Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH:3]([CH2:12][OH:13])[CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[C:19]([CH3:24])[C:18]=1[CH3:25]>CS(C)=O>[CH3:24][C:19]1[C:18]([CH3:25])=[C:17]([O:13][CH2:12][CH:3]2[CH2:4][O:5][C:6]3([CH2:7][CH2:8][O:9][CH2:10][CH2:11]3)[O:1][CH2:2]2)[CH:22]=[CH:21][N+:20]=1[O-:23]
Reactant: OCC1COC2(CCOCC2)OC1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2COC3(CCOCC3)OC2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a dimethylsulfoxide (30 ml) solution of the 1,5,9-trioxaspiro[5.5]undec-3-ylmethanol (3.80 g, 20.2 mmol) obtained in the step (10a), sodium hydride, in oil (770 mg, 19.3 mmol as the content was regarded as 60%) was added at room temperature. The mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (2.6 g, 16.5 mmol) was added, the mixture was stirred at 60° C. for 2.5 hours. After cooled to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: heptane, heptane/ethyl acetate=1/1, 1/3, ethyl acetate, ethyl acetate/methanol=10/1) to obtain the title compound (3.38 g, yield: 66.2%) as a pale yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH:7]=1)[CH2:13][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(Cl)cc(CBr)c1
Yield: 66.4 %

Procedure:
A solution of 3-chloro-5-(trichlorovinyl)toluene (7.56 g) and dibenzoyl peroxide (0.5 g) in 250 ml of benzene was heated at reflux. N-Bromosuccinimide (6.04 g) was added in portions and the reaction mixture stirred at reflux for 3 hours. The mixture was then evaporated and the residue titurated with hexane (200 ml). The precipitated succinimide was removed by filtration and washed with hexane (2×25 ml). The hexane was concentrated and the residual oil (10.1 g) chromatographed on silica with petroleum ether as eluant. The column afforded 1.39 g of starting toluene, 1.18 g of dibromide, and 6.57 g of the desired benzyl bromide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=O)C.[OH-].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:11]1
Reactant: CC(=O)OCCCCCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-(3-piperidinyl)-1-pentanol acetate (7.37 g, 31.9 mmol) in THF (50 ml) was added a solution of potassium hydroxide (5.36 g, 96 mmol) in water (30 ml) and the mixture was stirred in an ice-water bath. To this was added a solution of benzyl chloroformate (5.00 ml, 35.0 mmol) in THF (25 mL) dropwise over a period of 40 mins. After stirring in the cold bath for 30 mins., the mixture was allowed to warm to rt and stirred for 5 hours. The organic solvent was removed by evaporation in vacuo and the aqueous phase was diluted further with water (75 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts was washed with saturated NaCl solution (100 ml), separated, dried (Na2SO4), filtered the solvent evaporated in vacuo and the residue was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 2×100 g cartridges using a gradient of 0-100% ethyl acetate in cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (6.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:6][CH:5]=1)([O-])=O.O.[ClH:21]>C(O)C.[Pd]>[ClH:21].[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:8][CH:9]=1
Reactant: N[C@@H](CCCCNc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCCC[C@H](N)C(=O)O)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
2 g (7.48 mmol) of Nε-(4-nitrophenyl)-L-lysine are dissolved in 30 ml of ethanol, 9 ml of water and 5.2 ml (3.5 eq) of 5N hydrochloric acid in a 250 ml glass reactor (Paar apparatus). 2 g of palladium-on-charcoal with a moisture content of 50% and an active content of 10% are then introduced. The mixture is hydrogenated under a pressure of approximately 2.76×105 Pa for 1 hour and at a temperature of 10° C. After filtering through celite, the filtrate is evaporated. The purplish oily residue is taken up in ethanol and precipitated from a large volume of acetone with stirring. After filtration, 2.6 g of a white crystalline powder are obtained, i.e. a final yield of 99%.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:23])([CH2:20][CH2:21][CH3:22])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:24](O)C>[C].[Pd]>[OH:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]([CH3:24])[CH2:14][C:15]([CH2:20][CH2:21][CH3:22])([CH3:23])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCCC1(C)C=Cc2ccc(OCc3ccccc3)c(C)c2O1
Reactant: CCO
Agent: [Pd]
Product: CCCC1(C)CC(C)c2ccc(O)c(C)c2O1
Yield: 84.2 %

Procedure:
6.5 Grams of the compound obtained in (3) were subjected to catalytic reduction with 0.5 g. of 10% palladium-carbon and 50 ml of ethanol under atmospheric pressure. The subject compound in amount of 4.0 g. (yield: 84.2%) was thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[F:26].[Li+].[OH-]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:27][CH2:28][CH3:29])[C:3]([OH:30])=[O:2])=[C:7]([F:26])[CH:8]=3)[N:15]=2)=[CH:20][CH:21]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1F)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1F)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-fluoro-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-fluoro-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].C(=O)([O-])O.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>CO>[CH3:2][O:3][C:4]([CH:5]1[CH2:7][S:8][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6]1)=[O:9]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CSC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 76.3 %

Procedure:
1.72 g of L-cysteine methylester hydrochloride was neutralized by addition of 0.84 g of sodium hydrogen carbonate. The resulting ester was dissolved in 2 ml of methanol, and to this solution was added a solution of 0.94 g of benzaldehyde in 3 ml of methanol. The mixture was then stirred at room temperature for 40 hours under a nitrogen atmosphere. Ether was added to the reaction mixture, and then the mixture was extracted with diluted hydrochloric acid. The extract was neutralized by addition of sodium hydrogen carbonate and then extracted with ether. The organic portion was dried over anhydrous sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained 1.51 g of 4-methoxycarbonyl-2-phenylthiazolidine as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][NH:16][C:17]([NH2:19])=[O:18].C(OC(=O)C)(=O)C>CCOCC>[C:1]([CH2:3][C:4]([N:15]([C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:14])[NH:16][C:17]([NH2:19])=[O:18])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Cc1cccc(C)c1NNC(N)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: Cc1cccc(C)c1N(NC(N)=O)C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 mole of cyanoacetic acid, 1 mole of 1-(2,6-dimethylphenyl)semicarbazide and 300 ml of acetic anhydride is heated to 80° for 2 hours. The mixture is cooled to RT, 50 ml of ether is added and it is stirred at RT overnight. The reaction mixture is filtered, washed with ether (3X) and dried to give N-(2-cyanoacetyl)-1-(2,6-dimethylphenyl)semicarbazide.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10]1)C1C=CC=CC=1.CC(=O)OCC>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10]1
Reactant: CC(C)(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)[C@H]1CC[C@H](N)C1
Reaction time: 48 h
Yield: 75.1 %

Procedure:
A mixture of 2-(trans-3-(dibenzylamino)cyclopentyl)propan-2-ol (3 g, 9.3 mmol) and Pd(OH)2 (900 mg) in EtOH (30 mL) was hydrogenated under 50 psi of H2 for 48 h at room temperature. TLC (PE:EA=5:1) showed the reaction was complete. The mixture was filtered and concentrated in vacuo to give crude 2-(trans-3-aminocyclopentyl)propan-2-ol (1 g, 77%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])[C:25]([C:27]([OH:29])=O)=[CH:26][C:19]=2[N:18]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:27]([C:25]2[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])=[CH:23][C:20]3[N:21]([CH3:22])[C:17]([NH:16][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:18][C:19]=3[CH:26]=2)=[O:29])[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared from 2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 3-chloro-4-fluoro-aniline with HATU and TEA in THF in analogy to example 3e and purified via flash chromatography.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC(C)N1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)CCC2CCC(=O)OCc2ccccc2)cc1
Temperature: 55 °C

Procedure:
A solution of 50 g of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester in 800 ml of tetrahydrofuran is treated with 28.3 g of 4-methoxybenzoyl chloride. The mixture is heated to 55° C. and a solution of 20 g of triethylamine in 400 ml of tetrahydrofuran is added dropwise over a two hour period. The mixture is stirred and heated at 55° C. for 16 hours. The warm mixture is filtered through filter aid to remove triethylamine hydrochloride and concentrated at reduced pressure. Chromatography over silica using a Waters Prep 500 HPLC apparatus yielded 1-(4-Methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid benzyl ester mp 80°-83° C. After concentration and crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:27][C@H:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:18]2[NH:17][C:12]2[C:11]([CH2:28][CH3:29])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)=[O:38])=[CH:40][CH:41]=1)([O-:32])=[O:31]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (321 mg, 0.75 mmol), 4-nitrobenzoic acid (552 mg, 3.3 mmol), and triphenylphosphine (964 mg, 3.7 mmol) in benzene (19 mL) was purged with nitrogen and cooled to 0° C. The resulting yellow suspension was treated with diethylazodicarboxylate (0.58 mL, 3.7 mmol) becoming lighter in color with gradual warming to RT. After 18 hours, the volatiles were removed under reduced pressure with the resulting crude residue being absorbed on 6 g silica gel and purified by Biotage MPLC (40 g column, 15% ethyl acetate/heptane) to afford the title compound as a light yellow solid. IR (diffuse reflectance) 1725, 1568, 1550, 1527, 1498, 1467, 1392, 1372, 1349, 1320, 1273, 1119, 1103, 836, 719 cm−1; OAMS supporting ions at: ESI+ 576.8; MS (CI) m/z 577 (MH+); HRMS (FAB) calcd for C30H26CL2N4O4+H1 577.1409, found 577.1417.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.Cl.ClC1C=C2C(=CC=1)C=C(S(N1CC[N:51]([C:54](C3SC4C(C=NO)NC(N)CC=4N=3)=[O:55])CC1)(=O)=O)C=C2>>[C:54]([CH:29]1[NH:28][CH2:27][C:26]2[S:25][C:24]([C:22]([N:19]3[CH2:18][CH2:17][N:16]([S:13]([C:8]4[CH:7]=[CH:6][C:5]5[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=5)[CH:9]=4)(=[O:14])=[O:15])[CH2:21][CH2:20]3)=[O:23])=[N:32][C:31]=2[CH2:30]1)(=[O:55])[NH2:51]
Reactant: NC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2C(C=NO)N1
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Product: NC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1

Procedure:
In a similar manner to Referential Example 33 and Example B-24 by using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride as a starting material, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride and also 1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine were obtained. 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)#[CH:23]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH2:23][CH2:22][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(CCc3ccc(F)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.350 g (0.809 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 47 mg (0.040 mmole) tetrakis(triphenylphosphine)palladium(0), 15 mg (0.081 mmole) copper (I) iodide, 5mL degassed toluene, 0.338 mL (2.43 mmole) degassed TEA, and 0.139 mL (1.21 mmole)1-ethynyl-4-fluorobenzene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford a crystalline solid. MS (ES+) 425 (M+1, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>>[Cl:8][C:9]1[N:14]=[C:13]([S:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Sc1ncccn1
Product: Clc1nccc(Sc2ncccn2)n1
Yield: 93.4 %

Procedure:
In a procedure analogous to Example 3, reaction of pyrimidine-2-thiol (415 mg, 3.70 mmol) and 2,4-dichloropyrimidine (500 mg, 3.36 mmol) furnished the product (705 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:16]([F:19])([F:17])[F:18])[CH:6]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2C(F)(F)F)cn1
Yield: 101.1 %

Procedure:
4-Methyl-1-(2-(trifluoromethyl)-4-nitrophenyl)-1 H-imidazole (1.1 g, 4.1 mmol) was suspended in 50 mL of anhydrous ethanol. The mixture was hydrogenated with 0.11 g of 10% Pd—C at 40 psi for 3 hrs. Then Pd—C was removed by filtration. The filtrate was evaporated to give the title compound 1.0 g as a yellow solid (102.0%). 1H NMR (300 MHz, CDCl3) δ: 7.42 (1 H, s), 7.08-7.11 (1 H, d, J=8.4 Hz), 6.99 (1 H, d, J=2.4 Hz), 6.80-6.84 (1 H, dd, J=2.1 and 8.4 Hz), 6.74 (1 H, s), 4.14 (2 H, brs), 2.27 (3 H, s). LCMS: m/z [M+H]+ 242.0957.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13].O1CCCC1.O.[OH-].[Li+]>O>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[CH2:5][CH:4]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=2[F:26])=[CH:16][C:15]1=[O:28])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A mixture of 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (56 mg, 0.13 mmol) in a 1:1 solution of tetrahydrofuran:water (4 mL) was treated with lithium hydroxide monohydrate (11 mg, 0.26 mmol). The mixture was then stirred for 1 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with 1N aqueous hydrochloric acid until the pH was acidic and then extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (40 mg, 74%) as a tan solid: HR-ES-MS m/z calculated for C19H13NO4Cl2F2 [M+H]+ 428.0263, observed 428.0263.
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]#[CH:23]>C(O)C.O>[CH2:23]([O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[C:4]2[CH2:3][C@H:2]([OH:1])[CH3:14])[C:22]#[CH:21]
Reactant: C[C@@H](O)Cc1n[nH]c2ccc(O)cc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Temperature: 75 °C
Yield: 69.5 %

Procedure:
To a stirred mixture of the product from Step A (1.50 g, 7.81 mmol) in a mixture of ethanol in water (50 mL/10 mL) was added potassium carbonate (1.62 g, 11.7 mmol) and propargyl bromide (80% in toluene, 1.74 g, 1.30 mL, 11.7 mmol). The mixture was heated at 75° C. for 2 hours under nitrogen, evaporated to dryness, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 25% to 95% ethyl acetate in hexane) gave an oil (1.25 g, 69%): LC/MS (+APCI) m/z 231 (M+H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]2)([OH:3])=O.ClC(OCC(C)C)=O.[CH:28]1([CH2:34][NH:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:28]1([CH2:34][N:35]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3)=[O:3])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: C1CCC(CNCCN2CCCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.00 Grams of 6-(4-carboxybutoxy)carbostyril is suspended in 60 ml of chloroform. Thereto is added 1.40 g of DBu. The mixture is stirred for 30 minutes at room temperature. 1.05 g of isobutyl chloroformate is added with ice cooling. Then, there is dropwise added at room temperature 1.61 g of N-(cyclohexylmethyl)-N-[2-(1-pyrrolidinyl)ethyl]amine. The mixture is stirred for 3 hours at room temperature. Then, a 0.5N aqueous sodium hydroxide solution is added, and the mixture is stirred for 10 minutes. Extraction with chloroform is effected. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The resulting residue is purified by a silica gel column chromatography (chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 1.00 g of 6-[4-{N-cyclohexylmethyl-N-[2-(1-pyrrolidinyl)ethyl]aminocarbonyl}butoxy]carbostyril.