Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:46](O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.O>ClCCl>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2CCN(Cc3ccccc3)C[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25, diisopropylethylamine (40.5 μl) and benzyl alcohol (12.4 μl) in dichloromethane (2.0 ml), EPPA (17.3 μl) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: B(O)O.C([O-])([O-])=O.[K+].[K+].[CH:10]1[CH:15]=[C:14]2[C:16]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:17]=3[NH:18][C:13]2=[CH:12][CH:11]=1>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:18]1[CH:13]=[CH:14][CH:16]=[C:17]1[C:20]1[CH:21]=[CH:22][C:16]2[C:14]3[C:13](=[CH:12][CH:11]=[CH:10][CH:15]=3)[NH:18][C:17]=2[N:19]=1
Reactant: Clc1ccc2c(n1)[nH]c1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: C1COCCO1
Solvent: O
Product: c1c[nH]c(-c2ccc3c(n2)[nH]c2ccccc23)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
At room temperature and under an inert atmosphere, Pd(PPh3)4 (0.08 equiv.), boronic acid (1.1 equiv.), and a 0.3 M solution of K2CO3 (3 equiv.) in H2O were added to a 0.1M solution of 2-chloro-α-carboline in anhydrous 1,4-dioxane. This solution was stirred at 100° C. for 12 h. After cooling to room temperature, the solution was filtered through celite and solvents were removed under reduced pressure. A solution of crude product in CH2Cl2 (3.5 mL) was stirred under argon and treated with CF3CO2H (1 mL). After 90 min at room temperature, the resulting mixture was then cautiously quenched at 0° C. with H2O and a saturated aqueous NaHCO3 was added until pH 10. The solution was diluted with CH2Cl2, washed with H2O, dried with MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (CH2Cl2) to afford R355 in 10% yield as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.90 (bs, 1H), 8.89 (bs, NH), 8.28 (d, 1H, J=8.0 Hz), 7.98 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.1 Hz), 7.43-7.40 (m, 1H); 7.33-7.27 (m, 2H), 6.97 (s, 1H), 6.85 (s, 1H), 6.34 (dd, 1H, J=2.6, 5.5 Hz).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:32][C:26]3=[CH:27][N:28]=[C:29](O)[CH:30]=[C:25]3[C:24]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:29]1[CH:30]=[C:25]2[C:24]([C:33](=[O:34])[NH:35][CH3:36])=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[O:32][C:26]2=[CH:27][N:28]=1)(=[O:10])=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(O)cc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Triflic anhydride (Tf2O, 319 μL, 1.89 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-3-carboxamide (270 mg, 0.943 mmol) in pyridine (13 mL) at 0° C. and the mixture was allowed to warm to room temperature. It was allowed to stir for 1 hour then concentrated and diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-c]pyridin-5-yl trifluoromethanesulfonate (188 mg, 0.449 mmol, 34.8% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1H, s), 8.53-8.61 (1H, m), 8.01-8.11 (2H, m), 7.87 (1H, s), 7.46 (2H, t, J=8.91 Hz), 2.85 (3H, d, J=4.52 Hz). LC-MS retention time: 2.06 min; m/z (MH+): 419. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:15]N1C(=O)CCC1=O.C(Cl)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:4]1[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[CH:13]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc2c1OC(C)(C)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CC1(C)Oc2c(CBr)cc(F)cc2C1=O

Procedure:
A solution of provide 5-fluoro-2,2,7-trimethylbenzofuran-3(2H)-one (659) (100 mg, 0.515 mmol), N-Bromosuccinimide (100.8 mg, 0.567 mmol), benzoyl chloride (1.2 mg, 0.005 mmol) and carbon tetrachloride (2 mL) was heated at reflux overnight. Saturated sodium bicarbonate was added and extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (5%) to give 7-(bromomethyl)-5-fluoro-2,2-dimethylbenzofuran-3(2H)-one (660).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)O1.C(COC)OC.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N:7]=[C:6]([CH3:24])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc3c4c2CCCN4CCO3)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc2c3c1CCCN3CCO2
Temperature: 80 °C

Procedure:
Preparation of (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-ypacetate: A Smith process vial was charged with (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (52 mg, 0.133 mmol, 1 eq.), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline (48 mg, 0.159 mmol.), Pd(PPh3)4 (15 mg, 10%) and flushed with nitrogen. Dimethoxyethane (1.6 mL) and 2 M K2CO3 (0.24 mL, 0.48 mmol) was added. The reaction was heated in oil bath at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetate as atropisomer mixture (39 mg, 60%). LCMS-ESI+: calcd for C30H37N2O4: 489.52 (M+H+). Found: 489.3.
Reaction SMILES: [CH3:1][CH:2]([C:4]([C@@:6]12[C@@:16]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])([CH3:17])[C@@H:15]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C@@:11]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])([C:12]1=[O:13])[C:10]([OH:34])=[C:9]([CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])[C:7]2=[O:8])=[O:5])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][CH:2]([C:4]([C:6]12[C:16]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23])([CH3:17])[CH:15]([CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[CH2:14][C:11]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])([C:12]1=[O:13])[C:10]([OH:34])=[C:9]([CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])[C:7]2=[O:8])=[O:5])[CH3:1]
Reactant: CC(C)=CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@]1(C(=O)C(C)C)C(=O)C(CC=C(C)C)=C2O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCCC1(C)C(CC=C(C)C)CC2(CC=C(C)C)C(=O)C1(C(=O)C(C)C)C(=O)C(CC=C(C)C)=C2O

Procedure:
2 g of hyperforin (M. W. =536,01) are dissolved in 20 ml of THF under magnetic stirring; the solution is added with LiAlH4 in strong excess (1 g, 0.026 mol, M. W.=38). The progress of the reaction is monitored by TLC (eluent petroleum ether/EtOAc 9:1). After ten minutes the reaction is completed.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:20][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)cc1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (ddd, J=10.5, 8.3, 8.3 Hz, 1H), 7.77-7.86 (m, 2H), 8.04 (ddd, J=11.4, 7.6, 2.0 Hz, 1 H), 9.31 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: C#CCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCC#Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g) and 3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine (100 ml) was purged with nitrogen for 20 min under nitrogen. Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous iodide (800 mg) were added. The mixture was stirred for 18 h and then the solvent was removed in-vacuo. The residual oil was triturated with ethyl acetate (200 ml) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on Biotage (90 g) eluting with light petroleum 40-60°-diethyl ether (3:2) to give the title compound (21 g). LCMS RT=3.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (10 g) in tetrahydrofuran (60 mL) was added borane-dimethylsulfide complex (7.07 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 minutes, and stirred at 75° C. for 2 days. The reaction mixture was cooled to room temperature. A saturated aqueous potassium carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (9.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9](C1C(C)=NNC=1C)[NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[NH:10]
Reactant: NCCCN
Reactant: Cc1n[nH]c(C)c1C(N)=NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(=N)NCCCN
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
A mixture of tert-butoxycarbonyl-1-(3,5-dimethylpyrazolyl)-formamidine (0.38 g, 1.5 mmol) and 1,3-diaminopropane (0.56 g, 7.5 mmol) was stirred at room temperature for 17 h. The crystalline product was collected by filtration, washed with toluene (2×0.7) mL), and vacuum dried (35° C., 1.5h) to afford 0.15 g (47%) of white crystals of N-(3-aminopropyl)-N'-tert-butoxycarbonyl guanidine (IIIg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]([F:17])([CH3:16])[C:11](OCC)=[O:12])[C:5]([N+:23]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:23][C:11](=[O:12])[C:10]([F:17])([CH3:16])[CH2:9][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(C)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
To a suspension of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.4 g, 9 mmol), reduced iron (1.2 g, 23 mmol) in acetic acid (20 ml) was added dropwise concentrated hydrochloric acid (2 ml) at 0° C. The reaction mixture was stirred at 60° C. for 18 h. It was then concentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solution at 0° C. The whole was filtered through celite, washed with EtOAc. The filtrate was then separated. The organic layer was dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether to afford the product (620 mg, 23% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.67 (m, 7H) 1.72 (d, J=4.0 Hz, 2H) 1.77-1.91 (m, 2H) 3.58-3.77 (m, 2H) 5.01 (t, J=8.2 Hz, 1H) 7.97 (s, 1H) 10.36 (s, 1H). [M+H] calc'd for C13H16ClFN4O, 299. found 299.
Reaction SMILES: C([Mg]Br)C.Br[CH2:6][C:7]1([CH2:10][C:11]#[N:12])[CH2:9][CH2:8]1.[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([CH3:23])=[CH:19]2>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([CH3:23])=[C:19]2[CH2:6][C:7]1([CH2:10][C:11]#[N:12])[CH2:9][CH2:8]1
Reactant: Cc1cc2cccc(Br)c2[nH]1
Reactant: N#CCC1(CBr)CC1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Product: Cc1[nH]c2c(Br)cccc2c1CC1(CC#N)CC1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 53.6 %

Procedure:
Ethyl magnesium bromide (3.0M diethyl ether solution, 72 mL) was slowly added dropwise under an argon atmosphere and ice-cooling to a solution of [1-(bromomethyl)cyclopropyl]acetonitrile (15 g) and 7-bromo-2-methyl-1H-indole (45 g) in toluene (250 mL), followed by stirring at 100° C. for 80 minutes. The reaction mixture was cooled to room temperature; quenched with a saturated aqueous ammonium chloride solution, diluted with water; and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by a purification system CombiFlash CompanionXL (manufactured by Isco, Co., Ltd., column: RediSep 350 g; hexane:ethyl acetate=95:5->70:30) to obtain title compound (14 g) having the following physical properties.
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:41])[C@H:17]([CH3:40])[C@@H:18]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.CO>C1COCC1>[Si:33]([O:32][C@@H:18]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C@@H:17]([CH3:40])[CH2:16][OH:41])([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35]
Reactant: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Lithium borohydride (2.0 M in THF, 5 mL, 10 mmol) was added dropwise to a stirred solution of 11 (2.77 g, 5 mmol) and methanol (0.4 mL, 10 mmol) in anhydrous THF (20 mL) under an atmosphere of N2 at 0° C. The mixture was stirred for 20 min at 0° C. and then warmed to ambient temperature. After 3 h at room temperature, the reaction was quenched with aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, evaporated and chromatographed (hexane/EtOAc 7:3) to yield the alcohol (1.48 g, 78%) as a colorless oil: IR (CHCl3) 2948, 2856, 2302, 1612, 1265 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 4.43 (s, 2H), 3.78 (s, 3H), 3.67 (dd, 1H, J=8.6, 10.5 Hz), 3.51-3.41 (m, 3H), 2.78 (br s, 1H), 1.94 (m, 1H), 1.72-1.49 (m, 4H), 0.90 (s, 9H), 0.81 (d, 3H, J=7.0 Hz), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) 159.2, 130.6, 129.3, 113.8, 75.4, 72.6, 70.1, 65.8, 55.9, 55.3, 39.7, 29.1, 26.6, 25.9, 18.0, 12.1, −4.28, −4.38; LRMS (ESI) 405.2 (M+Na).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.O>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccc(-c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(-c2ccccc2)cc1)OCc1ccccc1
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a suspension of 3-(biphenyl-4-yl)propanoic acid (5 g, 22.10 mmol) and K2CO3 (6.11 g, 44.2 mmol) in DMF (22 ml), BnBr (3.94 ml, 33.1 mmol) was added. After stirred for 15 hours, additional BnBr (3.94 ml, 33.1 mmol) was added. After stirred for further 22 hours, the reaction was diluted with H2O, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was diluted with EtOAc (150 ml), and NH-silica gel was added to the suspension. The EtOAc was evaporated, and the resulted slurry was allowed to stir for 1 hour. The slurry was eluted with 10% EtOAc/heptane (150 ml) to give benzyl 3-(biphenyl-4-yl)propanoate (6.16 g); Retention time=1.71 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (t, J=7.8 Hz, 2H) 3.01 (t, J=7.8 Hz, 2H) 5.12 (s, 2H) 7.21-7.47 (m, 14H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.NC(C(C)C)[C:23](OC)=[O:24]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]([CH2:17][O:24][CH3:23])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(N)C(C)C
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl
Product: COC[C@@H](C(=O)OC)N1Cc2ccc(Br)cc2C1=O
Yield: 65 %

Procedure:
The compound of example 353 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 2-amino-3-methylbutanoate hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:19]1OCCOCCOCCOCCOCCOC1.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:19])[C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSCC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 22 h

Procedure:
A solution of N-(tert-butyloxycarbonyl)-D-methionine (20 g.) in tetrahydrofuran was added dropwise with stirring to a suspension of potassium hydride (35% in mineral oil, 27.5 g.) in tetrahydrofuran (160 ml.) containing 18-crown-6 ether (1 g.) maintained at ice bath temperature. Stirring was continued for one and one quarter hours. Methyl iodide (5 ml.) was added, stirring was continued, and the temperature was allowed to rise to room temperature during 22 hours. The pH was adjusted to 3 with aqueous citric acid (1 M) with cooling. The mixture was partitioned between ether and water. The ether layer was extracted with aqueous sodium bicarbonate. The aqueous sodium bicarbonate layer was extracted with ether. The latter ether layer was washed with water, dried and stripped of ether, affording N-(tert-butyloxycarbonyl)-N-methyl-D-methionine as a syrup (15.5 g.).
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][OH:32])=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2].[OH:33]P([O-])(O)=O.[K+].[O-][Mn](=O)(=O)=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CC(O)(C)C.CCOC(C)=O>[C:1]([O:4][CH:5]([C:7]1[C:8]([C:31]([OH:33])=[O:32])=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CC(=O)OC(C)c1c(CO)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(=O)OC(C)c1c(C(=O)O)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of alcohol (110 mg) from Step 6 in t-BuOH (6 mL) was added a KH2PO4 buffer solution (pH 7, 4 mL) and a solution of KMnO4 (90 mg/2 mL H2O). After 3 hrs at r.t., the reaction mixture was diluted with EtOAc and an aqueous solution of Na2SO3. The mixture was then acidified to pH 2, the organic phase was separated, washed with H2O, brine, dried over MgSO4 and evaporated to give the title product which was used as such for the next step.