for three hours in 1 mL of a 4N HCl dioxane solution, evaporated, then taken up in toluene and evaporated again (twice). The residue is taken up in 2 mL dichloromethane and stirred at room temperature for 65 hours in the presence of 74 mg (0.2 mmol) tetrabutylammonium iodide, 0.035 mL (0.2 mmol) diisopropylethylamine and 30 mg (0.2 mmol) 4-bromo-but-2-en-1-ol. The reaction mixture is extracted with EtOAc and saturated aqueous sodium bicarbonate, the combined organic phases washed with brine, evaporated to dryness and the residue column chromatographed (silica gel, EtOAc/EtOH 9:1) to yield the desired product as a thick liquid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:41]3[CH2:42][CH:43]=[C:38]([C:32]4[C:31]5[C:35](=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=5)[NH:34][CH:33]=4)[CH2:39][CH2:40]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)O3

Procedure:
A solution of 0.41 g (0.1.1 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.71 g (3.3 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 25 mL of DMSO were heated at 75-80° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.090 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 81-82° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1CCCI
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 72.7 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.823 g, 1.92 mmol), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.58 g, 1.92 mmol), and potassium carbonate (0.39 g, 2.88 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as a white solid (0.84 g, 73%); 1H NMR (DMSO-d6); δ0.93-0.96 (m, 1H); 1.14-1.25 (m, 4H); 1.52 (s, 9H); 1.57-1.62 (m, 9H); 1.79 (m, 2H); 2.29-2.36 (m, 4H); 2.63 (m, 3H); 3.82 (t, J=6.8 Hz, 2H); 4.08 (s, 2H); 4.43 (s, 2H); 6.97-7.01 (m, 3H); 7.14 (d, J=6.4 Hz, 1H); 7.44-7.49 (m, 2H); 7.72 (s, 1H); 7.81 (dt, J=2.4 Hz and 6.4 Hz, 1H); 10.8 (s, 1H); MS for C35H47N5O4 m/z 602 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.ON1C(=O)CCC1=O.[NH2:31][CH2:32][CH2:33][SH:34]>O>[C:1]([NH:31][CH2:32][CH2:33][SH:34])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: NCCS
Agent: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCC(=O)NCCS
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Myristoyl chloride (1.0 mmol) was added with vigorous string to ice-cooled dry pyridine (1.0 ml), and followed immediately by N-hydroxysuccinimide (1.5 mmol). The mixture was stirred for 4 h at ambient temperature (˜23° C.). 2-aminoethanethiol free base (1.1 mmol) was added as solid to the mixture and allowed to react for 6 h at ambient temperature, followed by 3 days at 4° C. The product was treated with water (5 ml), stirred for 1 h at ambient and filtered, washing with cold water. The white solid was dissolved in dimethylsulphoxide and reprecipitated with water and then vacuum dried over phosphorous pentoxide. The final yield was 0.21 g (˜70%). Thiol titration using Ellman's reagent indicated that the product contained ˜45% free thiol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[S:20])#[N:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: N#Cc1ccccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminobenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.56 (m, 3H), 7.67 (t, 1H), 7.75-7.76 (d, J=5.2 Hz, 2H), 7.89-7.91 (d, J=7.2 Hz, 2H), 7.98-8.01 (dd, J=1.6 Hz, J=8.2 Hz, 2H), 11.90 (s, 1H), 12.54 (s, 1H). MS 282 (MH+).