Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([OH:21])[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O.C(OCC)(=O)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([OH:21])[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 1.10 g of 8-[4-(tert-butyl)phenyl]-1,4-dioxaspiro[4.5]decane-8-ol. Then, 5.00 ml of 6 mol/L hydrochloric acid and 5.00 ml of water were added at an ice-cooled temperature and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting crystal was collected by filtration to obtain 0.67 g of 4-[4-(tert-butyl)phenyl]-4-hydroxy-1-cyclohexanone as a colorless crystalline product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]([OH:17])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:18]N1C(=O)CCC1=O.C(OOC(=O)[C:37]1[CH:42]=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:42]([O:16][C:15]([C:14]1[N:13]=[C:12]([Cl:18])[N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([Cl:1])[C:3]=12)=[O:17])[CH3:37]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ncn2c1c(Cl)nc1ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)n2c1c(Cl)nc1ccccc12
Yield: 50 %

Procedure:
To a suspension of 4-chloroimidazo[1,5-a]quinoxaline 3-carboxylic acid (2.7 g) in carbon tetrachloride (50 ml) was added N-chlorosuccinimide (3 g) and trace of benzoyl peroxide. The mixture was stirred and refluxed for 48 hours, then evaporated under vacuum to dryness. The residue was taken up in chloroform, washed with water, dried, concentrated to a small volume, then put through a silica gel dry column (chloroform as eluant). From column, the product was obtained as an off-white solid (1.6 g, 50% yield), m.p. 132°-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.P(N=[N+]=[N-])(=O)([O:21][C:22]1C=CC=CC=1)OC1C=CC=CC=1.C([N:34](CC)CC)C>C1COCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:22](=[O:21])[NH:34][C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(=O)O)c1N
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc2[nH]c(=O)[nH]c12
Temperature: 80 °C

Procedure:
To a round bottomed flask was added 2-amino-3-methoxybenzoic acid (2.2705 g, 13.58 mmol), diphenyl phosphorazidate (3.51 mL, 16.30 mmol), and triethylamine (3.79 mL, 27.2 mmol) in THF to stir at 80° C. Upon completion the reaction was allowed to cool to room temperature. Solvent was evaporated. The residue was taken up in DCM. The reaction mixture was diluted with water and extracted with DCM. A white precipitate was noted to form during extraction The solid was filtered to provide 4-methoxy-1H-benzo[d]imidazol-2(3H)-one. [M+H]=165.0.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(CCN)=CC=1.C1(=O)CCCCC1.C([O:47][C:48](=[O:51])[CH2:49][CH3:50])C>>[CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:50][CH2:49][C:48]([OH:51])=[O:47])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCc1ccccc1
Solvent: O=C1CCCCC1
Product: O=C(O)CCSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1

Procedure:
3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-phenethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]=1[C:19]([C:18]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:17]=1[Cl:16])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1Cl
Yield: 42 %

Procedure:
In a manner similar to that described above for compound 1aa, 4-Chloro-N-Boc-aniline and 2-chloro-6-fluoro-benzoyl chloride were converted to 1ab (42% yield) MS m/z=284 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>CN(C)C=O.O>[OH2:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.41 g, 0.0190 mole) was added dropwise to a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.28 g, 0.0184 mole) in anhydrous dimethylformamide (70 ml). The resulting solution was stirred at room temperature for 3 hrs and was then added dropwise to a stirred and chilled (15°-20° C.) solution of 3-aminopyridine (1.79 , 0.0190 mole), triethylamine (1.92 , 0.0190 mole) and dimethylformamide (30 ml). The reaction mixture was stirred at room temperature overnight and then poured into 300 ml of water. The mixture was filtered. The filter cake was suspended between methylene chloride (200 ml) and 5% sodium hydroxide (100 ml) and the methylene chloride was separated. The aqueous portion was extracted with methylene chloride (100 ml). The combined methylene chloride layers were washed with 5% sodium hydroxide (2×50 ml), water (50 ml), dried over sodium sulfate, and concentrated. The residue (4.3 g, 66%) was twice recrystallized from isopropyl alcohol-isopropyl ether to give 3.2 g of a white granular solid, mp 217°-218° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:20])[N:9]([CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=1)[C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: Fc1ccc(CBr)cc1F
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Sodium hydride (60%, 0.37 g, 9.19 mmol) was added to a solution of compound 125-B (2.2 g, 8.35 mmol) in DMF (30 mL), at 0° C. and the resultant mixture was stirred for 15 minutes. 3,4-Difluorobenzylbromide (1.18 mL, 9.2 mmol) was added, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic extract washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography, eluting with an ethyl acetate-heptane gradient, to afford compound 125-C as an oil (2.73 g, 84%). 1H-NMR (CDCl3): δ 1.40 (s, 9H), 1.97 (s, 3H), 4.72 (s, 2H), 6.93-7.19 (m, 3H), 7.28-7.39 (m, 2H), 7.61 (d, 1H), 7.70 (d, 1H).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]([CH2:17][O:18][C:19](=[O:50])[CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[CH:15][C:14]=1[O:53][CH2:54][CH:55]1[CH2:57][CH2:56]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][C:19]([O:18][CH2:17][C:16]1[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:15]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N(c1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
(S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzyloxy)-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (70 mg, 0.08 mmol) was dissolved in DCM (1 ml), and HCl 4M in Dioxane (500 μM) was added. The mixture was stirred at RT for 3 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by Preparative reverse-phase HPLC to yield 10 mg of the final product (Yield: 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](SCCC)[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1.Cl[C:31]1[CH:36]=CC=C(C(OO)=O)[CH:32]=1.[S:41]([O:44]S([O-])=O)([O-])=[O:42].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:41]([CH2:32][CH2:31][CH3:36])(=[O:44])=[O:42])[N:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]=2[CH:28]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCS(=O)(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 9 h

Procedure:
85 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of dichloromethane, mixed with 59 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 9 hours at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 30 mg was obtained.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]N)([O-:4])=[O:3].[C:13]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14]>>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:11][C:13]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[CH:14]2)([O-:4])=[O:3]
Reactant: CC(=O)c1cnccn1
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])c1cccc2cc(-c3cnccn3)[nH]c12
Yield: 13 %

Procedure:
2-Nitrophenylhydrazine hydrochloride (3.1 g, 16 mmol) and 2-acetylpyrazine (2.0 ml, 16 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (0.5 g, Yield 13%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[Cl:5][C:6]1[C:21]([F:22])=[CH:20][C:9]2[C:10](=[O:19])[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=1>O.C(O)C.C1C=CC=CC=1>[Cl:5][C:6]1[C:21]([F:22])=[CH:20][C:9]2[CH:10]([OH:19])[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: OC1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Yield: 94 %

Procedure:
A solution of sodium borohydride (0.42 g) in water (4 ml), containing 15% sodium hydroxide solution (0.1 ml), was added dropwise to a solution of the ketone from the preceding experiment (7.0 g) in a mixture of ethanol (70 ml) and benzene (25 ml). The mixture was refluxed for 3 hours, diluted with water and extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over sodium sulphate and taken down. The solid residue was crystallized from hexane (30 ml), yielding 6.60 g (94%) of 7-chloro-8-fluoro-10-hydroxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 86°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:7](=[O:19])[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)=[CH:4][CH:3]=1.[CH2:28]=[C:29]([CH:32]=[N:33][C:34]([O:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH2:35])[CH2:30][CH3:31]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:19])[C:6]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:35][C:34](=[O:36])[NH:33][CH:32]3[C:29](=[CH2:28])[CH2:30][CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([Si:37]([CH3:38])([CH3:39])[CH3:40])[CH3:14]
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(C=NC(=C)O[Si](C)(C)C)CC
Solvent: Cc1ccccc1
Product: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: COC(C)[Si](C)(C)C
Yield: 90 %

Procedure:
In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (3 g, 7.1 mmol) prepared in example 55a was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (19 g, 96 mmol) prepared in example 80a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 3.5 g, 90%).
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:40]=4[CH:41]=[CH:42][NH:43]5)=[O:36])=[CH:31][C:30]=3[Cl:48])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[NH2:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[CH:42][NH:43]3)=[O:36])=[CH:31][C:30]=1[Cl:48]
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Piperidine (88 μL, 0.89 mmol) was added to a solution of 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 30 min and then the solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give 3-amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester as an off-white solid (59 mg, 81%). N,N-Dimethylformamide (5 mL) was added, followed by HOAT (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), and thiophene-2-carboxylic acid (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-[(thiophene-2-carbonyl)amino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (58 mg, 78%). A solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in tetrahydrofuran/methanol/water (3:1:1) was added, and the solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by HPLC to give 3-(thiophene-2-carbonyl)amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (45 mg, 80% from ester, 48% for three steps) as a white powder.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].[CH2:20]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]I)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C.O1CCCC1>[C:1]([NH:4][C:5]([CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(CCI)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1

Procedure:
To a solution of diethyl acetamidomalonate (277 g) and sodium ethylate (86.6 g) in anhydrous ethanol (850 ml) is added a solution of 2-(4-octylphenyl)ethyl iodide (7) (146 g) in anhydrous tetrahydrofuran (533 ml), and the mixture is refluxed under heating for 6 hr. The reaction mixture is concentrated and partitioned between water and hexane, and the hexane layer is washed three times with water. The obtained hexane layer is dried over anhydrous magnesium sulfate and concentrated. The residue is recrystallized from hexane to give the title compound (8) as colorless crystals. The resulting Compound (8) has the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.C(N(CC)CC)C.[NH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>C(#N)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)=[O:9]
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)CCCCCBr
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCCCCBr)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromohexanoic acid (4.51 g, 23.1 mmol) in acetonitrile (50 mL) is added N,N'-disuccinimidyl carbonate (6.5 g, 25 mmol) and triethylamine (3.2 mL, 23 mmol). The solution is stirred at room temperature for 4 hours and tyramine (3.2 g, 23 mmol) is added and stirred continued at room temperature overnight, evaporated in vacuo, re-dissolved in ethyl acetate (100 mL) and washed with water (6×50 mL) and saturated sodium chloride solution (2×25 mL). The ethyl acetate solution is dried with sodium sulfate, filtered, and evaporated in vacuo to give a light brown gum. The crude product is purified by silica gel chromatography to give 6-bromo-N-[2-(4-hydroxyphenyl)ethyl]-hexanamide (II) as a light amber syrup.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>C1(C)C=CC=CC=1>[Br:14][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Br)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 176.5 %

Procedure:
t-Butyl ethyl malonate (25.00 g, 0.13 mol) was dissolved in toluene and warmed to 80° C. To the resulting solution was added 1,3-dibromo-5,5-dimethylhydantoin (25.00 g, 0.07 mol). The reaction was stirred at elevated (80° C.) temperature 18 hr. The reaction was cooled, concentrated and taken up in Et2O. The organic layer was washed with saturated NaHCO3 (2×), brine (3×), dried (MgSO4), filtered and concentrated. Purification by filtration on silica (70:30-heptane:ethyl acetate) yielded 33.0 g (93%) of a light yellow oil. NMR and MS indicated a mixture of three compounds, starting material (20%), monobrominated (55%) and dibromonated diesters (25%). The material was used without further purification.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: Brc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 79.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.04 g, 0.15 mmol) was reacted with 4-bromobenzaldehyde (0.028 g, 0.15 mmol) in the presence of glacial acetic acid (0.009 g, 0.15 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.012 g, 0.18 mmol) in methanol (5 ml) (Procedure D) to give compound 16l (0.052 g, 80%) as an oil.