Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=[CH:45][C:46](N2CCSC2)=[O:47])[CH:30]=[C:31]([O:40][CH3:41])[C:32]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]>CN(C)C=O>[CH3:41][O:40][C:31]1[CH:30]=[C:29]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH3:8])[CH2:17][CH2:16]2)=[O:47])[CH:28]=[C:27]([O:26][CH3:25])[C:32]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCSC2)cc1OC
Reactant: CC(OCCN1CCNCC1)(c1ccccc1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1OC
Yield: 60.7 %

Procedure:
To a solution of 527 mg (1.53 mmol) of N-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine in dry dimethylformamide (10 ml) was added, under argon atmosphere, 760 mg (1.73 mmol) of N-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine, and the mixture was allowed to react at room temperature for 67 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100:1), to give 618 mg (0.929 mmol) of N-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:6].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:6]
Reactant: C1CCNC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, brown gum, MS: m/e=403.4 [(M+H, was prepared in accordance with the general method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclopentyl)-4-trifluoromethyl-benzamide (intermediate M) and pyrrolidine. The cis- and trans-isomer could be separated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:23])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:27])([CH3:26])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.C(Cl)Cl.B(Br)(Br)Br>>[OH:21][C:19]1[CH:18]=[C:17]2[C:4]([C@H:5]3[C@H:14]([CH2:15][S:16]2(=[O:23])=[O:24])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:26])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]3)=[C:3]([O:2][CH3:1])[CH:20]=1
Reactant: COc1cc(OC)c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
To a solution of (1R,10S,11S,16S)-3,5-dimethoxy-11,15,15-trimethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (23) (7.6 g, 18.7 mmol) in CH2Cl2 (250 mL) BBr3 (1 M in CH2Cl2 18.7 mL, 18.7 mmol) was added dropwise at room temperature under N2. The mixture was stirred at room temperature for 18 h. Additional BBr3 (1 M in CH2Cl2 18.7 mL, 18.7 mmol) was added to the reaction and stirring continued for another 6 h. The mixture was poured onto crushed ice and the organic layer was separated and concentrated to dryness. The residue was purified by flash chromatography on silica gel (Hexanes/EtOAc, 3:1) to yield (1R,10S,11S,16S)-5-hydroxy-3-methoxy-11,15,15-trimethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (57) (4.2 g, 57%) as a pale brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)[CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:14]2[CH:15]=[CH:16][C:11]([C:10]([O:9][CH2:7][CH3:8])=[O:18])=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A suspension of piperazine (129.2 g, 1.5 mol), ethyl-4-fluorobenzoate (84 g, 0.5 mol), and potassium carbonate (103.65 g, 0.75 mol) in DMSO (200 mL) was stirred at 120° C. under N2 for six hours. The reaction mixture was then cooled to room temperature, poured into water (800 mL), and stirred for 30 minutes. The desired product was collected by filtration and carried to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:27])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CCOC(=O)c1ccc(N(C)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 66.4 %

Procedure:
Following general procedure F and using 4-[(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 17, 0.043 g, 0.127 mmol), potassium carbonate (0.139 g, 1 mmol) and iodomethane (0.144 g, 1 mmol) in 1 mL of anhydrous N,N-dimethylacetamide, the title compound (0.031 g, 70%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 2H, J=9.0 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.70 (d, 1H, J=2.1 Hz), 6.55 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.20 (s, 2H), 3.24 (s, 3H), 3.01 (heptet, 1H, J=7.0 Hz), 1.28 (t, 3H, J=7.1 Hz), 1.25 (s, 6H), 1.15 (d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([C:4]1[N:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[S:3])[NH2:2].CN(C=O)C.[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]2[N:2]=[C:1]([C:4]3[N:14]=[CH:13][CH:12]=[CH:11][C:5]=3[C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:3][CH:26]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cccnc1C(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
To a suspension of ethyl 2-carbamothioylnicotinate (1.9 g, 9.04 mmol) in 20 ml of DMF 4-fluorophenacylbromide (2.0 g, 9.22 mmol) was added, and the resulting mixture stirred for 2 hours at room temperature. The mixture was filtered under suction, the mother liquor evaporated to dryness, and the remaining oil purified by chromatography on silica gel (eluent: CH2Cl2+0-5% methanol) to give 434 mg of the title compound as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:3]=1
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(C=CC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)CNS(=O)(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propenyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.535 g) in EtOAc (100 mL) and EtOH (50 mL) was added Pt(IV)O2, and the mixture stirred under H2 for 1.5 h. The product was filtered and concentrated under reduced pressure to provide 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide as a yellow oily solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N2-Benzyl-4-fluoro-benzene-1,2-diamine (1.2 g, 5.55 mmol) was dissolved in DCM (20 mL) and (S)-2-tert-butoxycarbonylaminopropionic acid (1.14 g, 6.0 mmol) and HOAt (0.82 g, 6.0 mmol) added. The reaction mixture was cooled to 0° C. and N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (1.15 g, 6.0 mmol) added. The resultant dark brown mixture was stirred at 0° C. for 1 h. The mixture was allowed to reach RT and was diluted with DCM (20 mL) and washed with 10% aqueous citric acid. The organic fraction was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a dark yellow gum, which solidified on standing (1.7 g, 79%). LCMS (Method B): RT 3.67 min [M+H]+ 388.1
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](/[CH:15]=[CH:16]/OC(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][CH:16]=1)=[O:14]
Reactant: COC(=O)/C=C/OC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a mixture of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (12.0 g, 77 mmol) and 4-nitro-benzoic-acid (E)-2-methoxycarbonyl-vinyl ester (9.7 g, 39 mmol) in dichloromethane (200 mL) was added triethylamine (20.9 mL, 150 mml) and the resulting solution stirred overnight at room temperature. The mixture was then diluted with dichloromethane (500 mL) and the organic extract removed and washed with water, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (3.1 g, 40%) which was obtained as a light yellow oil. MS: m/e=204.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([NH2:1])=[N:3]2)=[C:8]([Cl:26])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc(N)[nH]c2c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Product: Nc1nc(Cl)c2[nH]c(N)nc2n1

Procedure:
A suspension of 8-aminoguanine (Fischer, Z. Physiol. Chem., 60, 69 (1909); Beaman et al., in Zorbach and Tipson, Synthetic Procedures in Nucleic Acid Chemistry, Vol. 1, pp 41-43, John Wiley & Sons, New York, 1968) (3.0 g, 18.1 mmol) in phosphorus oxychloride (90 mL) and N,N-diethylaniline (3 mL) was refluxed for 30 min and the excess phosphorus oxychloride was evaporated under reduced pressure. Ice (20 g) was added slowly to the resulting solution and the pH was adjusted to 6 with a concentrated aqueous sodium hydroxide solution. A yellow solid formed and was collected by filtration, washed with water, and dried to give a green solid. Crystallization from water with charcoal treatment produced 2,8-diamino-6-chloropurine as a white solid: yield, 2.11 g (63%); mp >275° C. dec.; 1H NMR d 6.09 (s, 2 H, NH2, exchange with D2O), 6.71 (s, 2 H, NH2, exchange with D2O); MS (EI) calcd. m/z for C5H5N635Cl 184.0264, found 184.0266; calcd. m/z C5H5N637Cl 186.0235, found 186.0237.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:16][CH2:15][O:17][C:18]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1)=[O:19]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (3.45 g 0.015 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (25 ml) was added ethylchloroformate (1.9 ml). The reaction mixture was stirred at 25° C. for 2 hours, poured into ice and excess hydrochloric acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and chromatographed after evaporation of the solvent on silica (150 g, 70-230 mesh) eluting with ethyl acetate-hexane 1:1 (v/v) to obtain 1.3 g of ethyl(2-sulfamoyl-6-benzothiazolyl)carbonate which melts at 144°-6° C.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15]C2CCCCO2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH2:37]([OH:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl.O1CCOCC1>>[CH2:37]([O:43][C:11](=[O:12])[C@@:10]([CH2:14][OH:15])([CH3:22])[CH2:9][C@H:8]([NH:23][C:24]([C:26]1[N:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:6][CH:5]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCO
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (100 mg, 0.2 mmol) was combined with 1-hexanol (0.3 mL, 2 mmol) and 4 M HCl in 1,4-dioxane (0.3 mL, 1 mmol). The mixture was stirred for 2 hours at 60° C. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to yield the title compound (51 mg). MS m/z [M+H]+ calc'd for C28H36N4O4, 493.27. found 493.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=2)[CH2:32][S:33][CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[O:28])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:24])[CH3:25])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=2)[CH2:32][S:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:28])[CH:11]=1)=[O:9]
Reactant: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-isopropoxyphenyl)carbamoyl)-benzylthio)propanoate (230 mg, 0.28 mmol, 1.00 equiv, 85%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (180 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 139.8 mg (76%) of a white solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.52 (s, 1H), 12.23 (s, 1H), 9.57 (t, J=8 Hz, 1H), 8.96 (d, J=4 Hz, 1H), 8.41-8.36 (m, 2H), 7.88-7.84 (m, 2H), 7.79-7.63 (m, 2H), 7.60-7.52 (m, 2H), 7.50-7.48 (m, 4H), 7.16-7.13 (d, J=12 Hz, 1H), 4.76-4.70 (m, 1H), 4.62 (d, J=6 Hz, 2H), 3.88 (s, 2H), 2.63-2.53 (m, 4H), 1.30 (s, 6H). MS (ES, m/z): 652 [M+H]+.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][C:19](OC)=[O:20])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CO>O1CCCC1>[C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][OH:20])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)CC(=O)CCCCCNC(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCCCCC(O)CCO)OCc1ccccc1
Temperature: 25 °C
Yield: 9 %

Procedure:
Methyl 8-(N-Cbz-amino)-3-oxo-octanoate (3,51.5 g, 0.16 moles) was dissolved in anhydrous tetrahydrofuran (350 mL) in a reaction flask equipped with a magnetic stirbar, reflux condenser, pressure equalizing addition funnel and nitrogen gas inlet. While stirring the mixture under nitrogen sodium borohydride (15.1 g, 0.4 moles) was cautiously added. The mixture was then heated to reflux and methanol was added dropwise over 90 minutes. Stirring was continued at reflux temperature for 60 minutes after the addition was complete. After allowing the solution to cool to ambient temperature, distilled water (78 mL) was added and 3N HCl was added to pH 3. The mixture was evaporated in vacuo to remove the organic solvents, and solid potassium carbonate was added to adjust the pH back to 12. The mixture was then extracted with ethyl acetate (5×100 mL). The extract was washed with saturated sodium chloride (2×50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in methanol (200 mL) and evaporated again. This was repeated a total of five times. The residue was crystallized from ether (700 mL) giving 8-(N-Cbz-amino)-1,3-octanediol (4,23 g). A second crop was collected on addition of cyclohexane (300 mL) to the mother liquor (6.8 g). Mass Spectrum: (M+H)+ (M+H)+ @m/z 296, (M+H4)+ @m/z 313.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](OOC(=O)C1C=CC=CC=1)(=[O:16])C1C=CC=CC=1.FC(F)(F)C(O)=O>CO>[Cl:8][C:5]1[N:6]=[C:7]([CH2:9][OH:16])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCc1nc(Cl)ncc1F
Temperature: 65 °C
Yield: 24.7 %

Procedure:
To a solution of 5-fluoro-2-chloropyrimidine (500 μL, 5.24 mmol) in methanol (50 mL) is added benzoyl peroxide (1.5 g, 6.0 mmol) and trifluoroacetic acid (450 μL, 5.95 mmol). The resulting colorless clear solution is degassed by bubbling nitrogen through for 5 minutes and it is then heated at 65° C. for 18.5 hours. The solution is then cooled and concentrated. The resulting residue is diluted with chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and the layers are separated. The aqueous layer is re-extracted with chloroform (50 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to dryness under reduced vacuum. The residue is purified by flash silica gel column chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (210 mg, 25%). 1H-NMR (CDCl3): δ (ppm) 8.42 (s, 1H), 4.85 (s, 2H), 3.57 (br, 1H).
Reaction SMILES: CCO.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:14]([O:16]CC)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:5])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(OCCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(OCCO)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 5:3 (v/v) solution of EtOH and THF (0.2 M) of ethyl 3-[(tert-butoxycarbonyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]propanoate from the previous step (1 eq.) was added LiOH (1 M aqueous solution, 2 eq.). The resulting mixture was stirred at RT for 48 h. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and washed further with ether. The aqueous layer was then acidified to pH ˜2 with conc. HCl and the resulting suspension extracted with dichloromethane. The combined dichloromethane extracts was concentrated in vacuo. The crude product thus obtained was recrystallized from EtOAc-hexane to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH3:27][N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:29]1=[O:33]
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)nc1C
Yield: 87.5 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (378 mg) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH2:12][C:13](=[O:15])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(=S)=S>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)CCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of aluminum chloride (0.2 mole) in carbon disulphide (200 ml.) at 0° C. was added a mixture of benzylacetone (0.1 mole) and p-chlorobenzoyl chloride (0.1 mole) throughout 20 minutes. After a further hour at 0° C., the reaction was allowed to reach room temperature and left overnight. The supernatant carbon disulphide was decanted off and the crude, brown residual oil, was poured carefully onto a mixture of ice and concentrated hydrochloric acid. Work-up in the usual way afforded an oil, which, after trituration with acetone and re-crystallisation from benzene/60°-80° C. petrol, gave pure 4-[4-(p-chlorobenzoyl)phenyl]-2-butanone as colourless needles, m.pt. 91°-2° C.