Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)[C:6](=[O:22])[N:5]([CH2:23][C:24]([OH:26])=O)[C:4]=1[CH3:27].[NH:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][NH2:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[Cl:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:20])[CH3:21])[CH:13]=2)[C:6](=[O:22])[N:5]([CH2:23][C:24]([NH:38][CH2:37][C:33]2[CH:32]=[C:31]3[C:36](=[CH:35][CH:34]=2)[NH:28][CH:29]=[CH:30]3)=[O:26])[C:4]=1[CH3:27]
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)NCc1ccc2[nH]ccc2c1
Yield: 95 %

Procedure:
The title compound was prepared by a similar method to preparation 9 from 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetic acid hydrochloride (preparation 22) (85 mg, 0.20 mmol) and 1H-indol-5-ylmethylamine (preparation 8) (35 mg, 0.24 mmol) to give the title compound (100 mg, 0.19 mmol, 98%). 1H NMR (CD3OD) δ 2.20 (s, 3H), 2.70 (s, 6H), 3.00 (m, 2H), 3.60 (m, 2H), 4.20 (s, 2H), 4.50 (s, 2H), 4.80 (m, 2H), 7.05 (m, 1H), 7.10-7.55 (m, 9H), 7.75 (m, 1H), 7.85 (m, 1H). LRMS m/z=507.3, 509.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:28][C:29]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]3[CH2:32][CH2:33][C:29]([F:34])([F:28])[CH2:30]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: FC1(F)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 3,3-difluoropyrrolidine hydrochloride (43 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (150 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HAM) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography purification (silica gel, gradient 10-20% ethyl acetate/isohexane) yielding Compound 62 as a solid (18 mg).
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18].Cl>C(O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[N:12]=[C:17]([OH:18])[CH:16]=[C:15]([OH:22])[N:11]=2)=[CH:8][CH:7]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccc(Cl)cc2)n1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
To sodium ethoxide (48 ml of a 21% wt solution in ethanol diluted with a further 130 ml ethanol) was added 4-chlorobenzamidine (8 g) and diethyl malonate (6.67 ml) and the solution left to stir at 40° C. for 96 hrs. The reaction mixture was subsequently cooled to 5° C. and acidified cautiously to pH 2 using concentrated hydrochloric acid. The solid thus precipitated was filtered, washed with excess cold water, then 50 ml diethyl ether and dried in vacuo yielding the title compound (7.51 g).
Reaction SMILES: O.O.O.[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl[CH2:16][C:17]([OH:19])=[O:18]>[OH-].[K+]>[N:8]1([CH2:16][C:17]([OH:19])=[O:18])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:4])[CH:6]=[CH:7]1
Reactant: Oc1ccnc2ccccc12
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1ccc(=O)c2ccccc21
Yield: 17.2 %

Procedure:
4-Hydroxyquinoline trihydrate (20 g., 0.2 mole) is dissolved in a 50% aqueous potassium hydroxide solution and chloroacetic acid (20 g., 0.2 mole) is incrementally added. The resulting solution is heated at its reflux temperature for 18 hours, chilled, acidified and filtered to give 7 g of 4-quinolone-1-acetic acid having a m.p. 278°-279° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: CN1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C)CC5)c34)cc2C)cn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 30% yield; NMR Spectrum: 2.10 (s, 3H), 2.19 (s, 3H), 2.30 (br s, 4H), 2.43 (s, 3H), 2.50 (hidden under DMSO, 4H), 2.79 (t, 2H), 4.43 (t, 2H), 6.96 (d, 1H), 7.17-7.24 (m, 2H), 7.61-7.64 (m, 2H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)C=O)=[CH:5][CH:4]=1.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1C=CC=CC=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[CH:49]=[CH:46][CH:47]=[O:48])=[CH:20][CH:21]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Reactant: COc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(OC)cc2)cc1
Yield: 74 %

Procedure:
A solution of 3,3-bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal (1.7 g; 4.86 mmole) in benzene (100 mL) was treated with triphenylphosphoranylidene acetaldehyde (1.55 g; 5.1 mmole) and heated under reflux for 3 hours. The solvent was removed by evaporation and the residue purified by chromatography using 30% EtOAc-hexane as eluent to afford the title compound as a yellow foam (1.35 g; 74%). MS (CI): m/e=377 for (M+H)+.
Reaction SMILES: [Si](Br)(C)(C)C.[CH2:6]([O:24][C:25]([P:27](=[O:32])([O:30]C)[O:28]C)=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH2:6]([O:24][C:25]([P:27](=[O:28])([OH:32])[OH:30])=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
Me3SiBr (0.812 mL, 6.15 mmol) was added to a solution of dimethyl octadecyloxycarbonylphosphonate (1.0 g, 2.46 mmol) in CH2Cl2 (20 mL) under argon, and the yellow solution was stirred at room temperature for 4 hours and evaporated under reduced pressure. Trituration of the oily residue with hexane, followed by filtration and drying afforded a hygroscopic white solid of the title compound (0.757 g, 81%); mp 81-82° C.; IR (KBr): υ 2960, 2920, 2860, 1730, 1720, 1475, 1465, 1265, 1240, 1225 cm−1; 1H NMR (CDCl3+CD3OD) δ0.8-1.8 (m, 35H, CH3 (CH2)16), 4.25 (t, 2H, OCH2). Anal. Calcd. for C19H39O5P.0.3H2O : C, 59.43; H, 10.42; P, 8.07. Found: C, 59.77; H, 10.91; P, 8.21.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[C:17]([Cl:18])=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1>CN(C)C=O>[Cl:18][C:17]1[C:13]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:14][O:15][C:16]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CN2CCC1CC2
Reactant: Clc1noc(-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(OC2CN3CCC2CC3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 1.96 g of 3-quinuclidinol in 30 ml of dimethylformamide was cooled to 5° C. in an atmosphere of nitrogen. 0.67 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was then added to the cooled solution, and then the solution was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was cooled to 5° C., and 3.0 g of 3,4-dichloro-5-phenylisoxazole were added. The resulting mixture was then stirred at room temperature for 5 hours. At the end of this time, it was poured into 100 ml of ice-water and extracted twice, each time with 100 ml of ethyl acetate. The ethyl acetate extracts were combined and washed twice, each time with 100 ml of a 10% w/v aqueous solution of sodium chloride; they were then dried over anhydrous magnesium sulfate, after which the drying agent was removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure. The residue thus obtained was purified by column chromatography through silica gel using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to afford 4.21 g (yield 98.7%) of the title compound as a colorless and transparent oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:16][C:15](=[O:17])O[C:12](=[O:13])[CH2:11]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[NH3:18]>>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:16][C:15](=[O:17])[NH:18][C:12](=[O:13])[CH2:11]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: N
Reactant: COC(=O)C1CCC2(CC1)CC(=O)OC(=O)C2
Product: COC(=O)C1CCC2(CC1)CC(=O)NC(=O)C2
Reaction time: 1 h

Procedure:
A mixture of 4-carbomethoxycyclohexane-1,1-diacetic acid anhydride and concentrated aqueous ammonia solution was slowly heated with a free flame until the temperature reached 200° C. where it was kept for 1 hour. After cooling the product was ued in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[ClH:10].[N:11]([O-])=O.[Na+]>[OH-].[Na+]>[ClH:10].[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][NH2:11]
Reactant: Nc1c(F)cccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NNc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-6-fluoroaniline (2.0 g, 11 mmol) was dissolved in hydrochloric acid (7.0 mL, 12 N aqueous, 84 mmol, 8 equiv) and cooled to 0° C. An aqueous solution (10 mL) of sodium nitrite (0.80 g, 12 mmol, 1.1 equiv) was added dropwise over 30 minutes via additional funnel and the mixture was stirred for an additional 30 minutes at 0° C. A hydrochloric acid solution (10 mL, 12 N aqueous) of stannous(II) chloride dihydrate (7.1 g, 32 mmol, 3 equiv) was then added to the mixture over 45 minutes via additional funnel and the mixture was stirred for an additional 1 hour at 0° C. To the mixture, sodium hydroxide (30 mL, 1 M aqueous) was added slowly until basic by pH paper. The mixture was warmed to ambient temperature, poured into sodium hydroxide (50 mL, 25% aqueous) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and partially concentrated in vacuo. The residue was taken up in diethyl ether and treated with gaseous hydrochloric acid. The solid was filtered and washed with diethyl ether, providing the titled compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14]OC2=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[BrH:17].C(O)(=O)C>CCOCC.CO>[BrH:17].[Br:17][CH2:14][CH2:15][NH:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=C1OCCN1CCn1ccnc1[N+](=O)[O-]
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1nccn1CCNCCBr
Reaction time: 18 h

Procedure:
To 3.5 g (15 mmol) of 3-[2-(2-nitro-1H-imidazol-1-yl)ethyl-2-oxazolidinone was added 30 ml of 31% HBr/acetic acid and the mixture was stirred for 18 hours at 20°-25° C. The mixture was diluted with ether and methanol and the resulting solid was collected. Recrystallization from ethanol/water gave 3.0 g of the desired product, N-(2-bromoethyl)-2-nitro-1H-imidazole-1-ethanamine, monohydrobromide (54%): mp 103°-104° C.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.CCCCCC.[CH:39]([C:41]1[CH:42]=[C:43]([CH:47]([S:55][CH2:56][CH2:57][C:58](=[O:62])[N:59]([CH3:61])[CH3:60])[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:44]=[CH:45][CH:46]=1)=O.C([O-])(=O)C.[NH4+]>C1COCC1>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:39][C:41]3[CH:42]=[C:43]([CH:47]([S:55][CH2:56][CH2:57][C:58](=[O:62])[N:59]([CH3:61])[CH3:60])[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:44]=[CH:45][CH:46]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-chloroquinolin-2-ylmethyltriphenylphosphonium bromide (Example 4, Step 2) (809 mg, 1.56 mmol.) in THF (15 mL) at -78° C., was added a solution of n-Buli (1.6 M) in hexane (0.89 mL, 1.43 mmol.). The mixture was stirred for 0.5 hrs at -78° C. Then, (+)-methyl 5-(3-formylphenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 3) (480 mg, 1.3 mmol.) in THF (4 mL) was slowly added. The mixture was stirred for 0.5 hr at -78° C. and then warmed up to room temperature and stirred for an additional 2 hrs. A solution of 25% ammonium acetate was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][C:18]([CH:25]([NH2:28])[CH2:26][CH3:27])([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]1.CC(O)C.Cl>O>[NH2:28][CH:25]([C:18]1([C:21]([F:23])([F:24])[F:22])[CH2:17][CH2:16][CH:15]([O:14][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:20][CH2:19]1)[CH2:26][CH3:27]
Reactant: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3ccnc(OC)c3cc2Cl)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 0.1 %

Procedure:
229 mg (480 mmol) of 1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-trifluoromethyl-cyclohexyl]-propylamine (75) were dissolved using 2 ml of 2-propanol and 2 ml of a 1N aqueous solution of HCl. The mixture was treated for 1 h at 100° C. under microwave irradiation. Afterwards, the mixture was diluted using 50 ml of water and lyophilized to yield 195 mg of Example 103 as the hydrochloride. Rt=0.64 min (Method P). Detected mass: 403.10 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>CCOC(C)=O>[Br-:36].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:24][CH2:23][N+:22]([CH2:37][C:38](=[O:39])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([CH2:27][CH2:26]3)[CH2:21]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O[C@H]1CN2CCC1CC2
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of (S)—((R)-quinuclidin-3-yl) 3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoate (590 mg, 1.23 mmol) in EtOAc (15 ml), was added portionwise 2-bromo-1-phenylethanone (232 mg, 1.17 mmol). The reaction was stirred at RT for 16 hours. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried under vacuum to obtain (R)-3-((S)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (720 mg, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:18][S:19][CH3:20])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].CC(C)([O-])C.[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:4]([C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6])=[C:3]([CH2:18][S:19][CH3:20])[C:2]=1[NH:1][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCBr
Reactant: CCCCCOC(=O)c1ccc(OC)c(N)c1CSC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1c(OC)ccc(C(=O)OCCCCC)c1CSC
Temperature: 100 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
Pentyl 3-amino-4-methoxy-2-methylthiomethylbenzoate (830 mg, 2.79 mmol) and DMF (4.0 ml) were mixed, and potassium t-butoxide (470 mg, 4.19 mmol) and bromopentane (0.62 ml, 5.0 mmol) were successively added to this solution. The mixture was stirred at 100° C. for 1 hour and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=15/1) to give pentyl 4methoxy-2-methylthiomethyl-3-pentylaminobenzoate (178 mg, 17%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:12])[NH:2]1.C(O[BH-](O[C:36](=[O:38])[CH3:37])OC(=O)C)(=O)C.[Na+].N>O>[O:38]([CH2:36][CH2:37][N:2]1[C@@H:3]([C:11]([NH:13][C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH3:15])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 147.6 %

Procedure:
To a stirring mixture of silica gel (200 g, 3.33 mol) and dichloromethane (1100 mL) at 22° C., add a solution of sodium periodate (56.2 g, 260 mmol) in water (352 mL) in a dropwise fashion. After the end of the addition, stir the mixture for an additional 30 minutes, then add 3-phenoxyl-1,2-propanediol (34.5 g, 195 mmol), resulting in a slight exotherm. Stir the mixture for an additional 30 minutes, then filter to remove the solids, discard the aqueous layer, and dry the organic layer over MgSO4, filter to remove the solids, and treat the filtrate with methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate (44 g, 130 mmol). Then, add sodium triacetoxyborohydride (57.4 g, 260 mmol) in small portions. Upon completion of the addition, stir the mixture for one additional hour, then add water (200 mL). Add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Separate the layers, dry the organic layer over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure. Dissolve the resulting crude oil in TBME (300 mL), then add water (250 mL) and 1 M aqueous hydrochloric acid (200 mL). Stir the resulting slurry for 30 minutes, concentrate under reduced pressure to remove the TBME, and isolate the resulting white precipitate by filtration. Pour this precipitate into a stirring mixture of water (400 mL) and TBME (400 mL), and add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Remove the aqueous layer, and wash the organic layer with a saturated aqueous sodium chloride solution (200 mL). Isolate the organic layer, dry over MgSO4, filter to remove the solids, and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel using a 30% to 70% EtOAc/hexanes gradient. Consolidate the fractions containing the product, and concentrate them under reduced pressure to furnish the title compound as a white solid (44 g, 74% yield). Mass spectrum (m/z): 459 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=O)[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36].C(=O)([O-])O.[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1.C(OCC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[S:51])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=S)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Yield: 71.2 %

Procedure:
A mixture of methyl 2-{{2-{5-[3,6-dihydro-3-methyl-4-(trifluoromethyl)-2,6-dioxo-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionate (2.00 g, 3.80 mmol), sodium hydrogen carbonate (1.24 g, 14.8 mmol) and Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 1.70 g, 4.20 mmol) in toluene is refluxed for two hours, filtered to remove solids, and concentrated in vacuo to obtain an orange foam. Column chromatography of the foam using silica gel, and 0% and 1% diethyl ether in methylene chloride solutions gives the title product as an orange foam (1.45 g, mp 110-112° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[O:13][CH2:12][C:11]([C:17]([CH3:21])=[CH:18][CH2:19][OH:20])=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[O:13][CH2:12][C:11]([C:17]([CH3:21])=[CH:18][CH:19]=[O:20])=[CH:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=CCO)C1=Cc2cc(-c3ccccc3)ccc2OC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=CC=O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Reaction time: 1 h

Procedure:
29.36 g (33.7 mmol) of manganese dioxide are added in three batches, at 15 minute intervals, to a solution of 9.4 g (33.7 mmol) of the alcohol obtained in Step E in 160 ml of anhydrous methylene chloride. After one hour's stirring, the reaction mixture is filtered over Celite and the methylene chloride is removed by evaporation under reduced pressure. The crude product is crystallised from diisopropyl ether, yielding, finally, 8.27 g of a yellow solid.