Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CCC[N:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)C.[CH:22]1[CH:23]=CC2[C:26](=CC(C(O)=O)=C(O)C=2CC2C(O)=C(C(O)=O)C=C3C=2C=CC=C3)[CH:27]=1>C1(C)C=CC=CC=1>[CH2:17]([NH2:7])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:23][CH2:22][CH2:27][CH3:26]
Reactant: CN(C)CCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN
Reaction time: 3 h
Yield: 100 %

Procedure:
To a 100 mL round-bottom flask equipped with a magnetic stir bar and addition funnel was charged 730 mg (0.769 mmol) imipramine pamoate, (2:1) salt (prepared as described in King, et al.) in 10.7 g toluene to form a suspension. A solution of 207.3 mg (0.769 mmol) octadecylamine in 12.5 g toluene was prepared and added dropwise to the above suspension over 1 hour. The suspension was stirred for an additional 3 hours and the solids collected by filtration through a medium fritted filter. The product was dried under vacuum to provide 600 mg (83%) of a white solid (2.5% water) which was characterized by DSC, FTIR (FIG. 63), PXRD (FIG. 64), 1H NMR (FIG. 65) and HPLC. The PXRD diffractogram indicated the isolated drug product was crystalline. The relative ratio of imipramine/pamoate was determined to be 1.2/1 by HPLC (and corroborated by 1H NMR). The relative ratio of stearylamine/pamoate was determined to be about 1/1 by 1H NMR. The filtrate from the above work-up was concentrated under reduced pressure and dried under vacuum to give 200 mg of a yellow oil which was characterized by FTIR and 1H NMR. The analyses were consistent with those obtained for imipramine free base described in U.S. Pat. No. 5,578,500. The DSC thermogram is provided in FIG. 62 wherein an endothermic phase change of at least 40 J/g is observed at a temperature above 70° C. and an endothermic phase change of at least 1 J/g is observed above 125° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[CH3:23][S:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])[O:9][CH:10]=1)(=[O:21])=[O:22]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2NS(C)(=O)=O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccccc1-c1coc(CCCCC(=O)O)n1

Procedure:
Combine 5-[4-(2-methanesulfonylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.75 g, 7.8 mmol) with THF (3 mL), EtOH (3 mL) and 1N NaOH (20 mL) and stir at room temperature until hydrolysis is complete. Concentrate the mixture and dilute the residue with water and adjust to pH 3.0-3.5 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (EtOAc) to allow for recovery of 5-[4-(2-methanesulfonylamino-phenyl)-oxazol-2-yl]-pentanoic acid (2.16 g, 82%). MS (ES): (M+1)+ 339.2, 340.3.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(NCCCCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 77.5 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 5-(4-nitro-3-methylphenylamino)pentan-1-ol (17) were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=C1Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C2(CCCCC2)O1

Procedure:
Prepared from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 245-246° C. 1H-NMR (CDCl3) δ8.39 (t, 1H, J=1.9 Hz), 8.20 (dd, 1H, J=8.2, 1.4 Hz), 8.11 (s, 1H, D2O exchangeable), 7.86 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.1 Hz), 7.50 (dd, 1H, J=8.2, 1.9 Hz), 7.39 (d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=8.2 Hz), 2.25 (d, 2H, J=12.7 Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M−H]−, 100%). Anal. Calc. For C19H18N2O4.0.35H2O: C, 66.21, H, 5.47, N, 8.13. Found: C, 66.22, H, 5.43, N, 7.86.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(-c3ccco3)cc2)c1
Yield: 26.5 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (0.1 g, 0.26 mmol) in dioxane (5 mL) was added 2-(tributylstannyl)furan (0.118 g, 0.33 mmol), LiCl (0.027 g, 0.64 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 0.5 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.026 g, 26.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
6-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3940 g, 0.0019 mol) is added to a slurry of pentane-washed NaH (0.0966 g, 0.0024 mol) in DMF (3 mL) and after stirring for 10 min, p-fluorobenzyl bromide (0.29 mL, 0.0023 mol) is added. After stirring for 4 h at room temperature, the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using methanol/dichloromethane (0.5/99.5) to give 0.5678 g (94%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 182.5-183° C.; MS (ESI+) for C19H15F2NO m/z 312.2 (M+H)+; IR (drift) 1631, 1511, 1483, 1466, 1449, 1256, 1228, 1218, 1137, 1094, 867, 836, 813, 808, 802 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.28, 6.94, 7.13, 7.96. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.27; H, 4.92; N, 4.54.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: O=c1c2cc3ccccc3cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc3ccccc3cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 48.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2n (200 mg, 0.563 mmol), 6-mercaptopurine monohydrate (105 mg, 0.619 mmol), K2CO3 (86 mg, 0.619 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 128 mg of a dark yellow solid (48%), mp 247.8-254.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.90 (s, 1H); 8.50 (s, 1H); 8.46 (s, 1H); 8.34 (s, 1H); 8.27 (d, J=8.2 Hz, 1H); 8.16 (d, J=8.2 Hz, 1H); 7.81 (dd, J=1.6, 7.3 Hz, 1H); 7.70 (t, J=7.5 Hz, 1H); 7.61-7.74 (m, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.44-7.53 (m, 1H); 4.44-4.56 (m, 2H). 13C NMR (DMSO-d6) ppm: 161.3, 151.6, 151.5, 143.9, 142.2, 136.7, 134.4, 132.5, 131.8, 131.6, 130.5, 129.7, 129.3, 128.8, 128.6, 128.3, 128.3, 127.1, 125.2, 119.5, 32.4. MS (ES): m/z 471.0 (M+). Anal. calcd. for C24H15ClN6OS.0.2C2H6O.0.05KCl: C, 60.57; H, 3.37; Cl, 7.69; N, 17.37; S, 6.63. Found: C, 60.24; H, 3.46; Cl, 7.50; N, 17.34; S, 6.69.
Reaction SMILES: CI.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:17][C:18]([C:23]4[CH:28]=[C:27]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:26]=[CH:25][N:24]=4)=[CH:19][C:20](=[O:22])[CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1>C(#N)C>[CH2:35]([N:32]1[CH2:31][CH2:30][N:29]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:18]3[NH:17][C:16]([C:12]4[CH:11]=[C:10]([N:7]5[CH2:6][CH2:5][N:4]([CH2:3][CH2:12][CH2:16][CH3:21])[CH2:9][CH2:8]5)[CH:15]=[CH:14][N:13]=4)=[CH:21][C:20](=[O:22])[CH:19]=3)[CH:28]=2)[CH2:34][CH2:33]1)[CH2:11][CH2:10][CH3:15]
Reactant: CN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(C)CC5)ccn4)[nH]3)c2)CC1
Solvent: CI
Solvent: CC#N
Product: CCCCN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(CCCC)CC5)ccn4)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.124 ml (1.99 mmol) of methyliodide are added dropwise to a suspension of 568 mg (0.994 mmol) 4,4″-bis-(4-methy-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-on in 18 ml acetonitril. The solution is stirred for 16 h at room temperature. The obtained whitish product (C33H49I2N7O) is filtered off and washed (with acetonitrile).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a mixture of ethyl 3-{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-3-yl)carbonyl](methyl)amino}propanoate (236 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (1.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow solid. The obtained solid was recrystallized from ethyl acetate/hexane to give the title object compound (143 mg, 64%) as colorless crystals.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:23][C:19]1[N:18]=[C:17]([C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH:22]=[CH:21][CH:20]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of isobutyronitrile (T) (830 mg, 12 mmol, 1 equiv.) in toluene (16 mL) at 0° C., a solution of KHMDS 0.5 M in toluene (26 mL, 13 mmol, 1.05 equiv.) was added. The resulting mixture was warmed to room temperature and stirred for 15 min. This mixture was then added to a solution of 2,6-dichloropyridine (S)(4.39 g, 29.7 mmol, 2.5 equiv.) in toluene (10 mL) and the resulting solution was stirred at room temperature for 1 h. The reaction was quenched with a saturated solution of NH4Cl, followed by aqueous NaHCO3. The crude reaction was diluted in diethyl ether, washed with brine, dried over anhydrous Na2SO4 and the solvent was then removed under reduced pressure. The resulting material was purified by flash chromatography on silica gel, eluting with mixtures of dichloromethane/hexanes (2:1). The title compound U was isolated as a white solid (1.1 g, 51%). 1-(6-chloropyridin-2-yl)cyclopropanecarbonitrile (V), 1-(6-chloropyridin-2-yl)cyclopentanecarbonitrile (W), 1-(6-chloropyridin-2-yl)cyclohexanecarbonitrile (X), and ethyl 2-(6-chloropyridin-2-yl)-2-methylpropanoate (Y) were made following the procedure for 2-(6-chloropyridin-2-yl)-2-methylpropanenitrile (U).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[C:10]([CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[CH:16]=2)[C:11]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)=[O:13])=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: NC1CCC(O)CC1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(O)CC3)c2)cc1
Yield: 39.4 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.1 g (0.28 mmol) and 4-amino-cyclohexanol (0.046 g, 0.42 mmol) were used to afford 0.05 g of the required product. Percentage purity (LCMS): 92.3%, (M+1)=453.1+1.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=O)[CH3:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH3:15])=[CH2:1]
Reactant: CC(=O)c1ccccc1Br
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccccc1Br
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
To a suspension of methyltriphenyl phosphonium bromide (108 g, 303 mmol) in THF (750 mL) at room temperature was added KOtBu (112.24 g, 303 mmol) in portions. After being stirred for 5 min, the reaction mixture was treated with 2′bromoacetophenone (50.3 g, 253 mmol). The reaction mixture was stirred for 3 hrs at room temperature then quenched with saturated ammonium chloride. Extracted 3× with Et2O and the combined organic layers were washed with brine, dried over MgSO4 and evaporated under vacuum. Purified by silica gel chromatography (100% petroleum ether) to give 43.8 g (88%) of 1-bromo-2-(prop-1-en-2-yl)benzene as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29][C:30]([Cl:32])=[O:31].CS(C)=O>N1C=CC=CC=1>[ClH:32].[CH3:27][O:28][CH2:29][C:30]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:31]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COCC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetyl Chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 16 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]([N:13]1[CH2:16][CH2:15][CH:14]1[C:17]([OH:19])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:17]([CH:14]1[CH2:15][CH2:16][N:13]1[C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])=[O:19])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Reactant: CCNCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)C1CCN1C(=O)OC(C)(C)C
Yield: 64.6 %

Procedure:
A solution of diethylamine (0.453 g), azetidine-1,2-dicarboxylic acid-1-t-butyl ester (Intermediate 209, 0.891 g), HATU (2.53 g) and DIPEA (1.72 g) in acetonitrile (20 ml) was stirred at room temperature under argon for 4 hours. The mixture was evaporated to dryness and ethyl acetate was added to the residue. The solution was washed with 1M NaOH, brine and water then dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-4% to give t-butyl 2-diethylcarbamoylazetidine-1-carboxylate (0.733 g) as light brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([S:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)(=[O:10])=[O:9])[CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23]([Mg]Br)#[C:24][CH3:25]>C1COCC1>[O:1]=[C:2]([C:23]#[C:24][CH3:25])[CH2:7][N:6]([S:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])=[O:9])[CH2:5][CH2:4][NH:3][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1=O
Solvent: C1CCOC1
Product: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1cccs1
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl 2-oxo-4-(2-thiophenylsulfonyl)-1-piperazinecarboxylate (600 mg, 1.73 mmol) in THF (8 mL) at 0° C. was added to a solution of 1-propynylmagnesium bromide (0.5 M in THF, 5.0 mL, 2.50 mmol, Sigma-Aldrich, St. Louis, Mo.). After 1.5 h at 0° C., additional 1-propynylmagnesium bromide (3.0 mL, 1.50 mmol) was added. After an additional 50 min, the mixture was quenched with ice (20 g) and saturated aqueous NH4Cl (15 mL). EtOAc (20 mL) was added and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel using (10 to 50% EtOAc in hexane) to give tert-butyl (2-((2-oxo-3-pentyn-1-yl)(2-thiophenylsulfonyl)amino)ethyl)carbamate as yellow oil (540 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:49])[CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)C.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][O:3][C:4](=[O:49])[CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)OCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-ethoxy-2-oxoethyl)ureido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (7 mg, 10.40 mmol) was dissolved in dioxane (2 ml) and methanol (1 ml). A solution of sodium hydroxide (1N, 0.021 ml, 0.021 mmol) was added. The mixture was stirred at 70° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by prep. HPLC to afford the title compound as a white solid (2 mg, 29.2%). LCMS: m/e 659.4 (MH+), 2.84 min (method 3). 1H NMR (500 MHz, MeOD) δ ppm 7.86 (d, J=8.2 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 5.23-5.38 (m, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 3.91 (s, 2H), 3.71-3.78 (m, 3H), 2.95-3.10 (m, 1H), 2.46-2.62 (m, 1H), 2.12-2.25 (m, 1H), 2.05 (s, 1H), 1.99-2.03 (m, 1H), 1.91-1.99 (m, 6H), 1.89 (br. s., 2H), 1.76-1.83 (m, 2H), 1.71-1.76 (m, 4H), 1.69 (br. s., 1H), 1.48 (br. s., 4H), 1.31 (br. s., 4H), 1.19 (s, 3H), 1.07 (br. s., 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH:17]=[CH:18][C:19](Cl)=[O:20]>ClCCl>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:20])/[CH:18]=[CH:17]/[C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: CNOC
Reactant: COc1cccc(C=CC(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(/C=C/C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).