Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[N:24]([CH2:29][C:30]([OH:32])=O)[C:23](=[O:33])[CH2:22]C2.CN([P+]([O:44]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:16])[C:30](=[O:32])[CH2:29][N:24]2[C:25]3[CH:26]=[C:27]([Cl:28])[C:18]([Cl:17])=[CH:19][C:20]=3[O:44][CH2:22][C:23]2=[O:33])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)CN1C(=O)CCc2cc(Cl)c(Cl)cc21
Reactant: CNC(CN1CCCC1)c1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCCC1)c1ccc(Br)cc1
Yield: 24.7 %

Procedure:
To a solution of [1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine (1.61 g, 5.68 mmol) and (6,7-dichloro-2-oxo-3,4-dihydro-1(2H)-quinolinyl)acetic acid (1.73 g, 6.25 mmol) in DMF (20 mL) was added BOP Reagent (3.77 g, 8.52 mmol) and triethylamine (1.72 g, 17.3 mmol). The resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduce pressure. The residue was diluted with ethyl acetate (100 mL) and extracted with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60 A, 85 ml/min, A: MeOH, B: CH2Cl2, A: 1% for 20 min) to give 0.76 g (25%) title compound as yellow solid. MS (ES) m/e 545.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]([Mg]Br)([CH3:45])[CH3:44].C(OCC)(=O)C>O1CCCC1>[OH:37][CH:36]([CH:43]([CH3:45])[CH3:44])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CC(C)[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.57 g) in tetrahydrofuran (5 mL) was added dropwise isopropylmagnesium bromide (1 M tetrahydrofuran solution, 2 mL) at 0° C., and the mixture was stirred for 1.5 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), sodium borohydride (0.04 g) was added, and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.31 g, 56%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[Si:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: Cc1ncc(CCCO)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1ncc(CCCO[Si](C)(C)C(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 2-{[5-(3-hydroxypropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.25 g, 0.564 mmol) in THF (10 ml) were added imidazole (0.077 g, 1.13 mmol) and tert-butyldimethylsilyl chloride (0.10 g, 0.676 mmol). The reaction mixture was allowed to stir overnight at rt and was then concentrated. Water (10 ml) and saturated NaHCO3 (10 ml) were added. The resulting mixture was allowed to stir for 1 h at rt. The mixture was extracted with EtOAc (2×30 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-{[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.16 g, 0.29 mmol, 51%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH2:50])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:39][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH:50][C:1](=[O:3])[CH3:2])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[CH:41][CH:42]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(CC(N)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Acetic anhydride (1.0 mL. 10.8 mmol) and triethylamine (2.4 g. 24 mmol) were added sequentially to a solution of rac.-2-amino-3-[4-[(1.1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester p-toluenesulfonic acid salt (5.0 g, 9 mmol) in dichloromethane (100 ml) at 0° C. After 2 h. the reaction mixture was diluted with dichloromethane (250 mL) and washed with 1N HCI (2×20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and dried (Na2SO4 ). Filtration and concentration provided the crude product which was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g. 8 mmol) in 91% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5].C(O[CH2:34][CH3:35])(=O)C.[CH2:36](O)[CH3:37]>>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:36][CH2:37][CH2:34][CH3:35])=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5]
Reactant: CCO
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCCCCCCCCCCCCCNc1ccc(C(=O)NCCC(=O)OC)cc1[N+](=O)[O-]

Procedure:
The same procedure is used as in (1). Rf value: 0.78 (silica gel; ethyl acetate/ethanol=50:2)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1sccc1Cl)C1CCNCC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3sccc3Cl)CC2)CC1

Procedure:
From (3-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (78 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (54 mg, intermediate AG) by procedure A.1. Yield: 52 mg (45%). White solid. MS (m/z): 397.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:11]([NH:12][N:13]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:9])=[O:14])[CH3:17]
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1ccccc1C

Procedure:
A solution of 2′-methylacetophenone (0.98 ml, 7.4 mmol), ethyl carbazate (0.81 g, 7.8 mmol) and p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) in toluene (30 ml) was heated at reflux temperature with a Dean-Stark apparatus for 2 h. Solvent evaporation and flash chromatography (silica gel, hexane-ethyl acetate, 80:20) gave N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester; 1H NMR (CDCl3, 400 MHz) δ7.72 (bs, 1H), 7.21 (m, 4H), 4.31 (q, 2H, J=7.1 Hz), 2.37 (s, 3H), 2.17 (s, 3H), 1.34 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CN1CCCC1=O.Cl>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=5)[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) in N-methylpyrrolidone (6.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (180 mg, 80%) as a white powder.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=O)[CH:13]=[C:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-:28].[Na+].Cl.[NH2:31]O.Cl>O.CN1CCCC1=O.C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH2:13][C:14]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=4)([C:15]([F:18])([F:17])[F:16])[O:28][N:31]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: [OH-]
Reactant: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-n3cncn3)nc2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to 0.50 g (1.21 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.49 g of water to 0.20 g (4.92 mmol) of sodium hydroxide, and then adding the solution in which 0.094 g (1.35 mmol) of hydroxylamine hydrochloride was dissolved into 0.20 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.77 g (7.38 mmol) of 35% hydrochloric acid and 2.31 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and the ethyl acetate phase was washed twice with 10 ml of water. The solvent was distilled off under reduced pressure to obtain 0.45 g of 3-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 87.3%).
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]\[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1/[CH:6]=[CH:5]\[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)/C=C\c1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\c1ccc2ccccc2c1
Temperature: 60 °C

Procedure:
A solution of (Z)-naphthalene-2-acrylic acid ethyl ester (1.38 g, 6.0 mmole) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) was treated with lithium hydroxide (0.88 g, 37 mmol) and heated to 60° C. for 6 hours. On cooling, the organic phase was separated and the. aqueous phase was acidified and extracted with diethyl ether. The ethereal phase was dried and the solvent removed in vaccuo to give (Z)-3-(2-naphthyl)prop-2-enoic acid as a white solid which was used without further purification, Mp 207-209° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:18]=[N:17][N:16]=[N:15]1.O.[OH-].[Li+].C(O)C.Cl>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)c(C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(CC(=O)O)ccc1-n1cnnn1
Reaction time: 1 h

Procedure:
Ethyl 2-(6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate (310 mg, 1.25 mmol) was dissolved in THF (6 mL) and water (3 mL). Lithium hydroxide monohydrate (68.31 mg, 1.628 mmol) was added. A small amount of ethanol was also added to ensure the reaction mixture was homogeneous. After 1 hr, the reaction was acidified with 2N HCl to pH ˜5-6 then extracted with a mixture of ethyl acetate/THF (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated to yield title compound: 1H-NMR (600 MHz, CDCl3) δ ppm 8.975 (s, 1H), 7.738 (d, J=8.1 Hz, 1H), 7.396 (d, J=8.1 Hz, 1H), 3.907 (s, 2H), 2.009 (s, 3H): LC-MS: M+1=220
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.C[CH:29]([C:33](Cl)=[O:34])[C:30](Cl)=[O:31].C1C[O:39][CH2:38]C1>>[CH3:38][O:39][C:33](=[O:34])[CH2:29][C:30]([NH:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1)=[O:31]
Reactant: C1CCOC1
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: CC(C(=O)Cl)C(=O)Cl
Product: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-amino-2,6-dimethyl-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (5.53 g, 14.3 mmol) in dry THF (30 mL) was added methyl malonyl chloride (1.68 mL, 15.7 mmol). The solution was stirred 2 h at RT then concentrated to a pink solid. The solid was dissolved in a minimal amount of CH2Cl2, passed through silica gel and eluted with 2% methanol in CH2Cl2 (750 mL). The solution was concentrated to a pink solid, and the solid was dissolved in EtOAc (30 ml) and cyclohexane (200 mL) was added gradually to give an oily solid, which became more crystalline on stirring at RT. The suspension was stirred 24 h at RT, then filtered. The white solid was washed with cyclohexane (3×20 mL) and petroleum ether (20 mL) and dried to give the title compound of Step E (4.88 g). MS (APCI+) Calc.:487.1, Found: 488.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[O:12])#[N:2].[CH3:22]I>>[CH3:22][O:12][C:11]1[N:13]=[C:1]([NH2:2])[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[N:10]=1
Reactant: CI
Reactant: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Product: COc1nc(N)c2c(C)c(C)sc2n1
Yield: 86 %

Procedure:
Prepared in a similar manner to Example 25 from N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (Example 4a) and methyl iodide in 86% yield. 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.36 (s, 3H), 3.53 (s, 3H), 6.0 (bs, 2H). MS 210 (MH+).
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:14](=[O:16])[NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[CH2:20](OC(Cl)C[Cl:25])[CH3:21].O>C(O)=O>[ClH:25].[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[O:16][CH:20]=[CH:21][N:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: CCOC(Cl)CCl
Reactant: CC(C)N(CCC(C(N)=O)c1ccccc1)C(C)C
Solvent: O=CO
Solvent: O
Product: CC(C)N(CCC(c1ccccc1)c1ncco1)C(C)C
Product: Cl
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of N,N-diisopropyl-3-carbamoyl-3-phenylpropanamine, prepared in Example 34.2 (4.05 g, 15.4 mmol), 1,2-dichloroethyl ethyl ether (2,32 g, 16.2 mmol), water (0.300 g, 16.6 mmol) and formic acid (50 mL) was stirred at 75° C. for 3 hours. The formic acid was evaporated and the residue was dissolved in water/diethyl ether. The aqueous phase was made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine 97:3). The pure amine was precipitated as hydrochloride salt with HCl-saturated diethyl ether, affording the title compound as white crystals, 0.61 g (12%): mp 157-158° C.; 1H NMR (DMSO(d6)) δ1.11 (m, 12H), 2.35 (m, 1H), 2.63 (m, 1H), 3.03 (m, 2H), 3.56 (m, 2H), 4.45 (m, 1H), 7.21-7.40 (m, 6H) 8.06 (d, 1H), 10.20 (br, 1H).
Reaction SMILES: [CH3:1][CH: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][CH2:3]1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[CH3:1][CH: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]([CH2:27][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Solvent: CC#N
Product: CC1CCN(C(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
(R)-Quinuclidin-3-yl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (58 mg, 0.17 mmol) and 2-bromo-1-phenylethanone (37.1 mg, 0.19 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. The solvent was evaporated and the residue was tritured with Et2O and filtered under vacuum. The recovered solid was further purified by preparative HPLC to obtain (3R)-3-(2-(4-methylpiperidin-1-yl)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (5 mg, 5.5% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:16])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:2][CH2:3][O:16][CH2:7][CH3:8]
Reactant: OCC(O)CO
Reactant: CCCCCCCC(=O)O
Agent: [Pd]
Product: CCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 48 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.63 g (713 mmol) of glycerol, 2.54 g (17.6 mmol) of octanoic acid, 0.26 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent:cyclohexane/ethyl acetate=4:1˜1:1). 1-O-octanyl-glycerol ether was obtained at an isolated yield of 48%.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][CH:7]([CH3:9])[CH2:6][CH2:5][O:4]1.[OH-].[Na+].[CH3:12][NH2:13]>>[CH3:9][CH:7]1[CH2:6][CH2:5][O:4][CH:3]([CH2:2][NH:13][CH3:12])[O:8]1
Reactant: CN
Reactant: CC1CCOC(CBr)O1
Agent: [Na+]
Agent: [OH-]
Product: CNCC1OCCC(C)O1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
2-bromomethyl-4-methyl-1,3-dioxane (160 grams) and 40% aqueous methylamine (150 ml) were charged into a pressure vessel and agitated for a period of about 6 hours at a temperature of about 50° C. under autogeneous pressure. The reaction mixture was cooled to room temperature and sodium hydroxide (40 grams) was added. The reaction mixture was then extracted with methylene chloride. The extract was dried and the methylene chloride stripped off using a rotary evaporator to yield the desired product N-(4-methyl-1,3-dioxan-2-ylmethyl)methylamine.
Reaction SMILES: [C:1]12([NH:12][C:13](=[O:17])[CH:14]([Cl:16])[CH3:15])[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.C1(=O)[NH:22]C(=O)C2=CC=CC=C12.O.NN.Cl>>[ClH:16].[C:1]12([NH:12][C:13](=[O:17])[CH:14]([NH2:22])[CH3:15])[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)C(=O)NC12CCCC(C1)C1CCC2C1
Agent: Cl
Agent: NN
Solvent: O
Product: CC(N)C(=O)NC12CCCC(C1)C1CCC2C1
Yield: 32 %

Procedure:
Under the same conditions as described in sections (D) and (E) of Example 8, N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloropropionamide was converted to the phthalimide derivative, the derivative was converted to an amine by 80% hydrazine hydrate and the amine was neutralized by hydrogen chloride gas to obtain viscous N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-aminopropionamide hydrochloride in a yield of 32%.