Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.[C-:8]1(CC(O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=C1.[Fe+2:22].C1(C)C=CC=CC=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[NH:31][NH2:32]>ClCCl>[C-:7]1([CH2:6][NH:3][C:4]([NH:32][NH:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:17]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:22]
Reactant: O=C(O)C[c-]1cccc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)NN
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)NC[c-]1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Under ice cooling, 0.57 mL (4 mmols) of triethylamine was added to a mixture of 0.5 g (2 mmols) of ferroceneacetic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.), 0.44 mL (2 mmols) of diphenylphosphyrylazide and 4 mL of toluene. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane. The dilution was washed sequentially with a 1% hydrochloric acid aqueous solution and saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure to give 4 mL of the toluene solution. To the toluene solution obtained, 2 mL of toluene was added and 0.32 g (3 mmols) of ethyl carbazate was added to the mixture while stirring at room temperature. The mixture was then heated under reflux for 3 hours and diluted with dichloromethane. The dilution was washed sequentially with a 1% hydrochloric acid aqueous solution and saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 0.55 g (78%) of ethyl 3-(ferrocenylmethyl)carbamoylcarbazate as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][N+](C)(C)C)=[C:27]2[C:23]=1[C:24]([CH3:38])=[C:25]([CH3:37])[N:26]2[CH3:36].[I-].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:28]2[CH:29]=[CH:30][C:22]([Cl:21])=[C:23]3[C:27]=2[N:26]([CH3:36])[C:25]([CH3:37])=[C:24]3[CH3:38])[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1c(C)n(C)c2c(C[N+](C)(C)C)ccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 100 °C
Yield: 15 %

Procedure:
To a stirred solution of 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (93 mg, 0.34 mmol) in DMF (10 ml) was added (4-chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-trimethyl-ammonium; iodide (132 mg, 0.34 mmol) followed by potassium carbonate (140 mg, 1.01 mmol). The resulting mixture was warmed at 100° C. over night and cooled to ambient temperature. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic phase was dried (MgSO4), filtered and concentrated to give the crude product. Purification via preparative TLC (1 mm silica gel, 20% EtOAc/hexanes) gave 25 mg (15%) of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([C@@H:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:20]=2)=[CH:12][CH:11]=1)(C)(C)C.Cl.[CH2:51]([O:58][C:59]1[CH:64]=[CH:63][C:62]([C@@H:65]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[CH2:66]Br)=[CH:61][C:60]=1[CH2:76][OH:77])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[NH3:7].[CH2:51]([O:58][C:59]1[CH:64]=[CH:63][C:62]([C@@H:65]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[CH2:66][NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:21]([C@@H:33]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:34][CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:42])[CH3:41])[CH:20]=3)=[CH:14][CH:15]=2)=[CH:61][C:60]=1[CH2:76][OH:77])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)cc2)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl{2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethoxy)phenyl]ethyl}carbamate (Preparation 41, 830 mg, 1.25 mmol) was treated with hydrochloric acid (8 ml of a 4M solution in 1,4-dioxane) and stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was dissolved in acteonitrile (8 ml) and {2-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanol (Sali patent, 560 mg, 1.24 mmol) and sodium hydrogen carbonate (368 mg, 4.34 mmol) added. Mixture heated to 85° C. and stirred overnight. Reaction was cooled to room temperature and ethyl acetate and water added, the aqueous layer was separated and washed with ethyl acetate and the combined organics dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (92.517.511 by volume) to furnish the title compound as a gum, 280 mg.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH3:38])(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:35][CH2:36][O:37][CH3:38])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCCOC)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), 2-Methoxyethyl p-Toluenesulfonate (0.084 ml, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to a yellow oil. The product was purified by flash column chromatography eluting with 0 to 2.5% EtOAc in hexane. 1H NMR (500 MHz, CDCl3) δ ppm 8.08, 7.39-7.23, 5.95, 5.33-5.28, 4.71, 3.79, 3.57, 3.45, 3.06, 2.61, 1.75-1.72, 1.60-1.54, 1.42-1.39; MS (EI) m/z 397 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](C(=O)O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To a solution of (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (10.0 g, 44 mmol) in DMF (25 mL) was added potassium carbonate (6.33 g, 45.8 mmol) followed by methyl iodide (4.0 mL, 64 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc. The solution was washed with water four times and brine one time, dried (MgSO4) and concentrated. The residue was dried under high vacuum overnight to provide the title compound (11 g, 99%). MS calculated for C12H19NO4: (M+H)+ 242; found 142.1 (M-Boc+H)+. 1H NMR (CDCl3) δ 5.86 (m, 2H), 4.90 (m, 1H), 4.80 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 2.51 (m, 1H), 1.86 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([O:25][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](OCCC1CC(O)C1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCCC1CC(OC2CCCCO2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105 %

Procedure:
3-(2-{[Tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanol (3.58 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 mL) and 2,3-dihydro-4H-pyran and 4-toluenesulfonic acid pyridine salt were added and the reaction was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo and purified on silica gel with a heptane-ethyl acetate gradient (5% ethyl acetate, then 20% ethyl acetate) to give crude tert-butyl(diphenyl){2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}silane (4.66 g, 105%) as a milky oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.05 (m, 0.80H), 4.30 (m, 0.20H), 4.52 (m, 0.20H), 4.56 (m, 0.80H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].Cl[CH2:16][C:17]1[N:21]=[C:20]([C:22]2[C:23]([CH3:28])=[N:24][O:25][C:26]=2[CH3:27])[O:19][N:18]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:16][C:17]3[N:21]=[C:20]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C)n1

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: MS (ESI) m/z 383 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:19]([N:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:9]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)N1CCCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCCN(Cc2ccccc2)CC1
Yield: 80.9 %

Procedure:
Potassium carbonate (0.80 g) was added to a solution of 0.86 g of ethyl 1-homopiperazinecarboxylate and 0.90 g of benzylbromide in 5 ml of tetrahydrofuran, and the mixture was refluxed for 4 hours. Thereafter, water was added, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (2:1) mixture gave 1.06 g of ethyl 4-benzylhomopiperazine-1-carboxylate.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(N)CCCCC1>CO>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (691 g, 1.77 mol) and ethyl acetate (7.0 liters) were added to an aqueous solution of citric acid (10%, 6.3 liters) and the organic phase was separated, washed with water (7.0 liters) and concentrated in vacuo to a yellow oil. A solution of the oil and 5% rhodium on carbon (51.6 g) in methanol (7.0 liters) was stirred at ambient temperature, under hydrogen (150 p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added cyclohexylamine (202 ml, 1.77 mol) and the methanol solution was stripped and replaced with methylethyl ketone by distillation at atmospheric pressure, to a volume of 5.5 liters. The mixture was allowed to cool to ambient temperature where it was stirred for 48 hours and then filtered. The residue was washed with methylethyl ketone (2×500 ml) and then dried in vacuo at 45° C. for 4 hours to leave the title compound as a colourless solid (495 g, 71%).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[NH:21]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:22]([C:31](O)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:37]([O:36][C:34](=[O:35])[NH:21][CH:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:31]([N:9]1[CH2:8][CH2:7][N:6]([CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])[CH2:11][CH2:10]1)=[O:32])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCN(CC)CC(c1ccccc1F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)CC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To Diethyl-[2-(2-fluoro-phenyl)-2-piperazin-1-yl-ethyl]-amine (513) (0.206 g, 0.738 mmol) was added Boc-4-chloro-D-Phe (0.221 g, 0.738 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.141 g, 0.738 mmol), 1-Hydroxybenzotriazole hydrate (0.099 g, 0.738 mmol), DCM (5.0 mL) and 4-methylmorpholine (0.243 mL, 2.215 mmol). The reaction was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated to dryness. The resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 and brine. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 5% MeOH/5% TEA in EtOAc) yielding 0.41 g (99%) pure product.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]2[Cl:27].[CH3:28][C:29]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>C1COCC1>[Cl:27][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:31]([C:30]3[C:29]([CH3:28])=[N:36][C:35]([CH3:37])=[CH:34][CH:33]=3)[OH:32])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(F)cc1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-3-(4-fluorobenzyl)-2-methoxyquinoline (0.826 g, 2.17 mmol, Intermediate 7: step d) in dry THF (11 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 2,6-dimethylnicotinaldehyde (0.23 mL, 1.8 mmol) in dry THF (3 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.6, 2.0 Hz, 1H), 7.26-7.21 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 2H), 6.07 (s, 1H), 4.22 (s, 2H), 4.05 (s, 3H), 3.77 (s, 1H), 2.46 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[Cl-].[C:31]([CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:32].O>ClCCl>[C:31]([CH:33]=[CH:3][C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)#[N:32]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=CC#N)cc3ccccc13)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of a 50% strength sodium hydroxide solution is added to a solution of 0.36 g (1 mmol) of the compound of Example 1 and of 0.34 g (1 mmol) of cyanomethyltriphenylphosphonium chloride in 3 ml of dichloromethane. The mixture is stirred at ambient temperature for 1 hour. 10 ml of water are then added and the aqueous phase is extracted with twice 10 ml of dichloromethane. The organic phase is washed, dried and evaporated. A purification is performed on a silica column (CH2Cl2 eluent).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([O:15][C@@H:24]1[CH:25]2[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]2)[CH2:23]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(NC(C(=O)O)c1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a solution of 2-(benzyloxycarbonylamino)-2-phenylacetic acid (I28) (855 mg, 3.00 mmol) in THF (20 ml), were added (R)-quinuclidin-3-ol (457 mg, 3.60 mmol), N,N′-methanediylidenedicyclohexanamine (742 mg, 3.60 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (486 mg, 3.60 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the clear solution was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The resulting crude is purified by silica gel flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzyloxy-carbonylamino)-2-phenylacetate (925 mg; 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[S:31])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Yield: 109.4 %

Procedure:
Estrone methyl ether (2, 17.64 g, 62.2 mmol) was dissolved in 500 mL of dry tetrahydrofuran (THF) and a first portion of Lawesson's reagent (13 g, 32 mmol) was added. The reaction mixture containing suspended solid was heated to reflux for 18 h when all solids dissolved and the solution became salmon red. A second portion of Lawesson's reagent (13 g, 32 mmol) was added and heating continued at reflux temperature for another 18 h. Similarly, a third portion of Lawesson's reagent (13 g, 32 mmol) was added; and after being heated for 18 h, the reaction mixture was cooled and the THF evaporated to give a thick slurry. The slurry was dissolved in a minimum amount of CH2Cl2 and passed through a pad of silica gel to remove a polar by-product of Lawesson's reagent. The eluent was concentrated to afford a bright orange solid which was further purified by column chromatography on silica gel with EtOAc-Hexanes (1:3) as eluent to afford a bright orange solid product (10.5 g, 35 mmol) in 56% yield as the first fraction and then starting material (4 g, 14.0 mmol) in 23% recovery. Crude thione 3 can be further purified by crystallizing from boiling EtOAc, although after column purification it is pure enough for subsequent reactions. 1H NMR (250 MHz, CDCl3) δ 0.94 (s, 3, C-S 8 CH3), 3.78 (s, 3, --OCH3), 6.64-6.75 (m, 2, ArH), 7.22 (d, J=10 Hz, 1 ArH); 13C NMR (250 MHz, CDCl3) δ 273.3 (C=S).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[S:30][C:29]([S:31]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:32])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.00 g, 4.25 mmol) in dichloromethane (50 ml) was treated with morpholinomethyl-polystyrene HL resin (2.10 g, 4.0 mmol/g loading, 8.50 mmol) followed by 5-bromo-2-thiophenesulfonyl chloride (1.33 g, 5.09 mmol). The resulting solution was stirred at room temperature overnight and was then filtered and the solvent evaporated. The residue was then chromatographed over silica gel (Flashmaster (II)) eluting with 0 to 10% methanol in dichloromethane 90% for 5 mins, 0-10% 20 mins and 10% 10 mins). The compound was then purified by mass directed autoprep HPLC and the residue further purified by SCX, eluting with methanol first and then NH4OH/methanol. (E122). MS (ES+) m/e 460/462 [M+H]+.