Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:20])[CH2:18][CH3:19])[C:14](=[O:21])[N:13]([CH2:22][CH2:23][N:24](C(OCC3C=CC=CC=3)=O)[CH3:25])[C:12]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:20])[CH2:18][CH3:19])[C:14](=[O:21])[N:13]([CH2:22][CH2:23][NH:24][CH3:25])[C:12]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CCC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccc(Cl)cc2S[C@H]1c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCC(=O)O[C@H]1C(=O)N(CCNC)c2ccc(Cl)cc2S[C@H]1c1ccc(OC)cc1
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 985 mg of (-)-cis-2-(4-methoxyphenyl)-3-propionyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.6 ml of 25% hydrogen bromide-acetic acid and 5 ml of benzene is stirred for 5 hours under ice-cooling. Then, the mixture is evaporated at room temperature to remove benzene. Ether is added to the residue, and the precipitates are collected by filtration and washed with ether. Water is added to said precipitates, and the aqueous mixture is neutralized with potassium carbonate and extracted with ethyl acetate. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. 660 mg of (-)-cis-2-(4-methoxyphenyl)-3-propionyloxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as caramel.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]>ClCC(Cl)(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:9]
Reactant: COc1ccccc1OC
Reactant: Cc1cccc(C(=O)Cl)n1
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc(C)n2)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled, stirred suspension of 6-methylpicolinic acid chloride and 2 equivalents of aluminum chloride in tetrachloroethane is added slowly an equivalent amount of 1,2-dimethoxybenzene. The reaction mixture is allowed to come to room temperature overnight, then decomposed over cracked ice. Extractive workup followed by chromatography of the organic residue gives the desired ketone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]1[NH:33][C:32](=[O:34])[CH2:31][CH2:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH:29]([CH3:28])[CH2:30][CH2:31][C:32]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 33.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (864 mg) described in Preparation Example 112 and 5-methylpyrrolidin-2-one (258 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (304 mg) was obtained.
Reaction SMILES: CO[C:3](=[O:14])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[NH2:5].[CH3:15][N:16]=[C:17]=[S:18]>>[C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:17](=[S:18])[N:16]([CH3:15])[C:3]1=[O:14])(=[O:13])[CH3:12]
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(C)=O
Product: CC(=O)NCCCCC1NC(=S)N(C)C1=O

Procedure:
Using an analogous procedure to Example 1 Nε-acetyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.CN(C)C(N(C)C)=N.C(O[CH:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:27]([N+]([O-])=O)[CH3:28])(=O)C.O>O1CCCC1.C(O)(C)C>[CH3:28][C:27]1[C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[NH:11][CH:12]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)OC(c1ccccc1)C(C)[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2[nH]cc(C)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a solution of p-toluenesulfonylmethyl isocyanide (6.1 g) and 1,1,3,3-tetramethylguanidine (8.3 mL) in tetrahydrofuran (18 mL) and isopropyl alcohol (18 mL) was added dropwise a solution of 2-nitro-1-phenylpropyl acetate (7.0 g) in tetrahydrofuran (3 mL) and isopropyl alcohol (3 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (yield 6.1 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>[Pd].CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)/C=C/c1c(C#CCCCCOC2CCCCO2)cccc1C#CCCCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC
Yield: 97 %

Procedure:
Rac-(E)-6-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-5-hexynoic acid methyl ester from the preceding example was catalytically hydrogenated over 10% palladium on carbon, in methanol, at room temperature and 1 atmosphere. The title compound was obtained, in 97% yield, as a pale-yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.[OH-].[Na+].O.[SH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>CCO>[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:12]=1
Reactant: COC(=O)CCS
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazole hydrochloride (4.6 g.) in EtOH (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8 g. in 15 ml. of water) over 10 minutes. The resulting solution was allowed to reach room temperature and was stirred for 1 hour. It was then poured into water and the precipitate filtered and crystallised from EtOH to give methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (1.93 g), m.p. 96°-98°.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[C:7]([C:8]2[N:12]([S:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:37]=3)(=[O:44])=[O:43])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2cccnc2F)c1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
To a solution of 5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (200 mg) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 84 mg) at room temperature and the mixture was stirred for 10 min. 15-Crown-5 (464 mg) was added dropwise, and the mixture was stirred for 5 min. 3-(Methylsulfonyl)benzenesulfonyl chloride (402 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) and crystallized from diethyl ether to give the title compound as colorless crystals (yield 280 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:6]1[CH:7]=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:31]
Reactant: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Product: COc1ccc(Cl)cc1C(=O)N(CCCC(=O)O)c1ccc(OC)c(-c2ccccc2)c1
Yield: 70 %

Procedure:
Analogously to Example 59, reacting 7.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate with 4.6 g of 5-chloro-2-methoxybenzoyl chloride, followed by saponification of the intermediate product, yields 7.1 g (70.1% of theory) of 4-[5-chloro-2-methoxy-N-(6-methoxybiphenyl-3-yl)benzamido]-butyric acid, MP 155° to 156°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[O:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[O:34][CH:27]([CH2:33][CH2:32]1)[CH2:28][N:29]([C:2]1[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]3[CH2:24][OH:25])[N:3]=1)[CH2:30]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](OCC)(=[O:16])[CH2:10][C:11](OCC)=[O:12]>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:9]([OH:16])=[CH:10][C:11](=[O:12])[NH:1]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc(N)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1ccc2c(O)cc(=O)[nH]c2n1
Reaction time: 1 h

Procedure:
The procedure used was a modification of that by Lappin et al. [G. A. Lappin, Q. R. Petersen and C. E. Wheeler, J. Org. Chem. 15, 377 (1950)]. 2,6-Diaminopyridine (10.9 g, 0.1 mole) and 16.0 g (0.1 mole) of diethyl malonate in 250 ml of diphenyl ether were heated with stirring under an air condenser at 170°-180° for 1 hr. Then the temperature was slowly increased to 245°. The total heating time from room temperature to final temperature was 4.5 hr. Off-white solid began to separate soon after 180° was reached. The slurry was cooled, diluted with 100 ml of benzene, filtered, and the solid product washed several times with benzene; 17.7 g (100%) after drying. The experiment was also readily performed on a 0.4-mole scale.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]([OH:9])[CH2:7][CH3:8])[CH3:2].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:9][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCOCCC(O)CC
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOCCC(CC)OCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 1-ethoxy-3-pentanol (1.32 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.0 mL, 9.5 mmol). The reaction mixture is stirred at rt for 2 h. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:3) gives 660 mg the product 487.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>[Pd].C(OCC)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)/C=C/c1cc(F)cc(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1cc(F)cc(F)c1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To palladium on activated charcoal (10 wt %, 2.5 g) was added a solution of (E)-3-(3,5-difluorophenyl)acrylic acid (25 g) in a mixture of ethyl acetate (100 mL) and ethyl alcohol (400 mL). The mixture was put on hydrogenator on 50 psi for 6 h. The catalyst was filtered and the solvent was removed to give 25.0 g the title compound (99% yield): 1H NMR (CDCl3, 500 MHz) δ 2.67 (2H, t, J=10 Hz), 2.93 (2H, t, J=10 Hz), 6.65 (1H, m), 6.72 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:20]([O-:23])(=[O:22])[CH3:21].[NH2:24][N+:25]1[CH:29]=[CH:28][N:27]([NH2:30])[C:26]=1[CH2:31][CH3:32]>C(O)(=O)C.C(O)C>[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[N:30][N+:27]3[CH:28]=[CH:29][NH:25][C:26]=3[CH2:31][CH3:32])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCc1n(N)cc[n+]1N
Reactant: CCOC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)N1CCN(c2ccc(C=N[n+]3cc[nH]c3CC)cc2)CC1
Reaction time: 18 h

Procedure:
1.95 g (7.4 mmol) of p-[4-(ethoxycarbonyl)-1-piperazinyl]benzaldehyde are added to a solution of 0.69 g (3.7 mmol) of 1,3-diamino-2-ethyl-imidazolium acetate in 10 ml of glacial acetic acid, the mixture is left to stand at room temperature for 18 hours, then diluted with 30 ml of ethanol and the product is crystallized out by the addition of ether. There is obtained 1,3-bis[[[p-(4-(ethoxycarbonyl)-1-piperazinyl]benzylidene]amino]-2-ethyl-imidazolium acetate diacetate of melting point 187°-188°.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17]>C(Cl)Cl.O>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:3][CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To the stirred solution of piperidin-4-one hydrochloride (2.0 g, 14.7 mmol) in DCM (60 mL) cooled at 0° C., was added triethylamine (5.15 mL, 36.75 mmol) and ethylchloroformate (1.59 mL, 16.6 mml). The reaction mixture was stirred at room temperature for 2 hours before being diluted with water. The two layers were separated, the organic layer was dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 4-oxo-piperidine-1-carboxylate (3.14 grams).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>COCCOC>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:26])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C1CCCC1C(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)C1CCCC1C(=S)N2

Procedure:
8-Cyano-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (70 mg, 0.33 mmol) is heated to 80° C. with Lawesson's reagent (146 mg, 0.36 mmol) for 2 hours in DME (20 ml). The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 50 mg (66%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Yield: 105.5 %

Procedure:
A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.35 g, 1.2 mmol) (as prepared in the previous step) in methanol was hydrogenated over 10% Pd/C at 20 psi for 1 h. The solution was filtered and concentrated to give 0.35 g (100%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C16H24N2O2, 277.2 (M+H), found 277.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H].C(OCC)(=O)C.C(O)C.N>C(O)C.ClCCl.[Pd]>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CNc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CNc1ncc(C(=O)OC)cc1N

Procedure:
To a solution of 3.1 g (15 mMol) of methyl 6-methylamino-5-nitro-nicotinate in 100 ml of ethanol/dichloromethane (3:1) was added 1 g of palladium on charcoal (10%) and the resulting suspension was hydrogenated at room temperature under 5 bar of hydrogen pressure for 1.5 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The crude oily product obtained was further reacted directly. Yield: 2.4 g (92% of theory), Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:40][CH2:39][CH2:37][OH:38])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCO)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-{[4-(methylsulfonyl)phenyl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1 H), 7.81 (d, J=8.2 Hz, 2 H), 7.19 (d, J=8.1 Hz, 2 H), 7.05 (s, 1 H), 6.98-6.95 (m, 4 H), 5.41 (br, 2 H), 4.00 (s, 2 H), 3.78 (t, J=5.2 Hz, 2 H), 3.60 (m, 2 H), 3.01 (s, 3 H); HRMS C26H24FN3O6S (M+H)+ calcd 526.1370, found 526.1434.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([S:8][C:9]1[S:13][C:12]([NH:14][C:15]([N:17]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[O:16])=[N:11][CH:10]=1)([CH3:7])[CH3:6])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH:29]1([CH2:28][N:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[C:15](=[O:16])[NH:14][C:12]2[S:13][C:9]([S:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[CH:10][N:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CC(C)(Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1)C(=O)O

Procedure:
The title compound was prepared via 2-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:38])([F:37])[F:36])[CH2:3][CH2:2]1.[C:39](Cl)(=[O:41])[CH3:40].CCN(CC)CC.[Li+].[OH-]>CC#N.O>[C:39]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:36])([F:37])[F:38])[CH2:3][CH2:2]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCC(Oc2ccc(N(CC=Cc3cc(C(=N)N)ccc3O)C(=O)CCC(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine (400 mg) in 100 mL CH3CN was added acetyl chloride (500 mg) and Et3N (1.28 g) at ambient temperature. The resulting solution was stirred at ambient temperature for 2 hours. LiOH (500 mg) in water (1.0 mL) was then added to the reaction mixture and the resulting reaction mixture was stirred at ambient temperature for 2 hours. Acidification with trifluoroacetic acid, concentration, purification on HPLC (H2O/CH3CN, gradient) and freeze-drying afforded 4-(N′-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine.