Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]([CH2:14][C:15]#[N:16])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:17][N:2]([CH3:1])[C:3]([N:5]([CH2:14][CH2:15][NH2:16])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:4]
Reactant: [H][H]
Reactant: Cc1cc(C)nc(N(CC#N)C(=O)N(C)C)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N(CCN)C(=O)N(C)C)c1

Procedure:
A solution of N,N-dimethyl-N'-(cyanomethyl)-N'-(4,6-dimethyl-2-pyridyl)urea from Part B (5.3 g., 0.023 mole) in ethyl acetate (100 ml.) containing platinum oxide (0.8 g.) is hydrogenated in a Parr apparatus at 50 psi of hydrogen until the required amount is taken up (12 hours). The catalyst is filtered off and the solvent removed under vacuum to give 4.6 g. of oily product.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][NH:4]1.[CH3:14]N(C)C=O>>[CH3:14][N:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[N:9][CH:8]=2)[C:3]1=[O:13]
Reactant: CN(C)C=O
Reactant: O=c1[nH]ccc2cnccc12
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2cnccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 328 mg, 8.2 mmol) was added portionwise to a suspension of 2H-[2,6]naphthyridin-1-one (1 g, 2.05 mmol) (see reference J. Het. Chem. 1981, 18(7), 1349) in anhydrous N,N-dimethylformamide (25 ml) under a nitrogen atmosphere and the mixture was stirred at room temperature for 1 hour. lodomethane (510 μl, 8.2 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (gradient from 2:98 to 5:95) to give the title compound (750 mg).
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].N1C=CC=CC=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Sc2ccccc2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)C(=O)Nc1ccc(Sc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Acetoxy-2-methylpropanoyl chloride (0.47 ml) was added to a solution of 2-fluoro-4-phenylsulphanylaniline (Method 7) (0.64 g) and pyridine (0.28 ml) in DCM (10 ml). The solution was stirred at ambient temperature for 90 minutes then volatile material was removed by evaporation. The residue was dissolved in methanol (20 ml) and a solution of lithium hydroxide monohydrate (0.378 g) in water (2.5 ml) was added. Stirring was continued for another 1 hour then the mixture was acidified to pH 1 with 2M hydrochloric acid and concentrated by evaporation to about 5 ml. Water (10 ml) was added and the product was extracted with ethyl acetate. Organic layers were washed with brine then combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-20% ethyl acetate/hexane to yield the title compound (0.784 g) as a solid. Mp 91-92.5° C.; NMR: 1.34 (s, 6H), 5.96 (s, 1H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.27-7.4 (m, 5H), 8.02 (t, 1H), 9.3 (s, 1H); MS (ESP−): 304; EA: found: C, 62.8; H, 5.3; N. 4.5; S. 10.5%; C16H16FNO2S requires: C, 62.9; H, 5.3; N, 4.6; S, 10.5%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1.O.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(CNS(C)(=O)=O)c1
Reaction time: 12 h
Yield: 81.5 %

Procedure:
The product of step C (900 mg, 2.00 mmol) was diluted with dioxane (10 mL) followed by the addition of LiOH—H2O (126 mg, 3.00 mmol) dissolved in water (2 mL). After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with methylene chloride:MeOH (95:5) to yield 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamido-methyl)phenoxy)benzoic acid (710 mg, 81.4% yield) as a clear oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].N1(CO)C2C=CC=C[C:25]=2N=N1.[BH4-].[Na+]>C(O)C.CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
N1-Methyl-5-(2-aminopyridin-4-yl)oxy-1H-1-indolecarboxamide (5.00 g, 17.7 mmol, Production example 5-1) was dissolved in ethanol (170 ml) and N,N-dimethylformamide (40 ml); 1H-benzotriazole-1-methanol (2.64 g, 17.7 mmol) was added thereto; and the reaction mixture was heated to reflux for 2 hours. After allowing to be cooled to room temperature, sodium borohydride (1.49 g, 35.4 mmol) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system). The obtained crystals were suspended in acetone: diethyl ether =1:3, filtered off, washed with hexane, and dried to yield the title compound (1.05 g, 3.55 mmol, 20.1%) as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Cl[C:9]([O:11][CH3:12])=[O:10]>ClCCl.N1C=CC=CC=1>[CH3:12][O:11][C:9]([O:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])=[O:10]
Reactant: OCC(CO)CO
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)OCC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (9.4 mmol) in dichloromethane (20 mL) and pyridine (7.5 mL) at 0° C. was added methyl chloroformate (9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:4) to give 650 mg of 2-(methoxycarbonyloxymethyl)-1,3-propanediol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-2-methylbenzene. MS 408 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 μM.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([NH2:22])([CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[OH:9][CH:7]([CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:8][NH:22][C:11]([CH3:21])([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)(C)C)cc1
Yield: 34.3 %

Procedure:
Using the method of Example 15, supra, t-butylglycidyl ether (142 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 106 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1. 0.3), 294 (0.5), 222 (1.8), 188 (67.9), 163 (14.6), 132 (100), 121 (19.1); 1H-NMR (CDCl3) δ7.09 (2H, d, J=8.6), 6.82 (2H, d, J=8.6), 3.78 (3H, s), 3.68 (1H, m), 3.37 (2H, m), 2.27 (1H, dd, J=11.5 and 4.2), 2.63 (3H, m), 1.19 (9H, s), 1.05 (3H, s), 1.03 (3H, s); 13C-NMR (CDCl3) δ156.0, 131.3, 130.3, 113.3, 72.9, 69.7, 64.5, 55.1, 52.9, 46.6, 44.7, 27.4, 26.9, 26.8.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10]>CO>[CH3:8][C:9]([CH3:12])([CH3:11])[CH:10]=[N:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: NCC1CCNC1
Reactant: CC(C)(C)C=O
Solvent: CO
Product: CC(C)(C)C=NCC1CCNC1
Reaction time: 1 h

Procedure:
2.0 g (20 mmol) of 3-aminomethyl-pyrrolidine are initially introduced into 10 ml of methanol, and 1.8 g (22 mmol) of 97% strength pivalaldehyde are added dropwise at room temperature, after which the internal temperature rises to 30° C. The mixture is subsequently stirred for 1 hour and then concentrated, and the residue is distilled through a Vigreux column. Yield: 2.8 g (80% of theory) of 97% pure product;
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[O:1]=[C:2]([O-:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH3+:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH3+:22]
Reactant: NCCCCCCN
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]
Product: [NH3+]CCCCCC[NH3+]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.71 %

Procedure:
Aqueous D-glucaric acid (1, ˜1 M, 5.0 mL) and aqueous hexamethylenediamine (1 M, 5.25 mL) were mixed in a round bottom flask, and stirred at room temperature for 10 min. The reaction mixture was then stirred at 78° C. for 16 h and concentrated to less than 25% of the total volume. Methanol (6˜8 mL) was added drop-wise to the concentrated solution to precipitate out a large quantity of white solid which was removed by filtration, washed with methanol (2×5 mL), and dried under vacuum at room temperature for 24 h to give hexamethylenediammonium D-glucarate salt (4a, 1.04 g, 3.19 mmol, 63.71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[C:10]([NH:32][C:29]2[CH:30]=[CH:31][C:26]3[N:25]=[CH:24][O:23][C:27]=3[CH:28]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2ncoc2c1
Reactant: Cc1ccc(-c2ncnc(Cl)c2OCc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncnc(Nc3ccc4ncoc4c3)c2OCc2ccccc2)cc1
Temperature: 115 °C
Yield: 25.9 %

Procedure:
5-(benzyloxy)-4-chloro-6-p-tolylpyrimidine (50 mg, 0.161 mmol) was dissolved in PhMe, to this was added benzo[d]oxazol-6-amine (23.7 mg, 1.1 eq), Pd(dba)2 (4.6 mg, 0.05 eq), t-BuONa (31 mg, 2 eq), and (±)-BINAP (15 mg, 0.15 eq). The mixture was degassed and heated at 115° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. Preparative TLC gave 17 mg of the title compound.
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:27][C:28]1[N:33]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=O)[CH:31]=[CH:30][CH:29]=1.CCOCC>C1COCC1>[CH3:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=[CH2:2])[N:33]=1
Reactant: Cc1cccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C)n1
Temperature: -50 °C
Yield: 50 %

Procedure:
Methyl triphenylphosphine bromide (commercially available from Aldrich) (2.2 g, 6.16, mmol) in THF(60 mL) at −70° C. was treated with nBuLi (2.44 mL, 2.5M in hexane). The reaction mixture warmed to −50° C. in 1 h. A solution of (6-methyl-pyridin-2-yl)-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate D3) (1.38 g, 3.2 mmol) in THF (25 mL) was added to the mixture via syringe at −50° C. The mixture was allowed to warm to rt for 1.5 h. The mixture was poured into ether (mL) and washed with water (2×10 mL). The organic solution was dried over MgSO4, filtered and evaporated to leave a residue. This was purified by chromatography on SiO2 with diethyl ether to give 2-methyl-6-[1-(1-trityl-1H-imidazol-4-yl)-vinyl]-pyridine (Intermediate D4) 0.68 g (50%).
Reaction SMILES: [C:1]([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1)(=[O:17])[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][CH3:16].O.[C@@H:38]1([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[O:45][C@H:42]([CH2:43][OH:44])[C@@H:40]([OH:41])[CH2:39]1>>[C:1]([O:41][C@@H:40]1[C@@H:42]([CH2:43][OH:44])[O:45][C@@H:38]([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[CH2:39]1)(=[O:17])[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][CH3:16]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)O[C@H]1C[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared using the procedure for Palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of 5'-O-dimethoxytrityl-deoxyguanosine for 2'-deoxyguanosine monohydrate and deprotecting the 5' hydroxyl group as follows: removing the dimethoxytrityl group by stirring in 80% aqueous acetic acid at 25 degrees C for 1 hour, isolating the crude product by filtration, triturating the crude product for 1 hour in methanol, recovering the product by filtration and drying.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=[O:15])[CH2:9]1)(=[O:7])=[O:6].[Li+].[BH4-]>C1COCC1>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)(=[O:7])=[O:6]
Reactant: CCOC(=O)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCS(=O)(=O)N1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 0.1 %

Procedure:
Ethyl 1-(2-(trimethylsilyl)ethanesulfonyl)piperidine-3-carboxylate (9.00 g, 28 mol) was dissolved in THF (200 mL) in a three-neck 500 mL flask and cooled to 0° C. A solution of LiBH4 (2.0 M in THF, 28 mL, 0.056 mol, 2.0 equiv) was added via addition funnel. The mixture was allowed to warm to rt and stir for 15 h. Significant amounts of the starting ester remained; an additional charge of the LiBH4 solution (28 mL, 0.056 mol) was added and the mixture stirred for an additional 17 h. After this period analysis by LC-MS showed consumption of the starting ester. The mixture was cooled to 0° C. and the excess LiBH4 was quenched by dropwise addition of MeOH (100 mL). The volatile materials were removed and the residue partitioned between ether (100 mL) and 1.0 M aq HCl (100 mL). The layers were separated and the aqueous layer extracted with additional ether (3×50 mL). The combined organic extracts were washed with brine and dried over Na2SO4. The clear solution was evaporated to yield (1-(2-(trimethylsilyl)ethylsulfonyl)piperidin-3-yl)methanol (5.25 g, 67%) as a white solid which was of sufficient purity to use in the next step. 1H NMR (CDCl3) δ 0.00 (s, 9H), 0.95 (m, 2H), 1.21 (m, 1H), 1.5-8 (m, 5H), 2.75-2.82 (m, 3H), 2.91 (t of d, 1H), 3.53 (m, 2H), 3.62 (d of d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[CH:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[CH:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1cc(F)c(F)c2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1CN(Cc2ccccc2)CC=C1c1cc(F)c(F)c2ccoc12

Procedure:
Beginning with 2.30 gm (6.44 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(4,5-difluorobenzofur-7-yl)piperidine and 4.90 gm p-toluenesulfonic acid monohydrate, the desired compound was prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:23]>>[CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([NH2:23])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: N
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CCC(N)=O)CCN(C)C1
Reaction time: 0.08 h

Procedure:
Ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (0.1 g, 0.33 mmol) was taken in 4 ml aqueous ammonia and heated at 120 deg C. for 5 min using in microwave. The solid product precipitated out after the reaction was filtered through a Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash to obtain 1.25 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) TFA SALT 9.85 (bs, 1H), 7.4-7.45 (m, 2H), 7.2 (s, 1H), 7.0 (d, 1H), 6.85 (s, 1H), 4.3-4.2 (m, 3H), 3.6-3.4 (m, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 2.3 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][N:6]([CH3:8])[CH3:7].[CH3:14][I:15]>C(Cl)(Cl)Cl>[I-:15].[F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][N+:6]([CH3:14])([CH3:8])[CH3:7]
Reactant: CI
Reactant: CN(C)Cc1cc(F)cc(F)c1O
Solvent: ClC(Cl)Cl
Product: C[N+](C)(C)Cc1cc(F)cc(F)c1O
Product: [I-]
Yield: 87 %

Procedure:
74 g (0.40 mol) of 3,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine was dissolved in 300 ml of chloroform, and 200 ml of methyl iodide was added thereto. The mixture was heated under reflux for 3 hr to deposit a yellow precipitate. The precipitate was recovered by filtration to prepare 114 g (yield: 87%) of the intended product.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:15][N:10]([CH2:9][C@H:8]([NH:7][CH3:6])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.4 %

Procedure:
A solution of of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.87 g, 7.12 mmol) in dichloromethane (7 ml) was cooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reaction mixture was stirred for 45 min at 0° C. Dichloromethane (10 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (10 ml) was added. Solid sodium hydrogen carbonate was added until pH 7.Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (120 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 1.24 g of N-methyl-N-((2R)-2-(methylamino)-3-(2-thienyl)propyl)methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:36][NH:37][O:38][CH3:39]>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:4]=1
Reactant: O=C(O)c1ccc(Cl)c(-n2cccc2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)c(-n2cccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
5.0 g of 4-chloro-3-(1H-pyrrol-1-yl)benzoic acid in 200 ml of dichloromethane were treated in succession with 3.13 ml of triethylamine and 4.33 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC.HCl). The mixture was stirred at room temperature until it became clear and was then cooled to 0° C. and 2.21 g of N,O-dimethylhydroxylamine hydrochloride were added. The mixture was then left to come to room temperature and was stirred for a further 18 hours, washed with 1M aqueous hydrochloric acid and with brine and then dried over anhydrous magnesium sulphate. Evaporation under reduced pressure gave 5.73 g of N-methoxy-N-methyl-4-chloro-3-(1H-pyrrol-1-yl)benzamide as a viscous oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:9]1([CH3:19])[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: CCCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCOCCOS(=O)(=O)c1ccccc1C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a cold (0° C.) solution of 118.18 (1 mol) of 2-butoxy-ethanol in anhydrous pyridine, was added 190.66 g (1 mol) of toluenesulfonylchloride. The resultant reaction mixture was allowed to react for approximately one hour at 0° C., then at room temperature for approximately two hours. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated in vacuo to provide a residue. This residue was partitioned between diethyl ether and a 1N aqueous hydrochloric acid solution and the organic phase was washed sequentially with a 2N sodium hydroxide solution, a 1N hydrochloric acid solution, water, and brine, and then dried over sodium sulfate, filtered and concentrated in vacuo to provide 200.39 g of a light gold oil.