Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:23])=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OCc2ccccc2)cc1C

Procedure:
Using 1.40 g (5.78 mmol) of 4-benzyloxy-2-methylbenzoic acid, 1.37 g (11.6 mmol) of thionyl chloride and 50 ml of methanol, the reaction was carried out in a manner similar to Reference Example 6 to obtain 0.77 g of methyl 4-benzyloxy-2-methylbenzoate.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1OC)[CH2:6][NH2:7].S([O-])([O-])(=O)=[O:14].[Mg+2].[CH3:19][O:20]C1C=C(C=CC=1OC)CN=C[C@H](C(=C(C)C)O)O.C(N(CC)CC)C>C(Cl)Cl>[C:19]1(=[O:20])[NH:7][C:6](=[O:14])[C:5]2=[CH:8][CH:9]=[CH:10][CH:3]=[C:4]12
Reactant: COc1ccc(CN=C[C@@H](O)C(O)=C(C)C)cc1OC
Reactant: O=S(=O)([O-])[O-]
Reactant: COc1ccc(CN)cc1OC
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 3,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and after 20 minutes 0.7 g (5.4 mmol) of isopropylidene-L-gylceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The resulting organic solution of isopropylidene-L-glyceraldehyde (3,4-dimethoxybenzyl)imine is cooled to -20° under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. Then, a solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is added dropwise thereto within 1 hour and the mixture is subsequently stirred overnight at room temperature. The mixture is worked-up as described in Example 1 and there are obtained after chromatography 1.56 g (62%) of N-(3S,4S)-cis-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α ]D =+16.2° (c=1.0 in methanol); MS: 466 (M+).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NCCCn1ccnc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCCCn2ccnc2)c1
Yield: 73.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)-imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.47 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)nicotinamide as a colorless solid (37 mg, 49% yield).
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(O)(=O)=O.[NH2:17][OH:18]>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:6](=[N:17][OH:18])[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C[N+](=O)[O-])C1CCCC1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])CC(=NO)C1CCCC1
Yield: 88.7 %

Procedure:
9.90 g (63 mmol) of 1-cyclopentyl-2-nitro-ethanone (example II) and 20.688 g (126 mmol) of hydroxylamine sulfate are heated under reflux, for 4 hours, in 310 ml of a toluene/ethanol mixture (1:1). The solvent is removed in vacuo and the residue is taken up in ethyl acetate; the organic phase is washed 2 times with water and dried over sodium sulfate and the solvent is removed in vacuo. 9.62 g (74%) of pale yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]1([NH:18][C:19](=[O:21])[CH3:20])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42](O)=[O:43])=O)(C)(C)C>>[C:19]([NH:18][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:42]([C:31]2[N:32]=[C:33]([C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=3)[S:34][C:30]=2[NH2:29])=[O:43])[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Reactant: CC(=O)NC1(C)CCCN(c2c([N+](=O)[O-])cnn2C)CC1
Product: CC(=O)NC1(C)CCCN(c2c(NC(=O)c3nc(-c4ncccc4F)sc3N)cnn2C)CC1
Yield: 29 %

Procedure:
Following the procedures in Example 378, starting from N-(4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 384 as an off-white foam (80 mg, 29% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (d, J=4.3 Hz, 1H), 7.90 (s, 1H), 7.52 (t, J=9.7 Hz, 1H), 7.31 (dt, J=8.4, 4.3 Hz, 1H), 6.32 (s, 2H), 5.75 (s, 1H), 3.74 (s, 3H), 3.33-3.15 (m, 4H), 2.38-2.21 (m, 2H), 2.02-1.84 (m, 4H), 1.82-1.74 (m, 3H), 1.51 (s, 3H). LCMS (ES+) m/z 487 (M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34](S(C)=O)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]4[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1
Reactant: OCCOCCN1CCNCC1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCOCCN2CCNCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
To a solution of 1-[2-(2-hydroxyethoxy)ethyl]piperazine (1.061 g, 6.09 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl) amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate forms. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.078 g, 17%). Mass (m/z): 454.2 (M++1), 452.2 (M+−1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1.CN1CCCC1=O>CO.[C].[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=[CH:7][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of tert-butyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (2.20 g, 6.37 mmol) in methanol (50 mL)/N-methylpyrrolidone (10 mL) was added 10% palladium-carbon powder (440 mg), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere (3.0 atm). 10% Palladium-carbon powder was filtered off by celite filtration, and water (20 mL) was added to the filtrate. The obtained precipitate was collected by filtration, and repeatedly washed with water to give the title compound (1.87 g, 93%) as a pale-gray powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25]CCC[CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.N1N2C(N=C3C(=C2C2C=CC([OH:45])=CC=2)CCCC3)=CC=1.BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17](=[CH:16][CH:15]=[N:14]3)[N:18]=[C:19]3[C:20]=2[CH2:21][O:45][CH2:25]3)=[CH:8][CH:7]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: ClCCCBr
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1

Procedure:
Using the method described for the preparation of 10-[4-(3-Chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 4-(5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazolin-9-yl)-phenol and 1-bromo-3-chloropropane provided the title compound which was used without further purification.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[N:25]([CH3:26])[N:24]=[CH:23][C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:38]([O:37][C@@H:9]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[N:25]([CH3:26])[N:24]=[CH:23][C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[CH2:8][OH:7])([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[4,3-b]pyridine-6-yl)benzo[d]thiazol-6-yl)ethyl pivalate: (68 mg, 0.115 mmol) in THF/CH3OH (1.5 mL/1.5 mL) was added 2N NaOH (0.57 mL, 1.15 mmol). The reaction mixture was heated at 45° C. for 2 h and cooled to rt. The reaction solution is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic solution is washed with water, brine, dried and concentrated to give crude product which was carried to next reaction without further purification. LCMS-ESI+: calc'd for C27H27ClN4O2S: 507.16 (M+H+); Found: 507.2 (M+H+).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:15]=1)#[N:13]>C1(C)C=CC=CC=1>[C:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:16]3[N:15]=[C:14]([C:12]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:13]=4)[CH:19]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(N2CCN(c3ccccc3)CC2)n1
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(N3CCN(c4ccccc4)CC3)n2)sc2ccccc12
Yield: 33.3 %

Procedure:
A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol), 2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol) triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure and the crude crystals were recrystallized from ethanol to give the titled compound (0.20 g, 33%) as crystals.
Reaction SMILES: [C:1]([C:3]([CH2:12][CH2:13][O:14][CH3:15])([CH2:8][CH2:9][O:10][CH3:11])[C:4]([O:6]C)=[O:5])#[N:2].[OH-].[Na+].CCCCCC.COC(C)(C)C>O1CCCC1>[C:1]([C:3]([CH2:8][CH2:9][O:10][CH3:11])([CH2:12][CH2:13][O:14][CH3:15])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: COCCC(C#N)(CCOC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCC(C#N)(CCOC)C(=O)O
Reaction time: 7 h

Procedure:
To a solution of methyl 2-cyano-4-methoxy-2-(2-methoxyethyl)butanoate (1.13 g) synthesized according to the method described in European Journal of Organic Chemistry, 2005, vol. 20, pp. 4313-4321 in tetrahydrofuran (10 mL), 1.0 mol/L aqueous sodium hydroxide (20 mL) was added at room temperature, and the mixture was stirred at the same temperature for 7 hours. To the reaction mixture, hexane and tert-butyl methyl ether were added. The aqueous layer was separated, and ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2-cyano-4-methoxy-2-(2-methoxyethyl)butyric acid (G19, 957 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52](Cl)(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1>C(#N)C>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4cccnc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0297 g, 0.0643 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.386 mmol) and 8-quinolinesulfonyl chloride (0.0440 g, 0.193 mmol) to obtain 4-(8-quinolinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0164 g, yield 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20](=[O:37])[N:21]([C:28]2[O:36][C:32]3=[CH:33][CH:34]=[CH:35][C:31]3=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCO.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20](=[O:37])[N:21]([C:28]2[O:36][C:32]3=[CH:33][CH:34]=[CH:35][C:31]3=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Reactant: OB(O)C1=CCCCC1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 125 °C

Procedure:
A solution consisting of 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromo phenyl)-propyl]-benzoic acid methyl ester (200 mg, 0.35 mmol), dichlorobis(tri-o-tolyl phosphine)-palladium(II), 1-cyclohexenyl boronic acid (222 mg, 1.76 mmol) and sodium carbonate (373 mg, 3.5 mmol) in DME (8 mL), EtOH (4 mL) and water (2 mL) was heated at 125° C. for 7 min in the microwave. The crude reaction mixture was partitioned between EtOAc and water. Evaporation of the organic portion afforded crude 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid methyl ester which was carried on as is for the next step. LC-MS m/z=570 [C38H35NO4+H]+.
Reaction SMILES: C[O:2][P:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: COP(OC)C1CCCCC1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C1CCCCC1
Yield: 51.2 %

Procedure:
A mixture of 10.47 grams (59 mmol) of dimethylcyclohexylphosphonite with 15.14 grams (59 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG #955-01-1) in 45 mL of toluene is refluxed for 2 hours and is cooled. The resultant precipitated crystals are collected by filtration, washed with toluene, then hexane and are dried under vacuum to obtain 11.5 grams (51% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-cyclohexyl-phosphinic acid methyl ester as a white solid mp 149-150° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9]C1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[CH2:1]([C:7]1[C:8]([OH:9])=[C:16]([B:29]([OH:30])[OH:28])[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCc1ccccc1OC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCc1cccc(B(O)O)c1O
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
2-(2-Hexylphenoxy)tetrahydropyran (1.162 g, 4.43 mmol) was dissolved in dry THF (20 ml) and the solution cooled to 0° C. n-Butyl lithium (1.6M in hexanes, 4.15 ml, 6.64 mmol) was added dropwise with stirring over 10 minutes. The ice-bath was removed and the reaction stirred at room temperature overnight. Triisopropoxy borane (1.43 ml, 6.2 mmol) was added and stirring continued for 24 hours. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (20 ml). The combined organic extracts were washed with 2N hydrochloric acid (50 ml), dried with sodium sulphate and concentrated under vacuum. The oily solid produced was dissolved in ether (30 ml) and stirred with 2N hydrochloric acid (15 ml) for 1 hour. The organic phase was separated, dried with sodium sulphate and concentrated under vacuum. The residue was triturated with cyclohexane and the solid filtered off to give the title compound (260 mg, 26%); MS 221 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=1)=[O:28]>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:21][CH2:22]3)[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: Cc1ccc(C(=O)CCCl)cc1
Product: O=C(CCCl)c1ccccc1
Product: O=C(NCC1CCNCC1)n1c(=O)n(C2CC2)c2ccccc21

Procedure:
The procedure given in Example 135 was followed using 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloro-4′-methylpropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give the title compound.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Yield: 83.1 %

Procedure:
A solution of 2-O-Octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 ml water-free pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 ml water-free pyridine under stirring. After 2 days at room temperature 162 ml diethyl ether are added and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 ml), 0.5N HCl (2×29 ml), 0.5N sodium carbonate (2×29 ml), and water (4×50 ml). Evaporation of the solvent under vacuum gives an oily product which becomes solid after drying in vacuo. The product, 1-p-toluenesulfonyl-2-O-Octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH2:4][C:3]1=[O:26].[Cl:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>C(OCC)(=O)C.C(#N)C>[Cl-:27].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:16][CH2:15][N+:14]([CH2:28][C:29](=[O:30])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH2:19][CH2:18]3)[CH2:13]2)=[O:10])[CH2:4][C:3]1=[O:26]
Reactant: CN1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1=O
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(C(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)CC1=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.1 %

Procedure:
(R)-Quinuclidin-3-yl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (169 mg, 0.47 mmol) was dissolved in a mixture of ethyl acetate (3 ml) and acetonitrile (1.5 ml). 2-Chloro-1-phenylethanone (80 mg, 0.52 mmol) was added and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated and the residue was triturated with EtOAc (10 ml). The product was purified by flash chromatography (DCM/MeOH=9/1 to 85/15) to obtain (3R)-3-(2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (99 mg, 0.193 mmol, 40.9% yield) as a pale yellow spongy solid.