Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][C:48]1[N:52]=[C:51]([CH2:53][O:54][CH2:55][C@H:56]([NH:64][CH3:65])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:50][N:49]=1>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:12])[N:64]([CH3:65])[C@@H:56]([CH2:55][O:54][CH2:53][C:51]1[O:50][N:49]=[C:48]([CH3:47])[N:52]=1)[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN[C@@H](COCc1nc(C)no1)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(COC[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (701 mg, 2.68 mmol) was dissolved in dichloromethane (4 mL) and N,N-dimethylformamide (4 mL). The solution was cooled to 0° C. 1-Hydroxy-7-azabenzotriazole (365 mg, 2.68 mmol) and N-(3- dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (617 mg, 3.22 mmol) were successively added. The solution was stirred for 15 min at 0° C. A solution of 3-methyl-5-(((2R)-2-(methylamino)-3-phenylpropoxy)methyl)-1,2,4-oxadiazole (701 mg, 2.68 mmol) in dichloromethane (4 mL) was added. The reaction mixture was stirred for 16 hours, while the temperature slowly rose to room temperature. It was diluted with ethyl acetate (100 mL) and extracted with a mixture of saturated sodium chloride solution (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution and dried over magensium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/heptane (2:1) to give 1.23 g of N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[O:22])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][OH:22])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of tert-butyl 4-(5-bromo-3-formylpyridin-2-yl)piperazine-1-carboxylate (1 g) and MeOH (20 ml) was added sodium borohydride (153 mg). After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure. To the obtained residue was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-[5-bromo-3-(hydroxymethyl)pyridin-2-yl]piperazine-1-carboxylate (922 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:29])[CH2:4]1)[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:20][CH:21]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:29])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(C)=O)cc3)oc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(C)O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
27 mg (69 μmol) 5-ethyl-6-{2-[4-(2-oxo-propoxy)-phenyl]-benzoxazol-6-yl}-4,5-dihydro-2H pyridazin-3-one are placed in 5 mL EtOH, 5.5 mg (145 μmol) sodium borohydride are added with cooling and the mixture is stirred for 3 h at RT. The reaction mixture is added to 50 mL ice water and extracted with DCM. The org. phase is washed with sat. saline solution and then the solv. is totally eliminated i.V. The residue is crystallised from cyclohexane/EA.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>CO>[Cl:1][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N+:4]=1[O-:37]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Yield: 64.4 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.0 g), m-chloroperoxybenzoic acid (85%, 2.3 g) and methanol (40 ml) was stirred under reflux for 2 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was poured into chloroform. The chloroform layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (6:4, v/v), ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4- dimethoxyphenyl)quinoline-3-carboxylate 1-oxide (2.0 g, 65%) was obtained and recrystallized from acetone/isopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]OS(C)(=O)=O)[CH2:38][CH2:37]1)(=[O:35])=[O:34]>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:43][CH2:42][N:39]4[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Reactant: CS(=O)(=O)OCCN1CCN(S(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(c2cc(F)cc(F)c2)=C(c2cccnc2)C3=O)CC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 of Example 128 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and methylsulfonyl 2-(4-(methylsulfonyl)piperazin-1-yl)ethyl ether (77 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O (5 mL) and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (65 mg, 69%).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[CH2:16]([O:23][C@H:24]1[CH2:29][C@@H:28](O)[C@H:27]([NH:31][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([O:23][C@@H:24]1[CH2:29][CH2:28][C@@H:27]([NH:31][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[C@H:26]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:25]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](N[C@@H]1CC[C@@H](OCc2ccccc2)C[C@H]1O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N[C@@H]1CC[C@@H](OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (8.8 mL, 38.5 mmole) was added to an ice-cooled, stirred solution of (1R,2R,5R)-5-(benzyloxy)-2-((S)-1-phenylethylamino)-cyclohexanol) (4.8 gm, 14.8 mmole) and TEA (8.2 mL, 59.1 mmole) in dry DCM (250 mL). After 15 min, this was washed with a saturated aq. solution of NaHCO3 and dried (Na2SO4). Removal of the solvent followed by column chromatography (silica gel, step gradient elution with hexane containing 0 to 30% EtOAc) afforded (1R,2R,4R)-4-(benzyloxy)-2-(tert-butyldimethylsilyloxy)-N-((S)-1-phenylethyl)cyclohexanamine (6.2 gm, 95%): MS: 440 (M+H)+; HPLC Ret Time: 2.73 min (YMC Xterra S5 3.0×50 mm column, 3 min gradient, 4 mL/min). A mixture of this material (6.2 gm, 14 mmole), di-tert-butyl dicarbonate (12.2 gm, 56 mmole) and palladium hydroxide (6.5 gm, 20 wt % on carbon, wet) in EtOH (250 mL) was hydrogenated (Paar apparatus, 50 psi H2, 16 hr, RT). Removal of the catalyst and solvent followed by column chromatography (silica gel, step gradient elution with hexane containing 0 to 30% EtOAc) afforded the product (3.3 gm, 68%): [a]25589−19.1 (c 5.9, MeOH); 1H NMR (CDCl3) 0.11 (s, 3H), 0.13 (s, 3H), 0.78 (s, 9H), 1.20 (m, 1H), 1.33 (s, 9H), 1.46 (m, 1H), 1.53 (m, 1H), 1.64 (m, 1H), 1.89 (m, 1H), 2.06 (m, 1H), 2.7 (br s, 1H), 3.36 (m, 1H), 3.36 (m, 1H), 3.67 (m, 1H), 4.38 (m, 1H); MS 346 (M+H).+
Reaction SMILES: Br[C:2]1[C:3]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1>CO.[Pd]>[OH:35][C:8]1([C:3]2[CH:2]=[CH:6][N:5]([CH3:7])[N:4]=2)[CH2:9][CH2:10][CH:11]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:12][CH2:13]1
Reactant: Cn1cc(Br)c(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Agent: [Pd]
Solvent: CO
Product: Cn1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
N-({1-[4-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 31a (100 mg, 0.18 mmol) in MeOH (25 mL) was passed through a 10% Pd on C cartridge in a H-Cube® Continuous-flow Hydrogenation reactor (ThalesNano, Budapest, Hungary) under full hydrogen mode (flow rate 1 mL/min). The resulting solution was concentrated to give the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]3)=[CH:19][CH:18]=1
Reactant: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCc2c(-c3ccc(Cl)cc3)ccc([N+](=O)[O-])c2C1

Procedure:
A mixture of 5-bromo-N-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline (4.07 g, 15 mmol), 4-chlorophenylboronic acid (3.5 g, 22.5 mmol), sodium carbonate (8.0 g, 75.5 mmol), 1,2-dimethoxyethane (60 ml), water (30 ml) and tetrakis(triphenyl-phosphine)palladium(0) (0.20 g, 0.17 mmol) was stirred at reflux for 3.5 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The crude mixture was recrystallized from ethanol (96%). Yield 3.62 g (80%). Mp 162-163° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:4].[OH-].[Na+].[O:14]=[C:15]1[NH:21][C:20]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:19]=2[N:18]([C:27](=[O:33])[C:28]2[S:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][CH:16]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:6]1([CH3:11])[C:5]([C:3]([CH2:2][N:21]2[C:20]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:19]=3[N:18]([C:27](=[O:33])[C:28]3[S:32][CH:31]=[CH:30][CH:29]=3)[CH2:17][CH:16]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:15]2=[O:14])=[O:4])=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
2-Bromo-2′-methylacetophenone (0.51 g), 1N aqueous sodium hydroxide (20 ml), toluene (20 ml) and tetra n-butylammonium bromide (20 mg) were added to 2-Oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.80 g), the mixture was stirred at room temperature for 4 hours. The reaction mixture was separated into organic layer and aqueous layer, the aqueous layer was extracted with ethyl acetate, the extract was combined with the former organic layer. The combined extract was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.02 g of the title compound as colorless amorphous (Yield: 96%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 1-chloro-4-nitrobenzene (158 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was scaled with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 196 mg (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[Sn](CCCC)(CCCC)CCCC)[CH:7]=1.Br[C:25]1[N:26]=[C:27]2[C:33]([CH:34]=[O:35])=[CH:32][N:31]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]2=[N:29][CH:30]=1.O>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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[C:25]2[N:26]=[C:27]3[C:33]([CH:34]=[O:35])=[CH:32][N:31]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]3=[N:29][CH:30]=2)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3ncn4cc(F)ccc34)cnc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 105.4 %

Procedure:
In a round-bottomed flask, 6-fluoro-1-tributylstannyl-imidazo[1,5-a]pyridine (577 mg, 0.81 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (210 mg, 0.59 mmol) were dissolved in DMF (5 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.029 mmol) and copper (I) iodide (22 mg, 0.12 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath for 4 h then cooled to room temperature. Water was added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 256 mg (95%) of 2-(6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cc3ccccc3)c2)CC1
Yield: 96.2 %

Procedure:
A mixture of 74 mg (0.21 mmol) of 1-tert-butoxycarbonyl-4-((3-benzyl)phenyl)-1,2,3,6-tetrahydropyridine (from Step D) and 6 mg of 10% palladium on carbon in 1 mL of EtOAc and 3 mL of MeOH was hydrogenated at 40 psi of hydrogen on a Parr shaker for 3 hours. The reaction was filtered and concentrated under reduced pressure to yield 71 mg (95%) of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3) δ1.43-1.83 (m, 13H), 2.62 (m, 1H), 2.80 (m, 2H), 3.99 (s, 2H), 4.25 (m, 2H), 7.06-7.33 (m, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[N:14]1[CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)[CH:17]=[N:16][CH:15]=1
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cn(-c2cncnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a vial containing methyl 1H-indole-3-carboxylate (471 mg, 2.69 mmol), pyrimidin-5-ylboronic acid (1.0 g, 8.07 mmol), copper (II) acetate (635 mg, 3.5 mmol), 4 {acute over (Å)} molecular sieves (4 g) and 1,10-phenanthroline (970 mg, 5.38 mmol) were added DCM (10.7 ml) and triethylamine (0.375 ml, 2.69 mmol). The mixture was stirred at RT for 7 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and filtration) afforded the title compound as a tan solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[CH2:11](S)[CH2:12][CH2:13][SH:14].CS(O)(=O)=O>C(O)(=O)C>[CH2:11]1[O:10][C:4]2([CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[S:14][CH2:13][CH2:12]1
Reactant: SCCCS
Reactant: O=C1CN2CCC1CC2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: C1COC2(CN3CCC2CC3)SC1
Yield: 99.8 %

Procedure:
A mixture of 3-quinuclidinone hydrochloride (10 g, 62 mmol), 1,3-propanedithiol (13.4 g, 124 mmol), acetic acid (40 ml), and methanesulfonic acid (2 ml) was refluxed overnight. Most of the acetic acid was evaporated, 200 ml of water was added, and the solution was washed twice with ether. The pH of the solution was adjusted to basic by the addition of 1 M aqueous sodium hydroxide and the product was extracted with two portions of ethyl acetate. Drying over magnesium sulfate and evaporation of the solvent gave the title compound (13.3 g, 61.9 mmol, 100%) as a colorless solid 71-72° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[CH:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:46]([O:48][C:49](=[O:63])[CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][C:53]=1[C:59]([F:62])([F:61])[F:60])[CH3:47]>C1COCC1>[CH2:46]([O:48][C:49](=[O:63])[CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([S:58][CH2:8][CH:7]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:54][C:53]=1[C:59]([F:60])([F:61])[F:62])[CH3:47]
Reactant: OCC=C(c1ccco1)c1ccco1
Reactant: CCOC(=O)COc1ccc(S)cc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCC=C(c2ccco2)c2ccco2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 3,3-bis-(2-furanyl)-prop-2-en-1-ol (104 mg, 0.55 mmol) and triphenylphosphine (275 mg, 1.09 mmol) in THF (10 ml) was added, at room temperature and under nitrogen atmosphere, DEAD (190 mg, 1.09 mmol). The reaction mixture was stirred for 5 min after which (2-trifluoromethyl4-mercapto-phenoxy)-acetic acid ethyl ester (230 mg, 0.82 mmol) was added over 15 min. The reaction mixture was stirred at 0oC for 2 hours followed by 18 hours at room temperature and 3 hours at 50° C. The reaction mixture was evaporated and the crude residue was purified on column chromatography using ethyl acetate as eluent. The desired {4-[3,3-bis-(2-furanyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester was isolated in 11 mg yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(Br)c1ccc(Br)cc1
Yield: 75 %

Procedure:
A solution of 1-(4-bromo-phenyl)-ethanol (4.21 g, 20.9 mmol) in 15 mL of CH2Cl2 was reacted with 15 mL of 1.0M PBr3 in CH2Cl2 at room temperature for 4 h. Quenched by pouring into ice and adjusted to pH 9 with 5% aqueous NaHCO3. Extracted with CH2Cl2 and dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (4.1 g, 75%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:13])=[O:12])[C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C@@H:23]3[CH:24]4[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]4)[CH2:22]3)=[O:12])[C:2]1=2
Reactant: O=C(O)C(Nc1ccccc1)c1cccc2ccsc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.9 %

Procedure:
A mixture of 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetic acid (I26) (303 mg, 1.07 mmol), (R)-quinuclidin-3-ol (136 mg, 1.07 mmol), DCC (221 mg, 1.07 mmol) and HOBT (164 mg, 1.07 mmol) in THF (20 ml) was stirred at r.t. for three days. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3, and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=9/1 to EtOAc/MeOH=9/1+0.5% NH4OH) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetate (180 mg, 42.9% yield).