Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH2:34](Br)[CH:35]=[CH2:36].Cl>CN(C)C=O.O>[CH2:36]([N:18]1[C:19]2[C:24](=[CH:23][C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])=[CH:21][CH:20]=2)[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:17]1)[CH:35]=[CH2:34]
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Sodium hydride (0.048 g of a 60% dispersion in oil) was added to a stirred solution of methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (0.5 g) in N,N-dimethylformamide (5 ml), under an atmosphere of nitrogen. After 0.5 hr, allyl bromide (0.14 g) was added and stirring continued for 3 hr. The solution was acidified with 1M hydrochloric acid (10 ml), diluted with water (20 ml), extracted with ethyl acetate (twice), and the organic phase was washed with water (4 times), brine, and dried (MgSO4). The solvent was evaporated to give an oil which was purified by flash chromatography, eluting with 2:1:1 hexane:methylene chloride:ethyl acetate, to give methyl E-4[1-allyl-5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl)-3-methoxybenzoate (0.36 g, 66%) as a white foam; partial NMR (250 MHz, DMSO-d6) 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2 H, CH2CH2CH3), 1.99(s, 3H, CCH3), 3.11(m, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.90(s, 3H, OCH3), 4.06(s, 2H, ArCH2Ar'), 4.77(br d, J=5.3 Hz, 2H, NCH2CH:C), 5.00-5.16(m, 2H, olefinic H), 6.0(m, 1H, olefinic H), 7.94(br t, 1H, NHCO).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.[F:23][C:24]1[S:28][C:27]([NH:29][S:30](N2C=CN=C2)(=[O:32])=[O:31])=[N:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([NH:29][C:27]1[S:28][C:24]([F:23])=[CH:25][N:26]=1)(=[O:32])=[O:31])[CH2:18]2
Reactant: O=S(=O)(Nc1ncc(F)s1)n1ccnc1
Reactant: FC(F)(F)c1ccc(Br)c(-c2cccc3c2CCNC3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2cc(C(F)(F)F)ccc2Br)C1
Yield: 38.1 %

Procedure:
A solution of 5-(2-bromo-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate T, 0.200 g, 0.509 mmol), N-(5-fluorothiazol-2-yl)-1H-imidazole-1-sulfonamide (Intermediate N, 0.506 g, 2.037 mmol), and triethylamine (1.420 ml, 10.19 mmol) in 3 mL THF was heated to 80° C. for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1N citric acid. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-bromo-5-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.104 g, 0.194 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])[NH:14][CH:13]=[C:12]2[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CI.[C:26]1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:19])[CH3:20])[N:14]([CH3:26])[CH:13]=[C:12]2[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Cc1c[nH]c2cc(C(C)C)c(OCc3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cc1cn(C)c2cc(C(C)C)c(OCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
5-Benzyloxy-6-isopropyl-3-methyl-1H-indole (0.320 g, 1.15 mmol), KOH (0.264 g, 4.7 mmol), benzyl tributylammonium chloride (0.071 g, 0.230 mmol), and methyl iodide (0.107 mL, 1.72 mmol) were added to 3 mL of toluene. The resulting mixture was stirred for 4 hours at 90° C., cooled to room temperature, poured into water, and extracted with ethyl acetate 2 times. The combined organic layers were washed with water, dried (MgSO4), and evaporated in vacuo to provide a crude oil that was was purified with flash chromatography (ethyl acetate/hexanes 1/9); yield 270 mg of 5-benzyloxy-6-isopropyl-1,3-dimethyl-1H-indole.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][CH3:9].CN(C=O)C.[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([OH:32])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1>O>[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:32][CH2:8][CH3:9])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: CCI
Reactant: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2CCC2)c(C2CC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.44 g) and iodoethane (0.55 mL) were added to a DMF (25 mL) solution of methyl 4-cyclobutyl-5-cyclopropyl-2-hydroxybenzoate (1.3 g) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, followed by extraction with ethyl acetate twice. Combined organic layers were washed with water and saturated saline in this order and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:21])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)=[C:44]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:43]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:21])/[C:13](/[C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)=[C:44]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:43]=1)=[CH:14]/[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCC1
Reactant: Cc1nnnn1-c1ccc(Br)cc1S(C)(=O)=O
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (440 mg, 1.5 mmol) in dry tetrahydrofuran (1 mL). The resulting reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.2 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(4-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (297 mg, 0.94 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was stirred at 40-45° C. over the weekend. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (289 mg, 78%) as an amorphous yellow solid: EI-HRMS Tile calcd for C18H22N4O4S (M+) 390.1362, found 390.1363.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13]C(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCCC(N)C1)(OC(C)(C)C)=O.[NH:45]1[C:49]2=[N:50][CH:51]=[CH:52][C:53]([NH:54][C:55]3[S:56][CH:57]=[CH:58][C:59]=3[C:60]([OH:62])=O)=[C:48]2[CH:47]=[CH:46]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:60]([C:59]2[CH:58]=[CH:57][S:56][C:55]=2[NH:54][C:53]2[CH:52]=[CH:51][N:50]=[C:49]3[NH:45][CH:46]=[CH:47][C:48]=23)=[O:62])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccsc2Nc2ccnc3[nH]ccc23)C1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-BOC-3-aminopiperidine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 428 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br. s.) 11.67 (1H, br. s.) 8.28 (1H, d, J=6.83 Hz) 8.15 (1H, d, J=5.42 Hz) 7.57 (1H, d, J=5.81 Hz) 7.38 (1H, dd, J=3.27, 2.68 Hz) 6.99 (1H, d, J=5.47 Hz) 6.93 (1H, d, J=6.05 Hz) 6.47 (1H, dd, J=3.49, 1.88 Hz) 4.40-4.59 (1H, m, J=12.24, 6.09, 6.09, 5.83 Hz) 3.51-3.64 (1H, m) 3.41 (1H, t, J=7.74 Hz) 3.21 (1H, td, J=9.91, 5.52 Hz) 2.06-2.19 (1H, m) 1.90 (1H, td, J=11.17, 6.61 Hz) 1.41 (9H, br. s.)
Reaction SMILES: [C:1]1([C:7]2(O)[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.S(Cl)([Cl:29])=O>>[Cl:29][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:18]=[N:17][CH:16]=[N:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: OC1(c2ccccc2)c2ccccc2-c2ncncc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1(c2ccccc2)c2ccccc2-c2ncncc21

Procedure:
Five grams of 5-phenyl-5H-indeno[1,2-d]pyrimidin-5-ol were stirred at reflux temperature in 25 ml of thionyl chloride and 100 ml of benzene for 5 hours. The solvents were removed by evaporation and the residue was tritrated with benzene and filtered. The solid was crystallized from diethyl ether to provide 3 g of the desired title product, m.p. 119°-120° C.
Reaction SMILES: C(OC([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15](OC(=O)C(F)(F)F)[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[I:22])=[C:10]([N+:32]([O-:34])=[O:33])[C:9]=1N)=O)(C)(C)C.[OH2:36]>C1COCC1>[C:11]([O:36][C:17](=[O:23])[NH:18][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[I:22])=[C:10]([N+:32]([O-:34])=[O:33])[CH:9]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: O
Reactant: COc1nccc(I)c1C(Cc1ccc(C(=O)OC(C)(C)C)c(N)c1[N+](=O)[O-])OC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1nccc(I)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of crude trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.88 g, 3.08 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.33 g, 8.74 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 hours. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (850 mg, 55%) as an oil. MH+ 497.9.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH2:16]>>[C:8]([OH:14])(=[O:15])[C@H:9]([CH3:10])[OH:16].[C:8]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O
Agent: O=C1CCCCCO1
Solvent: Cc1ccccc1
Product: C[C@H](O)C(=O)O
Temperature: 70 °C

Procedure:
There were weighed 30 mg of P(LLA-CL) (Mn=50,000; mole ratio of L-LA to CL: 6/4), 30 mg of Novozym 435, 1 ml of toluene, and water, the amount thereof being 10% by mass of P(LLA-CL), and then they were put into a small pressure-resistant test tube with a screw cap, in which a magnetic stirrer was put. The tube was purged with argon, and then the solution was stirred at 70° C. for a day. Next, thereto was added a small amount of chloroform, and then the immobilized lipase which was insoluble was filtrated off. An evaporator was used to concentrate the solvent from the filtrate under reduced pressure, so as to yield an oligomer mixture including, as main components, cyclic oligomers, wherein the polymerization degree thereof was 4 to 10, at a conversion ratio of about 100%. The composition ratio between L-LA and CL in the oligomers was distributed substantially in accordance with the composition ratio therebetween in the charged polymer. FIG. 8 shows the MALDI-TOF MS (Na30 adduct) of the depolymerization product. In FIG. 8, LA represents lactic units in the oligomers, and CL represents caprolactone units in the oligomers. The number at the side of LA or CL represents the number of the units thereof.
Reaction SMILES: [OH-].[Na+].CCCCCC.[OH:9][CH2:10][C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:9][CH2:10][C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1
Reactant: BrCCCCCCBr
Reactant: CC1(CO)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(COCCCCCCBr)COC1

Procedure:
A 50% aqueous sodium hydroxide solution (65.0 g), tetrabutylammonium bromide (0.8 g, 2.5 mmol) and hexane (200 ml) were cooled with stirring in an ice bath. Compound 29 (16.32 g, 0.16 mol) and 1,6-dibromohexane (30) (100.00 g, 0.41 mol) were added and the reaction was left stirring until it reached room temperature; the reaction mixture was then heated under reflux for 3 h and then cooled to below 5° C. Water (300 ml) was added and the organic layer was retained and dried (Na2SO4). The drying agent was filtered off and the solvent was removed in vacuo. The resulting oil was purified by column chromatography [dichloromethane:hexane (1:6), to remove excess dibromohexane, dichloromethane, to isolate the product and then ethyl acetate to obtain the doubly reacted product) on silica.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:12]1[CH:13]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:18][N:17]=[C:1]2[CH3:2]
Reactant: NN
Reactant: COC(=O)c1ccc(OC)cc1C(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)[nH]nc(C)c2c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a solution of methyl 2-acetyl-4-methoxybenzoate (5) (2.47 g, 11.86 mmol) in methanol (14.5 mL) is added hydrazine monohydrate (1.78 g, 35.60 mmol). The mixture is stirred at 95° C. under argon for 6 h, the cooled to room temperature, diluted with H2O (50 mL), and extracted with CHCl3 (2×100 mL) and ethyl acetate (100 mL, 2×50 mL, and 2×40 mL). The extracts were washed (brine) and dried. After solvent removal at reduced pressure, the residue is suspended in ethyl acetate (30 mL), heated, cooled, and filtered to give 2.13 g (94%) of 6 as a white solid, mp 252-254° C. IR 3298, 2941, 1732, 1055 cm−1; 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 4.00 (s, 3H, CH3O), 7.12 (d, J=1.6 Hz, 1H, 5-PhthH), 7.35 (dd, J=5.6, 1.6 Hz, 1H, 7-PhthH), 8.41 (d, J=5.6 Hz, 1H, 8-PhthH), 10.12 ppm (s, 1H, NH).
Reaction SMILES: [H-].[Na+].[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].Br[C:12]1[S:13][C:14]([Br:17])=[CH:15][N:16]=1.Cl>CN(C)C=O.[Cl-].[Na+].O.O>[Br:17][C:14]1[S:13][C:12]2=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:4][N:16]2[CH:15]=1
Reactant: Brc1cnc(Br)s1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncn2cc(Br)sc12
Temperature: 1 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A suspension of sodium hydride (60% in mineral oil, 13.6 g, 368 mmol) in N,N-dimethylformamide (160 ml) was cooled to −10° C. or below under a nitrogen atmosphere. Ethyl isocyanoacetate (36.2 g, 320 mmol) was gradually added dropwise to the cooled suspension, and the mixture was stirred at −3 to 5° C. for 2 hr. This solution was cooled to −20° C. or below and was added dropwise to a solution of 2,5-dibromothiazole (38.8 g, 160 mmol) in N,N-dimethylformamide over a period of about 20 min, and the mixture was stirred at −5 to −20° C. for 2 hr. Water (8 ml) was added thereto to stop the reaction, and the reaction solution was added to 15 wt % brine (960 ml) under ice cooling. Subsequently, the mixture was adjusted to pH 6 to 7 by the addition of 1 M hydrochloric acid. Subsequently, common salt (102 g) was added thereto at the same temperature, and the mixture was stirred overnight. The resultant precipitate was collected by filtration, was washed with water (136 ml), and was dried under the reduced pressure to give ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (40.4 g, yield 91.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl.[Cu]I>[C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8])#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C#CCCCCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 72.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (425 mg, 1.1 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)3Cl2 (20 mg), CuI (catalytic amount) and triethylamine (0.5 mL) in methylene chloride (8 mL) was heated at reflux for 16 hours. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 100:6-100:15 to afford to give the title compound (335 mg, 72% yield). MS (DCI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.48 (s, 9H), 1.49 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.00 (m, 2H), 2.48 (m, 2H), 3.34 (m, 2H), 3.90 (m, 1H), 4.12 (m, 2H), 7.30 (br s, 1H), 7.98 (m, 1H).
Reaction SMILES: [CH:1]12[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]3[O:16][N:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=3)=[O:9])[CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)C(C)C)(C)C.Cl[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:42])[CH:38]=2)[N:33]=1>FC(F)(F)C([O-])=O>[F:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([N:3]1[CH2:4][CH:5]3[CH:1]([CH:6]3[NH:7][C:8]([O:10][CH2:11][C:12]3[O:16][N:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=3)=[O:9])[CH2:2]1)[CH:41]=[CH:40]2
Reactant: CCOC(=O)c1cc(COC(=O)NC2C3CNCC32)on1
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Yield: 36.5 %

Procedure:
Starting from 1.55 g (3.79 mmol) of ethyl 5-{[(3-azabicyclo[3.1.0]hex-6-ylcarbamoyl)oxy]methyl}isoxazole-3-carboxylate in trifluoroacetate form, 1.98 ml (11.37 mmol) of N,N-diisopropylethylamine, and 0.68 g (3.79 mmol) of 2-chloro-6-fluoro-quinoline, and eluting with a 99/1 to 98/2 mixture of dichloromethane and methanol, 0.61 g (36%) of product is obtained in the form of an orange oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[CH:10]=[C:11]([C:15]([O:17]CC)=[O:16])[NH:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2c(=O)cc(C(=O)OCC)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ccc2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 66.9 %

Procedure:
Treatment of ethyl 7-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.5 g, Example 5b) with sodium hydroxide (0.326 g), as described in Example 1c, gave 7-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.3 g), mp 247°-250° C. (decomp), δ (360 MHz, DMSO-d6) 0.91 (3H, t, CH3), 1.32 (2H, m, CH2CH3), 1.60 (2H, m, CH2CH2CH2), 2.69 (2H, t, CH2CH2CH2CH3), 6.60 (1H, s, 3-H), 7.20 (1H dd, 6-H), 7.75 (1H, s, 8-H) and 7.98 (1H, d. 5-H), (Found: C, 66.44; H, 6.68; N, 5.62%. C14H15NO3. 0.5H2O requires C, 66.13; H, 6.34; N, 5.51%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:19]([N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH2:20][CH2:21][CH3:22].O>FC(F)(F)C(O)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[CH:32]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:35][CH:34]=1)[OH:33])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 32.9 %

Procedure:
5.34 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.02 mol, 1 eq) is dissolved in 40 mL of trifluoroacetic acid and 8.7 g of 4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.03 mol, 1.5 eq) is added to the solution. The reaction mixture is heated to 40° C. and stirred for 10 hours at this temperature. The mixture is cooled to room temperature and 100 mL of water is added. After 15 min of stirring, the product is extracted with 2×50 mL of dichloromethane. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent:toluene:MTBE:methanol=50:40:10) to obtain 3.68 g of compound (VI) (33%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=1.C(=O)([O-])[OH:22].[Na+]>Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]([NH2:17])=[O:22])[N:12]=1
Reactant: Cc1ccncc1-c1nc(-c2cccc(C#N)c2)cs1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1ccncc1-c1nc(-c2cccc(C(N)=O)c2)cs1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
3-{2-[4-Methylpyridin-3-yl]-1,3-thiazol-4-yl}benzonitrile (100 mg) was dissolved in conc. hydrochloric acid (4 ml) and the mixture was stirred at 40° C. for 16 hrs. The reaction mixture was added to aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate-methanol to give the title compound (72 mg) as pale-yellow powder crystals.