Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:13][CH:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CCCCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(Br)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-chloro-2-oxohexanoate (2.9 g, 15 mmol) in carbon tetrachloride (30 mL) was treated with bromine (0.85 mL, 16.5 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with Na2S2O3 solution, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to provide (95%) of the desired product ethyl 3-bromo-6-chloro-2-oxohexanoate (23A) as a pale yellow oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 5.25 (1H, dd), 4.29 (2H, q), 3.71 (2H, t), 2.16 (1H, m), 1.91 (1H, m), 1.29 (3H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.O.C(=O)(O)[O-].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCOCC1>[C:31]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:33])[CH3:32]
Reactant: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A stirred solution of 5-[4-(2-(2-pyrimidinylamino)ethoxy)benzyl]-2,4-thiazolidinedione (800 mg) in acetic anhydride (15 ml) and 1,4-dioxan (5 ml) was boiled under reflux for 3 hours. After cooling, the mixture was added to water (300 ml), neutralized (sodium bicarbonate) and extracted with dichloromethane (3×200 ml). The organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica-gel in dichloromethane of the residual oil afforded the title compound (m.p. 137° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCOCCCCCl

Procedure:
1-[2-(2-Hydroxyethyl)piperidino]octadecan-l-one and 1-bromo-4-chlorobutane are reacted in acetone in the presence of potassium carbonate at reflux temperature to obtain 2-[2-(4-chlorobutoxy)ethyl]-1-octadecanoylpiperidine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11](O)=[O:12])[CH2:8]2.S(Cl)(Cl)=O.[NH2:18][N:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]1[NH:18][C:11]([CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:12]
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nn1c(-c2ccccc2)nc2ccccc2c1=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of adamantane-2-carboxylic acid (110 mg, 0.61 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in thionyl chloride (1.5 mL, 20.6 mmol) was heated at 80° C. for 90 minutes and then cooled to room temperature and concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and 3-amino-2-phenylquinazolin-4(3H)-one (145 mg, 0.61 mmol, Aldrich) and diisopropylethylamine (0.2 mL, 1.14 mmol) were added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with hexanes-EtOAc, 90:10-70:30), then by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white powder (56 mg, 23%): 1 H NMR (300 MHz, CD3OD) δ ppm 1.21 (br. d, J=12.9 Hz, 1 H), 1.31 (br. d, J=12.9 Hz, 1 H), 1.51 (br. d, J=12.7 Hz, 1 H), 1.58-1.72 (m, 3 H), 1.73-1.91 (m, 5 H), 1.90-2.01 (m, 2 H), 2.21 (br. s, 1 H), 2.61 (br. s, 1 H), 7.44-7.56 (m, 3 H), 7.56-7.65 (m, 3 H), 7.76 (d, J=8.3 Hz, 1 H), 7.89 (ddd, J=8.4, 7.0, 1.6 Hz, 1 H), 8.27 (dd, J=7.9, 1.6 Hz, 1 H); MS (DCI) m/z 400 (M+H); Elemental analysis calculated for C25 H25N3O2.0.7 H2O: C, 72.86; H, 6.46; N, 10.20. Found: C, 72.72; H, 6.30; N, 10.06.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH:13](C(O)=O)[CH2:12][CH2:11]1.O.[OH-].[K+].[C:22]1(C)C(C)=CC=CC=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:22]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1ccccc1C
Reactant: Nc1cc(Cl)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2oc(N3CCCCC3)nc2c1
Temperature: 180 °C

Procedure:
2-Amino-4-chlorophenol (400 mg) and 4-piperidinecarboxylic acid (360 mg) were mixed with polyphosphate (2 g) in xylene (30 ml) and stirred with heating at 180° C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 5-chloro-2-(1-piperidyl)benzoxazole (218 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[C:16]([F:19])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1.[NH2:38][C:39]1[CH:43]=[CH:42][O:41][N:40]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:20]([NH:38][C:39]4[CH:43]=[CH:42][O:41][N:40]=4)(=[O:22])=[O:21])=[C:16]([F:19])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)cc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)c(F)cc21
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.440 g, 0.700 mmol), 3-aminoisoxazole (0.057 ml, 0.770 mmol) and THF (7.0 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in TI-IF) (1.47 ml, 1.47 mmol) was added dropwise. After 60 min, the mixture was diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was concentrated and then triturated with in Et2O. The resulting suspension was sonicated, then filtered. The collected solid was washed with Et2O (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-bromo-5-chloro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.370 g, 0.700 mmol, 100% yield) as an off white solid. m/z (ESI) 527.7 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)C.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:24]([N:37]2[CH2:38][CH2:39][N:34]([C:31](=[O:33])[CH3:32])[CH2:35][CH2:36]2)=[O:26])[N:8]([C:6](=[O:7])[CH3:27])[CH2:12]1
Reactant: CC(=O)Cl
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CC(=O)N1CCN(C(=O)[C@@H]2CC(=NOCc3ccc(Cl)c(Cl)c3)CN2C(C)=O)CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acetyl chloride, and 1-acetylpiperazine the title compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=455.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][N:20]1[CH2:24][C@@H:23]2[C@H:25]([NH2:28])[CH2:26][CH2:27][C@@H:22]2[CH2:21]1.[CH2:34](N1C[C@H]2[C@@H](N)CC[C@H]2C1)[C:35]1C=CC=C[CH:36]=1>>[CH:7]1([CH:3]([CH:2]2[CH2:13][CH2:36][CH2:35][CH2:34][CH2:1]2)[C:4]([NH:28][C@H:25]2[C@@H:23]3[C@@H:22]([CH2:21][N:20]([CH2:19][C:18]4[CH:29]=[CH:30][CH:31]=[C:16]([C:15]([F:32])([F:14])[F:33])[CH:17]=4)[CH2:24]3)[CH2:27][CH2:26]2)=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)C(C(=O)O)c1ccccc1
Reactant: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: N[C@@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21
Product: O=C(N[C@@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 2,2-dicyclohexylacetic acid for 3-methyl-2-phenylbutanoic acid in and (3aR,4R,6aS)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Step D of Example 14: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.66 (d, J=7.7, 1H), 7.55 (d, J=7.3, 2H), 7.50 (t, J=7.7, 1H), 4.50-4.43 (m, 1H), 3.54 (d, J=12.9, 1H), 3.46 (d, J=12.9, 1H), 2.74 (td, J=2.6, 10.5, 2H), 2.51-2.42 (m, 2H), 2.31 (t, J=8.3, 1H), 2.20 (dd, J=7.8, 9.8, 1H), 1.94-1.54 (m, 15H), 1.46 (d, J=13.0, 1H), 1.40 (d, J=14.4, 1H), 1.35-1.07 (m, 9H), 0.98 (qd, J=3.0, 12.3, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[C:11]([CH3:14])[CH:12]=O.C(O)C>C(O)(=O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:12]=[C:11]([CH3:14])[CH:10]=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CC(C=O)=CN(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cnc2c(Br)cnn2c1
Yield: 71.6 %

Procedure:
3-Amino-4-bromopyrazole (0.331 g, 2.04 mmol) and 3-(dimethylamino)-2-methyl-2-propenal (0.220 g, 1.94 mmol) were dissolved in acetic acid (6.48 mL) and ethanol (9.72 mL) and the reaction stirred at room temperature for 16 h. Solvents were removed under reduced pressure. The remaining residue was taken up in dichloromethane and purified by column chromatography (20-80% EtOAc/Hex) to give the title compound (0.294 g, 1.39 mmol). LRMS (APCI) calc'd for (C7H6BrN3) [M+H]+, 212.0; found 211.9. 1H NMR (500 MHz, cdcl3) δ 8.44 (s, 2H), 8.04 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](Cl)=[O:6])[CH:3]=1.C(N(CC)CC)C.[F:20][C:21]1[C:22](=[O:33])[NH:23][C:24](=[O:32])[N:25]([CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH:26]=1.[OH:34][C:35]1[CH:40]=[CH:39][NH:38][C:37](=[O:41])[CH:36]=1>O1CCOCC1>[O:41]=[C:37]1[CH:36]=[C:35]([O:34][C:1]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([N:23]2[C:22](=[O:33])[C:21]([F:20])=[CH:26][N:25]([CH:27]3[CH2:31][CH2:30][CH2:29][O:28]3)[C:24]2=[O:32])=[O:6])=[O:11])[CH:40]=[CH:39][NH:38]1
Reactant: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Oc1cc[nH]c(=O)c1)c1cccc(C(=O)n2c(=O)c(F)cn(C3CCCO3)c2=O)c1
Yield: 18 %

Procedure:
A 1.00 g quantity of isophthaloyl chloride and 0.70 ml of triethylamine were added to a solution of 1.00 g of 5-fluoro-1-(2-tetrahydrofuranyl)uracil in 30 ml of dried dioxane. The mixture was refluxed for 2 hours. Thereto added was 1.00 ml of triethylamine and the mixture was refluxed for 2 hours. Thereto further added was 0.60 g of 4-hydroxy-2(1H)-pyridone and the mixture was refluxed for 3 hours. The solvent was distilled off and 30 ml of ethyl acetate and 30 ml of water were added to the residue. The insolubles were removed by filtration. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated. The concentrate was subjected to silica gel column chromatography to conduct gradient elution using chloroform and mixtures of methyl (up to 2%) and chloroform. The fractions corresponding to the title compound were collected and concentrated, giving 0.40 g of a powder in a yield of 18%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][CH:10]=3)=[CH:3][CH:2]=1.[NH2:19][CH:20]([CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21](O)=[O:22].F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:21]([CH:20]([NH:19][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[CH:15]2)=[O:18])[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:22])[NH2:39]
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: NC(CSc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(CSc1ccccc1)NC(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.20 g (0.84 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid was admixed with 0.21 g (1.07 mmol) of 2-amino-3-phenylsulfanylpropionic acid in 40 ml of DMF and, at 0° C., 0.66 g (1.27 mmol) of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and 0.37 ml (2.12 mmol) of N-ethyl-N,N-diisopropylamine were added, and the solution was stirred at 20° C. for 2 h. The solution was concentrated under reduced pressure and purified by medium pressure column chromatography (CH2Cl2/CH3OH:9:1). This gave 0.19 g (54%) of N-(1-carbamoyl-2-phenylsulfanylethyl)-2-pyridin-4yl-1H-indole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH2:32][O:33]C3CCCCO3)[N:29]=[C:28]([CH3:40])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:40])[N:29]=[C:30]([CH2:32][OH:33])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 1.5 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (140 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31]I>>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:15])([F:16])[F:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)Cc1ccc(OCC(F)(F)F)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Yield: 52 %

Procedure:
Step AW (1): 2-(4-(2,2,2-Trifluoroethoxy)phenyl)acetic acid (6.00 g, 25.6 mmol, reference: D. Page, et al. Bioorganic Med. Chem. Lett. (2008), 18, 3695) was deprotonated with NaHMDS (2.0 M in THF, 38.4 mL, 77 mmol) and reacted with 1-chloro-4-iodobutane (8.40 g, 38.4 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (4.32 g, 13.3 mmo, 52% yield) as a clear viscous oil that eventually formed a waxy solid. LC-MS (M−H)− 323.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24-7.27 (m, 2 H), 6.90 (d, J=8.5 Hz, 2 H), 4.32 (q, J=7.9 Hz, 2 H), 3.45-3.56 (m, 3 H), 2.00-2.12 (m, 1 H), 1.71-1.83 (m, 3 H), 1.29-1.49 (m, 2 H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14](C=O)=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(=[CH:56][C:57]([O:59][CH3:60])=[O:58])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOC[CH2:62]1>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:62]=[CH:56][C:57]([O:59][CH3:60])=[O:58])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCO1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 84 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]-3-methoxybenzoate (1.2 g) and methyl (triphenylphosphoranylidene)acetate (1.8 g) in dioxane (12 ml) was heated at reflux for 48 hours. The solvent was evaporated. The resultant residue was purified by flash chromatography on silica gel (600 ml), eluting with 3:7 ethyl acetate:hexane, to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylvinyl)indol-1-ylmethyl]-3-methoxybenzoate (1.1 g, 84%) as a yellow solid; mp 163°-164°.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:25][S:26][CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][S:26][CH3:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 74.4 %

Procedure:
A mixture of 6 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, 4.8 g of 2-chloroethyl methyl sulphide and 10.5 g finely powdered potassium carbonate in 100 ml of dimethylformamide is heated to 100° for 20 hours. The cooled reaction mixture is diluted with water and extracted several times with ethyl acetate. The crystalline residue obtained after drying and evaporating the organic phase is recrystallized from hexane and gives 5.5 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl sulphide in colourless crystals, melting point 94°-96°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc23)CC1
Yield: 81.9 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.6 mg (0.0458 mMol) 3,4-dichlorobenzoyl chloride, 14.4 mg (82%) of the title compound were recovered.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[NH:34]1[C:42]2[CH2:41][CH2:40][NH:39][CH2:38][C:37]=2[N:36]=[CH:35]1>C(OCC)(=O)C.C(N(CC)CC)C>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:39]2[CH2:40][CH2:41][C:42]3[NH:34][CH:35]=[N:36][C:37]=3[CH2:38]2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a suspension of 3,3-diphenylpropionic acid (14 mg, 0.06 mmol) and HOBt (9 mg, 0.07 mmol) in ethyl acetate (1.5 mL) a solution of EDC (12 mg, 0.06 mmol) in ethyl acetate (0.5 mL) was added. The resulting mixture was shaken for 20 min at room temperature and then 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (12 mg, 0.06 mmol) and triethylamine (0.02 mL) were added. After shaking for 16 h the mixture was washed with brine (2×2 mL), and the organic phase was concentrated. 12 mg (60%) of the title amide was obtained.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:43]=[CH:42][CH:41]=[CH:40][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([O:31][CH2:2][C:1]#[N:4])=[O:30])=[O:22])=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reaction time: 1.5 h
Yield: 112.8 %

Procedure:
N,N-Diisopropylethylamine (52 μL, 0.298 mmol) and subsequently bromoacetonitrile (94 μL, 1.352 mmol) were added to a solution of (S)-6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk40) (114 mg, 0.270 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk41) (140.2 mg, quant.).