Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:25])(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:27]([O:29][NH:30][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH2:6][C:5]1=[O:25])[CH3:2])[CH3:28]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(OC(F)(F)F)cc2)CC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(OC(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.19 Gram of 2-acetyl-5-[2-(4-trifluoromethoxyphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.07 g of ethoxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.12 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-trifluoromethoxyphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:13][C:14]([OH:18])([CH3:17])[C:15]#[CH:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:14]([OH:18])([CH3:17])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
1-Bromo-4-pentylbenzene (102 g), 3-methyl-1-butyne-3-ol (38 g), triphenylphosphine (2 g) and bis(triphenylphosphine)palladium(II) chloride (1 g) were dissolved in triethylamine (390 ml) under nitrogen atmosphere, and then copper(I) iodide (0.3 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed twice with 10% hydrochloric acid, and further with water twice, and then chloroform was distilled off therefrom. The residue was purified using silica gel-chloroform column chromatography to give 3-methyl-1-(4'-pentylphenyl)-1-butyne-3-ol (82 g).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[O:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.C(Cl)Cl>B(F)(F)F.CCOCC.C(OCC)(=O)C>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: c1ccoc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccco1
Temperature: 25 °C

Procedure:
A solution of 1.6 g. (0.006 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 0.7 g. (0.01 mol.) of redistilled furan in 75 ml. of methylene chloride was cooled to -78° and 4 drops of boron trifluoride etherate was added with stirring. The reaction mixture was warmed to room temperature and left for 3 hours Chromatography on silica gel with methylene chloride and methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:9]([OH:11])=O.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:9]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)=[O:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(CO)c(Br)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
EDC (1.3 equiv.) was added to a solution of 3-bromo-4-(hydroxymethyl)benzoic acid (1.0 equiv), 3-(trifluoromethyl)aniline (1.1 equiv.), HOAt (1.3 equiv.) in DMF (0.43 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by ISCO(50% EtOAc/Heptane) to yield 3-bromo-4-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)benzamide in 35% yield. LC/MS (m/z)=374.0 (MH+), Rt=0.93 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])[CH3:27].COC1C=CC(C=O)=CC=1>CCOC(C)=O.CN(C=O)C>[Si:29]([O:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)([C:26]([CH3:28])([CH3:27])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COC1CCCCO1
Agent: COc1ccc(C=O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To a 5 L three neck flask fitted with a thermometer, mechanical stirrer, under argon was added 3 (108 g, 0.39 mol) and DMF (700 mL). To the light yellow solution was added imidazole (53 g, 0.78 mol) and TBDPSCl (tert-butyldiphenylchlorosilane) (150 mL, 0.58 mol). The solution turned cloudy and colorless. After stirring 18 hours the reaction was shown to be complete by TLC (EtOAc:hexanes; 3:7, anisaldehyde dip reagent). The clear yellow solution was concentrated under reduced pressure to a yellow residue (415 g). The residue was dissolved in diethyl ether (2 L) in a 4 L flask with a mechanical stirrer. To this solution was added 1.2M HCl (300 mL) to pH 3-4. The solution was stirred for 10 min. The layers were separated and the organic layer was washed with sat. NaHCO3 (300 mL) to pH 7 and brine (400 mL). The organic layer was dried over MgSO4 (60 g), filtered and concentrated under reduced pressure to 248 g of an oil. The oil was flashed chromatographed in portions over flash silica as follows. The oil (60 g) was flash chromatographed over flash silica gel (440 g) with anhydrous Na2SO4 (100 g) on top of the column packed with hexanes. Fractions of 500 mL were collected. Fractions 1-2 were eluted with hexanes, 3-10 with 4% ethyl acetate in hexanes, 11-18 with 10% ethyl acetate in hexanes. Fractions were monitored by TLC (EtOAc:hexanes; 2:8, anisaldehyde dip reagent) and HPLC. Fractions 9-18 were combined and concentrated under reduced pressure to give 37 g (18%) of product 4 as a viscous colorless oil. HPLC analysis showed a purity of 98%. The total weight of product 4 after purifications was 164 g (82%). 1H NMR (60 MHz, CDCl3) δ 7.0-7.7 (m, 10H), 3.2-5.2 (m, 9H), 1.0-2.0 (m, 24H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]=[CH:5][N:6]([CH3:24])[C:7]=2[N:8]2[N:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:9]2[N:10]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[CH3:24][N:6]1[CH:5]=[N:4][C:3]2[C:2]([NH:25][CH2:26][CH2:27][OH:28])=[N:10][C:9]3=[CH:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:13][N:8]3[C:7]1=2
Reactant: Cn1cnc2c(Cl)nc3cc(OCCOc4ccccc4)nn3c21
Reactant: NCCO
Product: Cn1cnc2c(NCCO)nc3cc(OCCOc4ccccc4)nn3c21
Yield: 62 %

Procedure:
A solution of Example 84 Part D (22.6 mg, 0.066 mmol) in 2-aminoethanol (5 mL) was heated at 100° C. for 24 h. 2-aminoethanol was then removed under vacuum, and the residue was purified by prep-HPLC, furnishing the title compound (15 mg, 62% yield). ESI m/z=369.24 [(M+H)+; calcd for C18H20N6O3+H: 369.17].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21]C(C)(C)[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:25])[O:26][C@H:27]2[C@H:34]3[C@H:30]([O:31][CH2:32][CH2:33]3)[O:29][CH2:28]2)[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R) 5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-{4-[(3-cyanobenzyl) oxy]benzyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in 3 mL of dioxane was added 4M hydrochloric acid in dioxane (1.5 mL) and water (0.05 μL). The solution was stirred for 1 hour followed by neutralization with 10% aqueous Na2CO3. The solution was extracted with dichloromethane (3×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8:2) as eluent to provide 17 mg (61%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][C:3]1=S.[BH4-].[Na+]>CO.C1COCC1.[Ni]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:1])[CH2:3][NH:4]2
Reactant: CCOC(=O)CC1(C)C(=S)Nc2cccc([N+](=O)[O-])c21
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C)CNc2cccc(N)c21
Reaction time: 1 h

Procedure:
To a solution of (±)-ethyl (3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (3.65 g, 12.4 mmol) and nickel (H) chloride hexahydrate (23.6 g, 99.2 mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH4 (11.3 g, 298 mmol) in portions, over 1 h. The resulting mixture was stirred for 10 min, then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6](N2C=CC(=O)NC2=O)[CH2:5]1)=[N+:2]=[N-:3].[NH2:26][C:27]1[N:35]=[C:34]2[C:30]([NH:31][CH:32]=[N:33]2)=[C:29]([Cl:36])[N:28]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[O:7][CH:6]([N:33]2[CH:32]=[N:31][C:30]3[C:34]2=[N:35][C:27]([NH2:26])=[N:28][C:29]=3[Cl:36])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC(n2cnc3c(Cl)nc(N)nc32)C[C@@H]1N=[N+]=[N-]
Temperature: 85 °C

Procedure:
A suspension of 1-((2R,4S,5S)-4-azido-5-((tert-butyldimethylsilyloxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H, 3H)-dione, 75 (TBS protected AZU)1 (0.2 g, 0.544 mmol) and 2-amino-6-chloropurine (0.25 g, 1.51 mmol) in acetonitrile (6 mL) was added BSA (2 ml, 1.51 mmol). The reaction mixture was heated to 85° C. for 30 min, then cooled to 0° C. TMSOTf (0.51 mL) was added. The reaction mixture was heated to 85° C. overnight, cooled to room temperature, poured into saturated sodium bicarbonate, extracted with ethyl acetate (20 mL×2), dried, conc., and purified by flash column chromatography with ethyl acetate:hexane=1:1 to get the desired compound 0.1 g. 43%. It contained two isomers (alpha:beta=1.1:1)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:42]1([CH:45]=O)[CH2:44][CH2:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH:42]1([CH2:45][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[N:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH2:44][CH2:43]1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)nc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(CC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(4Z)-6-Iodo-4-{[(6-piperazin-1-ylpyridin-3-yl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (150 mg, 0.315 mmol) is dissolved in N-methylpyrrolidinone (3 mL) and methylene chloride (0.9 mL), followed by addition of sodium triacetoxyborohydride (0.77 mg, 3.63 mmol), cyclopropanecarbaldehyde (0.61 mL, 8.14 mmol) and acetic acid (0.47 mL, 8.2 mmol). After stirring at room temperature for 1 h, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 110 mg (69%) of the title compound as a brown solid. MS (ESI) m/z 530.4 (M+H)+1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:31]1[CH2:33]C1)[C:15](=[O:30])C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[CH2:34]([O:41][C:42](=[O:47])[NH:43]CCBr)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCCCCC.C[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>>[C:57]([O:56][C:15](=[O:30])[N:14]([CH2:31][CH2:33][NH:43][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:47])[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:60])([CH3:59])[CH3:58]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(c1cnccc1-c1ccccc1Cl)C1CC1
Reactant: COC(C)(C)C
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CCNC(=O)OCc1ccccc1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from [4-(2-chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (example 124, intermediate d) and (2-bromo-ethyl)-carbamic acid benzyl ester (CAS RN 53844-02-3) and using a gradient of n-heptane:tert-butyl methyl ether (100:0 to 30:70) for the chromatographic separation. Colorless foam (53%). MS (ESI): m/z=482.18 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:7]([NH:28]C(=O)OC(C)(C)C)[C:8](=[O:27])[N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C@@H:10]2[C:18](=[O:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([NH:19][C:18]([C@@H:10]2[N:9]([C:8](=[O:27])[C@@H:7]([NH2:28])[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
For Intermediate 4: In a 100 mL round-bottomed flask, tert-butyl (R)-(1S)-1-cyclohexyl-2-oxo-2-(2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylcarbamate (100 mg, 209 μmol, Eq: 1.00) was combined with DCM (2 mL) to give a colorless solution. TFA (2 mL, 26.0 mmol, Eq: 124) was added and the reaction was stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give (R)-1-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (56 mg), m/z=379 (M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Br)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-benzylamine hydrochloride (367.8 mg, 1.7 mmol) was dissolved in dichloromethane (15 mL), and the solution was cooled to 0° C. DIEA (380 μL, 2.2 mmol) was then added, and the reaction was stirred at 0° C. for 5 minutes. Then cyclopropanecarbonyl chloride (180 μL, 2.3 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. The reaction was quenched with distilled water, and the solvents were removed. The resulting mixture was redissolved in DMF (10 mL) and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([C@H:12]([CH2:14][CH3:15])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>C(#N)C>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH:12]([CH3:13])[CH2:14][CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: CCC(C)[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of L-isoleucine benzylester (1.41 g, 6.4 mmol) in acetonitrile (12 mL) was added 1,3-propane sultone (706 mg, 5.8 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone (2×20 mL). The solid material was dissolved in 50% EtOH/water (50 mL). Dowex Marathon C ion exchange resin (strongly acidic, 10 g) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and lyophilized affording the title compound (778 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.49 (m, 5H), 5.42 (d, 1H, J=11.7 Hz), 5.31 (d, 1H, J=11.7 Hz), 3.24 (m, 2H), 2.98 (m, 2H), 2.13 (m, 3H), 1.46 (m, 1H), 1.34 (m, 1H), 0.93 (m, 6H). 13C (D2O, 125 MHz) δ ppm 168.53, 134.69, 129.28, 129.22, 129.06, 68.86, 64.45, 48.12, 46.56, 36.21, 25.97, 21.31, 13.73, 11.05. [α]D=−1.5° (c=0.0031 in water), ES-MS 342 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1cccc(O)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 3-amino-phenol (Aldrich) according to the method described in Example 1c. Melting Point: 175-179° C. (diethylether)
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8]O.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.C1(C)C=CC=CC=1.C(#N)C>[Cl-:3].[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(Cl)c1CO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 5 drops of dimethylformamide and 0.75 ml of thionyl chloride were added to a solution of 1.24 g of 2-chloro-6-methylbenzyl alcohol in 15 ml of toluene. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was then azeotropically distilled with 5 ml of toluene 3 times to give an oil. The resulting oil was dissolved in 15 ml of acetonitrile, and 2.08 g of triphenylphosphine was added to the solution. The mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure and the collected crystals were washed with ethyl acetate to give 3.15 g of (2-chloro-6-methylbenzyl)(triphenyl)phosphonium chloride as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][C:24](O)=[O:25])=[C:9]2[CH3:27])=[CH:4][CH:3]=1.[NH2:28][C@@H:29]([CH2:33][OH:34])[C:30]([OH:32])=[O:31]>>[OH:34][CH2:33][C@H:29]([NH:28][C:24](=[O:25])[CH2:23][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:27])[C:30]([OH:32])=[O:31]
Reactant: Cc1c(CC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: N[C@@H](CO)C(=O)O
Product: Cc1c(CC(=O)N[C@@H](CO)C(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 90 %

Procedure:
Obtained from 6g and (S)-2-amino-3-hydroxypropionic acid similarly to example 28-II, yield 90%, m.p. 120° C. 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, 2H), 7.31 (m, 4H), 7.22 (m, 2H), 6.73 (s broad, 1H), 6.50 (s, 1H), 4.70 (m, 1H), 4.20 (m, 2H), 3.54 (s, 2H), 3.01 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[Cl:17])=[O:4].[H][H]>[Pt].O1CCCC1>[CH3:1][N:2]([CH3:18])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[Cl:17])=[O:4]
Reactant: CN(C)C(=O)c1cc2cc([N+](=O)[O-])cc(Cl)c2[nH]1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(N)cc(Cl)c2[nH]1

Procedure:
A mixture of 2.6 g I.7 (7-chloro-5-nitro-1H-indole-2-carboxylic acid dimethylamide), 0.3 g Pt/C 10%, 10 ml methanol and 90 ml tetrahydrofuran was stirred ambient temperature under a pressure of 50 psi hydrogen. The catalyst was filtered and the solvent was evaporated. The resulting crude material was used for the next step without purification.