Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([N:32]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
(S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g) was dissolved in 2 mL dry THF and triphenylphosphine (0.29 g) and (R)-(+)-1-phenyl-1-propanol (0.15 g) were added. The mixture was stirred at 0° C. for 10 min, then DIAD 933 μL (0.22 g, 1.1 mmol) was added over 2 minutes. The reaction stirred at room temperature for 5 hours, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (0.42 g). This material was dissolved in DMF (0.7 mL), and then mercapto acetic acid (0.15 g) and DBU (0.48 g) were added and stirred at room temperature for 2 hours. The reaction was quenched by addition of NaHCO3 solution (4 mL) and product was extracted with ether. The ether layer was washed with water and brine, and then dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column (5% EtOAc in hexanes to 15% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g). LCMS (m/z): 607.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[N+:43]([O-:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+].C(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.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[C:35]([N+:43]([O-:45])=[O:44])[CH:36]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 81.7 %

Procedure:
tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (82, 50 mg, 0.102 mmol), 4-methyl-3-nitrophenylboronic acid (28 mg, 0.153 mmol), Tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol), and sodium carbonate (42 mg, 0.407 mmol), were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70 C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, triturated in methanol, centrifuged, decanted and the resulting solid was dried under vacuum and treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 84 as a white powder (35.2 mg, 43%). 1H NMR (500 MHz, DMSO d6) δ=13.48 (br, 1H), 12.57 (br, 1H), 7.96 (s, 1H), 7.86 (m, 2H), 7.76 (d, 1H), 7.64 (d, 1H), 7.57 (t, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 2.55 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:5])[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)C(=O)c1cccc2ccccc12
Product: CCN(CC)C(=O)c1c([Si](C)(C)C)ccc2ccccc12
Yield: 71 %

Procedure:
N,N-Diethyl-1-naphthalenecarboxamide was reacted with 2 eq TMSCl according to General Method A. The resulting reaction mixture was worked up in the usual manner, then purified by chromatography with 20% ethyl acetate/80% hexanes to afford 2.1 g of the desired compound as a clear oil, a 71% yield.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8](=[NH:10])[NH2:9])[S:6][CH:7]=1.CC[O-].[Na+].O=[C:18]([C:25]1[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[CH2:19][C:20](OCC)=[O:21]>C(O)C>[F:12][C:2]([F:1])([F:11])[C:3]1[N:4]=[C:5]([C:8]2[N:9]=[C:20]([OH:21])[CH:19]=[C:18]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[N:29]=3)[N:10]=2)[S:6][CH:7]=1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Reactant: CCOC(=O)CC(=O)c1nc(C(F)(F)F)cs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(-c2nc(C(F)(F)F)cs2)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of compound 27 (0.43 mmol) and NaOEt (2.15 mmol) in ethanol (2 mL) was added compound 28 (0.43 mmol). The reaction mixture was stirred at 100° C. overnight. The solvent was evaporated and water and AcOEt were added. The aqueous layer was acidified to pH˜4-5 by addition of 2.5M HCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM/MeOH 0 to 5%) to give compound 29 as a beige solid in 11% yield. MS (ESI, EI−): m/z=396.91 (MH−).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N+]=[N-].[CH2:31]([OH:33])[CH3:32]>[Pd]>[C:31]([NH:1][CH2:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Reactant: CCO
Agent: [Pd]
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CNC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 449 mg of cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine in 80 ml of ethanol is added 200 mg of 10% palladium on charcoal, and the mixture is subjected to hydrogenation for 1.5 hours at room temperature and atmospheric pressure. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness in vacuo. The residue is taken up in 30 ml of methylene chloride. Under stirring at 0° C., 0.20 ml of triethylamine is added to the resulting methylene chloride solution, and a solution of 0.10 ml of acetyl chloride in methylene chloride is added dropwise over 10 minutes thereto. The reaction mixture is stirred for 40 minutes and then washed with dilute hydrochloric acid, water, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution in this order, and dried over magnesium sulfate, and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue and the resulting crystals are collected by filtration to give cis-4 -acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, m.p. 205°-207° C.
Reaction SMILES: C[Si]([NH-])(C)C.[Na+].[CH3:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]([O:8][CH3:7])[CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:23]=1)[OH:26]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: COCC(=O)OC
Agent: C[Si](C)(C)[NH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Sodium trimethylsilylamide 1M in THF (20.73 mL, 20.73 mmol) was added to a 2-neck round bottom flask under nitrogen. The flask was placed in an acetone bath cooled to about −78° C. A solution of methyl 2-methoxyacetate (2.34 mL, 23.55 mmol) and 3-benzyloxybenzaldehyde (4.0 g, 18.85 mmol) in dry THF (24 mL) was added dropwise via cannula over 10 minutes. The mixture was stirred at −78° C. for 3 hours. HPLC-MS showed the presence of starting aldehyde at this time. Additional 10 mL of NaHDMS were added, and the mixture was stirred for another hour, and then HCl 3N (50 mL) was added to the mixture at −78° C. The bath was removed, and the mixture was extracted with diethyl ether (4×50 mL). The combined organic layers were dried over MgSO4 and concentrated to afford an oil that was purified by chromatography (silica gel, hexanes/ethyl acetate 3:1). Rf. 0.13. (two isomers) 1H-NMR (CDCl3, 200.15 MHz): 7.45–7.22 (m, 12H), 7.05–6.89 (m, 6H), 5.07 (d, 4H, J=1.1), 4.93 (dd, 2H, J=11.8, 5.9), 3.97 (d, 1H, J=5.6), 3.89 (d, 1H, J=5.4), 3.67 (s, 3H), 3.65 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.92 (br s, 1H), 2.83 (br s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17].Cl>CC(O)C>[CH:1]1[C:13]2[C:12](=[N:16][NH2:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: NN=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
9-Fluorenone (200 g, 1.1 mol, from Aldrich, Milwaukee, Wis.) and hydrazine monohydrate (160 ml, 3.3 mol, from Aldrich, Milwaukee, Wis.) were dissolved in 1000 ml of 2-propanol in a 2000 ml 2-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. Concentrated hydrochloric acid (4 ml) was then added, and the mixture was refluxed for one hour. The mixture was cooled slowly to room temperature, and the crude solid product was harvested by filtration. The solid was washed with isopropanol and then recrystallized from dioxane to obtain 150 g (74% yield) of 9-fluorenone hydrazone.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[CH3:23][S:24]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (15 g, 69.67 mmol, 1.00 equiv) and triethylamine (15.5 g, 153.18 mmol, 2.00 equiv) in dichloromethane (150 mL) was added methanesulfonyl chloride (9.6 g, 83.81 mmol, 1.21 equiv) dropwise with stiffing at 0° C. The resulting solution was stirred for 10 min at 0° C. and warmed to room temperature overnight. Water (100 mL) was added to quench the reaction. The resulting mixture was extracted with 3×200 mL of dichloromethane. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 7 g (34%) of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate as a white solid.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[F:59][C:60]([F:69])([F:68])[C:61]1[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=1>>[OH:56][CH2:55][CH2:54][C:52]1[N:51]=[N:50][N:49]([C:47]2[CH:46]=[CH:45][C:44]([CH3:57])=[C:43]([C:41]([C:38]3[CH:39]=[CH:40][C:35]([NH:67][C:63]4[CH:64]=[CH:65][CH:66]=[C:61]([C:60]([F:59])([F:68])[F:69])[CH:62]=4)=[CH:36][C:37]=3[CH3:58])=[O:42])[CH:48]=2)[CH:53]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2cccc(C(F)(F)F)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-trifluoromethyl-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.5, 146.8, 145.7, 142.3, 142.2, 142.1, 135.3, 135.1, 134.4, 132.2, 130.6, 130.2 (q), 127.6, 124.1 (q), 122.0, 120.7, 120.5, 118.5, 117.7 (q), 114.9 (q), 112.0, 60.2, 29.2, 21.9, 18.9
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([O:18][CH3:19])[C:13](=O)[NH:14][C:15](=O)[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@:11]2([O:18][CH3:19])[C@@H:10]([CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@]12CNC[C@H]1CN(Cc1ccccc1)C2
Temperature: 45 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of (+/−)-cis-5-benzyl-3a-methoxytetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (4.5 g, 17 mmol) in THF (200 mL) was added LAH solution (35 mL, 35 mmol, 1 M in THF) at 0° C. The resulting mixture was stirred at 45° C. overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. The mixture was quenched by water (3 mL) and filtered. The filtrate was concentrated to afford crude title compound (3.7 g, crude), which was used for the next step directly.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH2:18]=O>CO>[ClH:1].[CH2:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1
Reactant: C=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
5.09 g of L-tryptophan methyl ester hydrochloride are dissolved in 60 ml of methanol. 1.89 g of 35% formalin are added thereto, and the mixture is stirred at room temperature overnight. After distilling off the solvent, the resulting residue is recrystallized from methanol. 4.42 g of methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride are obtained as colorless needles. Yield: 82.9%
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23]C=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH3:44][N:45]1[CH:49]=[CH:48][N:47]=C1C=O>C1COCC1.C(OCC)C.O>[CH2:2]([O:9][C:10]1[C:11]([CH:19]=[CH:24][C:23]2[N:45]([CH3:44])[CH:49]=[CH:48][N:47]=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cc2c(cc1OCc1ccccc1)CCO2
Reactant: Cn1ccnc1C=O
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1C=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A flame dried, N2 purged, 100 ml round bottom flask equipped with a dropping funnel, thermometer and magnetic stirrer was charged with 5-(benzyloxy)-2,3-dihydrobenzofuran-6-yl methyltriphenylphosphonium iodide (3.0 g, 4.8 mmoles) and anhydrous THF (15 ml). The suspension was cooled to -20° C. and a 1.55 M solution of n-butyllithium (3.1 ml, 4.8 mmoles) was added dropwise, while maintaining an internal reaction temperature of -20° C. The suspension became a red solution and stirring was continued 1 hour more at 0° C. The reaction mixture was chilled to -25° C. and a solution of 1-methylimidazole-2-carboxaldehyde (525 mg, 4.8 mmoles) in THF. (10 ml) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to room temperature and stir for 12 hours. It was then cooled to 0° C. and water (1.0 ml) added. It was further stirred for 1/2 hour whereupon the solvent was removed in vacuo to afford the crude product. The crude product was dissolved in ethyl ether (20 ml) and water (20 ml). The layers were partitioned and separated. The organic phase was washed with water (2×20 ml), dried over MgS04, suction filtered, and the filtrate concentated in vacuo to yield a crude yellow oil. Further purification was achieved by high performance liquid chromatography to produce approximately a 1:1 ratio of cis and trans isomers of 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2-(1-methyl-imidazol-2-yl)ethene (600 mg, 38%).
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C:24]3(O)[C@H:29]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@@H:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:27]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[O:25]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]2[CH:64]=[CH:65][CH:66]=[CH:67][C:9]1=2.O>C(Cl)Cl>[S:8]1[C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C@H:24]3[C@@H:29]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:27]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[O:25]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]2[CH:64]=[CH:65][CH:66]=[CH:67][C:9]1=2
Reactant: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: c1ccc(COC[C@H]2O[C@@H](c3cc(Cc4cc5ccccc5s4)cc4ccccc34)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
In a nitrogen stream, triethylsilane (0.34 ml, 2.06 mmol) and a boron trifluoride-diethyl ether complex (0.24 ml, 1.89 mmol) were added dropwise to a solution of (3R,4S,5S,6R)-2-[3-(benzo[b]thiophen-2-ylmethyl)naphthalen-1-yl]-3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-ol (1.4 g, 1.72 mmol) in methylene chloride (15 ml) at 0° C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto and extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate n-hexane (1:10)] to obtain the title compound (1.1 g, 80.2%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[N:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH2:21][NH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:5]=[CH:4][N:3]=1.[NH2:25][CH2:26][C@@H:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[F-].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:8][C:7]1[C:2]([NH:25][CH2:26][C@@H:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[N:3][CH:4]=[N:5][C:6]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: Cc1c(Br)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 37.4 %

Procedure:
A mixture of 620 mg (1.6 mmoles) of 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 565 mg (1.92 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0), 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane is heated under reflux for 5 hours. After cooling down another 280 mg (0.96 mmoles) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0), and 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl are then added and the reaction mixture is heated under reflux for 5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed a first time on silicagel eluting with a gradient of ethyl acetate-methylene chloride-triethylamine-methanol from 50-50-0-0 to 50-50-2-2. The product obtained is chromatographed a second time on alumina eluting with a mixture of heptane-methylene chloride 50-50 then with ethyl acetate-diisopropyl ether 50-50. 360 mg (Yield=37%) of expected product is obtained in the form of an amorphous white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:28])=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: Cc1ccccc1/C=C/C(=O)O
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-o-tolyl-acrylic acid.