Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]=[S:28]1(=[O:43])[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([N:31]4[CH2:30][CH2:29][S:28](=[O:43])(=[O:27])[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, light yellow solid (116 mg, 82%), MS (ISP) m/z=564.4 [(M+H)+], mp 269° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomor-pholin-4-yl)-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:17]1[CH2:18][CH:13]3[CH2:19][CH:16]1[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.245 g, 1 mmol), (s,s) tert-butyl 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.22 g, 1.1 mmol) and potassium carbonate (0.14 g, 1 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=405, 407). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with 1:1 hexane/ethyl acetate to give (0.18 g) tert-butyl 5-(6-bromophthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate as a yellow solid. Found MS (ES+): 405, 407(M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.O1CCOCC1.C(O)C>Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N

Procedure:
Ethyl 5-[(tert-butoxycarbonyl)amino]-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylate (634 mg, 1.46 mmol) was taken up in 4 N HCl in dioxane (7.3 ml, 29.2 mmol) and ethanol (5 ml) and stirred at ambient temperature for 20 hours. The mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. Combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C15H19N4O3S) [M+H]+, 335.1; found 335.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2,6-dibromo-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@H:19]([CH3:30])[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][C@H:19]([CH3:30])[CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 108c (624 mg, 1.3 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid dropwise (300 mg, 2.6 mmol) at room temperature. Then the mixture was stirred for overnight. 2.0 N NaOH was added to adjust pH to greater than 10. Then the mixture was extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 108d as a brown solid (300 mg, 61%). LCMS: [M+H]+ 380
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][O:8]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.Cl>O1CCOCC1.O>[OH:8][CH2:7][C@H:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:37])[F:38])[CH:29]=1
Reactant: N#Cc1ccc(N2C(=O)CC[C@@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(N2C(=O)CC[C@@H]2CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of (R)-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoro methyl)benzonitrile 1d (3 g, 5.69 mmol) in 1,4-dioxane (30 mL), cooled to 0° C., 2M HCl in dioxane (30 mL) was added. The reaction mixture was then warmed up to room temperature and stirred for 16 h. After completion (by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the alcohol 1e (1.6 g, 93%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=O.O.[NH2:16][NH2:17]>C(O)C>[OH:14][N:12]1[C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[N:17]=[N:16]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: On1nnc2ccc(C(F)(F)F)cc21
Yield: 89.5 %

Procedure:
The title compound is prepared according to the procedure described by K. Takeda [J. Org. Chem., 50, 273, (1985)]. A mixture of 4-chloro-3-nitro-α,α,α-trifluorotoluene (50.0 g, 0.22 moles) and hydrazine hydrate (33.0, 0.33 moles) in absolute ethanol (75 ml) is refluxed for 24 h. After removal of the solvent under reduced pressure, the residue is dissolved in 10% aqueous sodium carbonate solution. The solution is washed with ether to remove the starting material and acidified with concentrated HCl to precipitate the product, which is washed with water and dried to obtain 40.0 g of the title compound. This product is recrystallized from ether.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([N+:38]([O-:40])=[O:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=3[N+:38]([O-:40])=[O:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=[N+]([O-])c1ccc(Cl)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-chloro-2-nitro-benzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 548.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-boc-4-hydroxypiperidine (32.2 g, 0.160 mol) in DCM (400 mL) was added TEA (26.8 mL, 0.192 mol), methanesulfonyl chloride (13.6 mL, 0.176 mol), DMAP (0.20 g, 0.0016 mol) at 0° C. under nitrogen atmosphere. The resulting mixture was slowly warmed to rt and stirred at the same temperature overnight. The mixture was washed with sat. aq. NaHCO3 (3×80 mL), brine (2×80 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to give crude 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester as a white solid, 44.7 g (yield: 100%). 1H-NMR (CDCl3, 400 MHz): δ 1.47 (s, 9H), 1.80-1.85 (m, 2H), 1.95-1.99 (m, 2H), 3.05 (s, 3H), 3.28-3.34 (m, 2H), 3.68-3.74 (m, 2H), 4.89 (m, 1H) ppm. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 90.3 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.0153 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (83.7 mg, 0.149 mmol, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:10]([CH:12]1[CH2:14][CH2:13]1)=O)=[CH:6][N:7](C)C)[CH3:2].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:10]([CH:12]3[CH2:14][CH2:13]3)=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:6]=[N:7]2)=[CH:20][CH:19]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C1CC1

Procedure:
Ethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate (Intermediate#32) (316 mg, 1.5 mmol) was dissolved in ethanol (5 mL). 4-bromophenylhydrazine hydrochloride (335 mg, 1.5 mmol) and DIPEA (264 μL, 1.5 mmol) were added and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient and evaporated under reduced pressure. The residue was dissolved in DCM (10 mL) washed with water and poured through a phase separating tube. The product was recovered from the filtrate by flash column chromatography (SiO2, elution gradient 0-25% EtOAc in isohexane). Pure fractions were combined and evaporated to give ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate as an oil that crystallised on standing. (343 mg, 87%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[N:8]=1)=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium hydride (4.6 g, 150 mmol, 80% in paraffin oil) indry THF (100 mL), a solution of 3-indazolecarboxylic acid methyl ester [(J.Am. Chem. soc, 74, 2009 (1952)] (22.0 g, 125 mmol) in dry THF (100 mL) was added dropwise with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (28.0 g, 150 mmol) in dry THE (100 mL) was added dropwise to the stirring reactant. After 4 hours, the solvent was evaporated in vacuo and the residue partitioned between water and CH2Cl2. The organic phase was separated, dried over Na2SO4 and the solvent evaporated to leave a solid which was recrystallized from ethyl acetate (31.0 g, 75%), m.p. 163°-165° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:6]([CH3:7])[CH3:5])[C:13]=1[O:14][C:1]([Cl:4])=[O:2])([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 20% solution of phosgene in toluene (139 mL, 0.269 mol) was added to a stirring solution of propofol (40 g, 0.225 mmol) in toluene (80.0 mL) under a nitrogen atmosphere at 0° C. N,N-Dimethylaniline (34.0 mL, 0.269 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature slowly and stirred for 14 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The crude product (2) was carried to the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 1H), 7.19-7.17 (m, 2H), 3.04-3.01 (m, 2H), 1.25 (d, J=7.2 Hz, 12H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1[CH2:22][CH2:21][O:20][CH2:19]C1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:22][CH:21]1[O:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1CC1CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of L-proline benzyl ester (156 mg, 0.49 mmol) in DMF (2 mL), cooled to 0° C., NMM (56 μL, 0.53 mmol) and HOBt (198 mg, 1.47 mmol) were added. The solution was stirred at 0° C. for 15 minutes and a solution of glycidic acid21 (100 mg, 1.13 mmol) in CH2Cl2 (2 mL) was added. Finally a solution of DCC (253 mg, 1.23 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred 16 h at room temperature and filtered to remove the precipitate. The residue was diluted with CH2Cl2 (10 mL) and washed with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL) and NaCl (10 mL, sat), dried (Na2SO4), filtered and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/1) to yield 120 (95 mg, 70%) as white foam. Rf 0.26 (AcOEt/Hexanes 1/1). 1H-NMR (500 MHz, CDCl3): mixture of rotamers 1.87-1.92 (m, 2H), 1.91-1.98 (m, 2H), 1.99-2.03 (m, 1H), 2.19-2.20 (m, 2H), 2.20-2.22 (m, 1H), 2.66-2.68 (m, 1H), 2.80-2.82 (m, 1H), 2.94-2.95 (m, 2H), 3.30-3.31 (m, 1H), 3.56-3.57 (m, 2H), 357-370 (m, 2H), 3.72-3.85 (m, 1H), 4.57-4.59 (m, 1H), 4.70-4.72 (m, 1H), 5.16 (s, 2H), 5.22-5.29 (m, 2H), 7.25-7.38 (m, 10H). 13C-NMR (125 MHz, CDCl3): 22.2, 24.9, 28.7, 30.9, 31.5, 45.9, 46.3, 46.4, 47.2, 48.0, 48.5, 58.7, 59.3, 66.9, 67.4, 128.1, 128.2, 128.4, 128.5, 128.7, 170.0, 182.3. HRMS m/z cald for C15H17NO4a (M+Na): 298.1055 found 298.1047.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.C([SiH](CC)CC)C>[Pd].CO>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: OC1(c2cc(F)cc(F)c2)CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of (+)-1-benzyl-3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.853 g, 2.95 mmol), methanol (15 mL) and palladium on carbon (170 mg) was purged with nitrogen. Triethyl silane (3.42 g, 29.5 mmol) was added in 7 equal portions over 3.5 h and the resulting mixture was stirred at ambient temperature for 3 h. The mixture was filtrated over celite, evaporated and Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (0.53 g). MS m/z (relative intensity, 70 eV) 199 (M+, bp), 141, (61), 127 (73), 114 (59), 113 (88).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13]C)=[O:11])=[CH:7][C:6]=2[CH:15]=1.C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(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>[CH3:13][O:12][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:6]=2[CH:7]=1)=[O:11]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(-c3cccnc3)ccc2o1
Temperature: 100 °C
Yield: 184.2 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate 15 (6 g, 22.3 mmole), diethyl 3-pyridylborane (3.66 g, 25 mmole), tetrakis(triphenylphosphine)palladium (0) (270 mg), and potassium phosphate (11.4 g, 53.7 mmole) in DMF (60 ml) was stirred under an argon atmosphere and heated to 100° C. for 16 hrs. The mixture was allowed to cool to room temperature, poured into ethyl acetate and washed with 10% HCl. The organic layer was washed with brine, dried, and evaporated to give 10.4 g of 5-pyridin-3-yl-benzofuran-2-carboxylic acid methyl ester. 534 mg the carboxylic ester were then dissolved in 11 ml t-butanol and stirred under nitrogen. Addition of 198 mg NaBH4 followed by 1.75 ml methanol and the reaction was stirred at 55° C. overnight. After cooling, the reaction was poured into brine and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography to give 330 mg of (5-pyridin-3-yl-benzofuran-2-yl)-methanol 61.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:42][CH2:43][OH:44])[O:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:51](Cl)([C:54]1[CH:60]=[CH:59][C:57]([CH3:58])=[CH:56][CH:55]=1)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:58][C:57]1[CH:59]=[CH:60][C:54]([S:51]([O:44][CH2:43][CH2:42][C@@:10]2([O:40][CH3:41])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:11]2)(=[O:53])=[O:52])=[CH:55][CH:56]=1
Reactant: CO[C@@]1(CCO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
2-((2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethanol (8) (0.46 g, 0.77 mmol) was dissolved in CH2Cl2 (2 mL). Pyridine (0.31 mL, 3.85 mmol) and TsCl (0.29 g, 1.54 mmol) were added and the reaction mixture was heated at 50° C. for 18 h. Additional TsCl (0.05 g, 0.26 mmol) was then added and the reaction mixture was heated at 50° C. for another 4 hours. The mixture was concentrated onto celite and chromatographed over SiO2, (ISCO system, 0-40% EtOAc/hexanes) to provide an oil (0.317 g, 55%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.66 (d, J=8.4 Hz, 2H), 7.14-7.32 (m, 22H), 4.77-4.89 (m, 4H), 4.46-4.57 (m, 4H), 3.86-4.07 (m, 1H), 3.48-3.64 (m, 4H), 3.31 (d, J=9.3 Hz, 1H), 3.17 (s, 3H), 2.36 (s, 3H), 2.13 (t, J=8.1 Hz, 1H). LC/MS tR=3.37 min, calcd for C44H48O9S: 752.3, found 775.2 (M+Na)+.