Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][OH:8].[C:9]([C:11]1([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:13][CH2:12]1)#[N:10]>CCO>[CH3:18][C:17]([CH3:20])([S:15]([NH:14][C:11]1(/[C:9](=[N:7]/[OH:8])/[NH2:10])[CH2:13][CH2:12]1)=[O:16])[CH3:19]
Reactant: NO
Reactant: CC(C)(C)S(=O)NC1(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)S(=O)NC1(/C(N)=N/O)CC1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
Potassium carbonate (4.45 g, 32.2 mmol) and hydroxylamine hydrochlordie (1.1 g, 16 mmol) was added to a stirring solution of N-(1-cyanocyclopropyl)-2-methylpropane-2-sulfinamide (1.5 g, 8.1 mmol) in EtOH (27 ml) at rt. The reaction was heated to 60° C. for 2 h. Then the reaction was allowed to cool to rt. Celite was added and the mixture was filtered through a pad of celite washing with 100 mL of EtOAc. The filtrate was concentrated to give the expected product (Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclopropanecarboximidamide (1.7 g, 7.8 mmol, 96% yield) consistent by LCMS. LC-MS retention time: 1.09 min; m/z (MH+): 220. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[S:17])=[O:7])[CH2:2][CH2:3][CH3:4].BrBr.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:6](=[O:7])[N:8]2[C:9](=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=32)[S:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1c(=S)[nH]c2ccccc21
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCn1sc2nc3ccccc3n2c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution of 1-(butylcarbamoyl)-1,3-dihydrobenzimidazole-2-thione (39.89 g, 0.16 mole) in 250 mL of chloroform, was added 25.57 g (0.16 mole) of bromine, in 110 mL of chloroform, at 0° C. After the addition was complete, triethylamine (44.6 mL, 0.32 mole), in 80 mL of chloroform, was added dropwise to the reaction mixture. The mixture was stirred at 0° C. for an additional 4 h, and then stirred at room temperature for 14 h. The resulting mixture was washed with water and then with a 10% sodium sulfate solution. The organic layer was dried over magnesium sulfate and evaporated to give the crude product. Recrystallization from methanol gave 27.10 g (69%) of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one as colourless crystals: mp 153-154° C. (lit.: 156-157° C., Martin et al. Tetrahedron 1983, 39, 2311).
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S@:12]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:13])[C:6]=1[CH3:23])(=O)=O.[CH2:24]([OH:29])[C:25]([F:28])([F:27])[F:26]>>[CH3:23][C:6]1[C:7]([CH2:11][S@:12]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:8][CH:9]=[CH:10][C:5]=1[O:29][CH2:24][C:25]([F:28])([F:27])[F:26]
Reactant: Cc1c(S(C)(=O)=O)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Reactant: OCC(F)(F)F
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1

Procedure:
In accordance with yet another embodiment of the present invention, there is provided a process for producing (R)-(+)2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzimidazole comprising reacting 4-chloro-2,3-dimethyl-pyridine-1-oxide with sodium methane thiolate to give 2,3-dimethyl-4-methylsulfanyl-pyridine-1-oxide followed by oxidation using a suitable oxidizing agent to obtain (4-methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide, chlorinating the resultant in the presence of suitable chlorinating agent to obtain 2-chloromethyl-4-methanesulfonyl-3-methylpyridine, condensing the 2-chloromethyl-4-methanesulfonyl-3-methylpyridine in presence of a suitable base in a solvent, optionally in the presence of a phase transfer catalyst with 2-mercaptobenzimidazole to obtain 2-(4-methanesulfonyl-3-methyl-pyridine-2-ylmethylsulfonyl)-1-H-benzimidazole, stereoselective oxidation of the 2-(4-methanesulfonyl-3-methyl-pyridine-2-ylmethylsulfonyl)-1-H-benzimidazole using an optically active compound in presence of a metal catalyst and a suitable solvent to obtain (R)-2-(4-methanesulfonyl-3-methyl-pyridin-2-ylmethanesulfinyl)-1H-benzimidazole and subsequently reacting the (R)-2-(4-methanesulfonyl-3-methyl-pyridin-2-ylmethanesulfinyl)-1H-benzimidazole with trifluoroethanol to obtain the (R)-(+)2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzimidazole.
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:22][CH3:23])=[C:11]([O:18]C(=O)C)[CH:12]=2)[CH:7]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=1)=O)C.[OH-].[K+]>CO>[OH:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:22][CH3:23])[CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=1)[NH:6][CH:15]=[C:14]2[CH:16]=[O:17]
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cccc(CC2NC=C(C=O)c3cc(O)c(OC)cc32)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
To a solution of 6-acetoxy-1-(3-ethoxy-benzyl)-4-formyl-7-methoxy-1H-isoquinoline-2-carboxylic acid ethyl ester (1.0 g, 2.20 mmol) in methanol (50 mL) was added powdered potassium hydroxide (741 mg, 11.1 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs. The solvent was evaporated and the residue was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (660 mg, 88% yield). The crude product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[C:29]([CH:35]=O)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:35][C:29]1[C:28]([CH3:27])=[CH:33][C:32]([CH3:34])=[CH:31][N:30]=1)[CH2:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCCNCc1ncccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2-c2ccccc2)c(C)c1

Procedure:
Using General Procedure B, reaction of {4-[(3-Phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester, 3,5-Dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.03-1.21 (m, 4H), 1.44 (s, 9H), 1.89 (s, 3H), 2.24 (s, 3H), 2.29-2.40 (m, 2H), 2.76-2.90 (m, 2H), 3.63 (s, 2H), 3.79 (s, 2H), 4.85 (s, 1H), 7.09 (s, 1H), 7.26 (dd, 1H, J=7.6, 4.5 Hz), 7.54 (dd, 1H, J=7.8, 1.8 Hz), 8.08 (s, 1H), 8.60 (dd, 1H, J=4.7, 1.2 Hz). Conversion to the HBr salt gave COMPOUND 233 as a white solid (40.3 mg, 88%). 1H NMR (D2O) δ 1.36-1.52 (m, 4H), 2.33 (s, 3H), 2.46 (s, 3H), 2.58-2.69 (m, 2H), 2.79-2.91 (m, 2H), 4.09 (s, 2H), 4.33 (s, 2H), 7.38-7.47 (m, 2H), 7.54-7.63 (m, 3H), 8.03 (dd, 1H, J=7.8, 6.0 Hz), 8.14 (s, 1H), 8.36 (s, 1H), 8.48 (dd, 1H, J=8.1, 1.2 Hz), 8.79 (dd, 1H, J=5.7, 1.2 Hz); 13C NMR (D2O) δ 16.99, 17.50, 22.52, 24.92, 39.53, 53.74, 54.46, 54.73, 126.46, 129.58, 129.62, 130.23, 134.13, 136.97, 137.55, 138.16, 140.85, 141.09, 147.55, 148.07, 149.10, 150.39; ES-MS m/z 375 (M+H). Anal. Calcd. for C24H30N4.3.4 HBr. 3.1H2O: C, 40.86; H, 5.66; N, 7.94; Br, 38.51. Found: C, 40.66; H, 5.89; N, 7.82; Br, 38.79.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:8]([OH:10])=O)=[CH:5][NH:6][CH:7]=1)#[N:2].Cl.CN.O[N:15]1[C:19]2C=CC=CC=2N=N1.Cl>O1CCCC1.C(N(CC)CC)C>[CH3:19][NH:15][C:8]([C:4]1[C:3]([C:1]#[N:2])=[CH:7][NH:6][CH:5]=1)=[O:10]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1c[nH]cc1C(=O)O
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1c[nH]cc1C#N
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 4-cyano-1H-pyrrole-3-carboxylic acid (0.034 g), methylamine hydrochloride (0.034 g), triethylamine (0.084 g) and 1-hydroxybenzotriazole (0.034 g) in tetrahydrofuran (2.5 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (0.058 g) at room temperature, and this mixture was stirred at same temperature overnight. This reaction mixture was poured into 1 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (0.035 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[OH:24][B:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[CH2:27][O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:34][C:31]3[CH:32]=[CH:33][C:28]4[CH2:27][O:26][B:25]([OH:24])[C:29]=4[CH:30]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc2c(c1)B(O)OC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A 8-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (20 mg, 0.052 mmol, 1.05 eq.), 1-hydroxy-3H-2,1-benzoxaborol-6-amine (7.5 mg, 0.05 mmol, 1 eq.) and DMSO (0.5 ml). The mixture was stirred at 90° C. under Ar for 2 hr. After cooling to room temperature, the mixture was added to water (5 ml). The precipitate was collected by filtration and washed with water. After dried, the mixture was purified by prep. TLC using 10% of ethyl acetate in dichloromethane as a mobile phase to give the title compound as a solid (10 mg, 52% yield). MW=385.68. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.92 (d, J=4.0 Hz, 1H), 6.58 (brs, 1H), 5.15 (s, 1H), 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: C(OC(=O)[N:7](C)[C@@H:8]([C:16](=[O:24])[NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.F[C:28](F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:28][C@@:8]([NH2:7])([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@](N)(Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester (5.5 g; 15.2 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred for 1 hour at room temperature. Methylene chloride (100 mL) and an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9, 50 mL) were added and solid sodium hydrogen carbonate was added until pH 8. The aqueous phase was extracted with methylene chloride (100 mL) and the combined organic phases were dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.62 g of (2R)-2-Methyl-amino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:12][C:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5]([NH:16][C:13]2([CH3:12])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC1(N)CC1
Reactant: CSc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CSc1nc(NC2(C)CC2)ncc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirring suspension of 5-bromo-2-chloro-4-(methylthio)pyrimidine (1.0 g, 4.18 mmol) in ethanol (6.0 mL) was added 1-methylcyclopropanamine hydrochloride (0.674 g, 6.26 mmol) and DIEA (2.188 mL, 12.53 mmol). The mixture was stirred at 90° C. for 16 h. Upon completion of the reaction as indicated by LCMS and TLC the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0%-20% ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 5-bromo-N-(1-methylcyclopropyl)-4-(methylthio)pyrimidin-2-amine (0.665 g, 58% yield) as a white solid. MS (ESI) m/z 276.2 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[CH3:19])=[CH:13]/[C:14](OCC)=[O:15])=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[CH3:19])=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccco2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccco2)cc1

Procedure:
(E)-Ethyl 3-(4-furan-2-yl-phenyl)-but-2-enoate was reduced with DIBAL-H by a procedure analogous to that described in example 50b, to give the colourless solid (E)-3-(4-furan-2-yl-phenyl)-but-2-en-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][C:14]=2[N:13]=1.FC(F)(F)S(O[C:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.O.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=3)=[CH:20][C:14]=2[N:13]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3[nH]c(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)-1H-benzo[d]imidazole (880 mg, 2.12 mmol), tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (700 mg, 2.12 mmol) and sodium carbonate (1.13 g, 11.48 mmol) were dissolved in DMF (20 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Cl2.CH2Cl2 (138 mg, 0.17 mmol). This mixture stirred at 80° C. for 90 mins in microwave. Reaction mixture diluted with water and work up (AcOEt/H2O) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (35:65) to afford the titled compound (240 mg) as an off-white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.80 (s, 1H), 8.49 (t, J 7.5, 1H), 8.02 (d, J 10.4, 1H), 7.92 (d, J 8.2, 1H), 7.88-7.67 (m, 1H), 7.66-7.54 (m, 1H), 7.48-7.39 (m, 1H), 6.18 (bs, 1H), 4.02 (bs, 2H), 3.57 (bs, 2H), 3.34 (s, 3H), 2.60-2.55 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1([S:16](N)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>C(OCC)(=O)C.O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 0.42 h

Procedure:
15.6 ml of hexamethyldisilazane (75 mmoles) were added to a refluxing suspension of 15.72 g (0.1 mole) of benzenesulfonamide and 18 mg (0.1 mmole) of saccharin in 45 ml of ethyl acetate under nitrogen and the nitrogen was passed through water to determine the amount of ammonia evolved. By titrating with 1 N H2SO4, it was found that the calculated amount of ammonia was set free in 25 minutes and the residue of N-trimethylsilylbenzensulfonamide obtained after evaporating the volatile materials in vacuo melted at 62°-63° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([CH2:19][CH3:20])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH3:18].CC(N=NC(C#N)(C)C)(C#N)C.[SnH](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH2:19]([C:4]1([CH2:3][CH3:2])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH3:18])[CH3:20]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCCl)OCC3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC)OCC3
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a stirred solution of compound 4 (103 mg, 0.35 mmol), AIBN (11 mg, 0.07 mmol, 0.2 eq), and toluene (3 mL) at room temperature under argon, HSnBu3 (380 μL, 1.41 mmol, 4.0 eq) was added in a dropwise manner. The resulting mixture was stirred overnight at 110° C. and concentrated. The residue was diluted with hexane and extracted three times with acetonitrile. The acetonitrile layers were combined, concentrated, and purified by column chromatography using 3:97:EtOAc:Hexane to give an off-white solid (56 mg, 62%): mp 133-134° C. 1HNMR (CDCl3, δ TMS): 0.88 (t, 6H), 1.37 (t, 3H), 1.87 (q, 4H), 2.78 (t, 2H), 2.86 (q, 2H), 4.02 (t, 2H), 7.01-7.38 (m, 3H, Ar—H), 7.46 (br, 1H, NH). MS−: m/z 256 ([M−H]−). Anal. (C17H23NO): C, H, N.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][C:25](O)=[O:26].CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][C:25](=[O:26])[CH2:24][CH2:23][N:22]([CH3:28])[CH3:21])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCC(=O)O
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)CCC(=O)O/N=C(\N)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by the method of Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et al, WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[3-(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH:37]([C:38]([NH2:40])=[O:39])[CH2:36][CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH:37]([C:38]([NH2:40])=[O:39])[CH2:36][CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: NC(=O)C1CCNCC1
Agent: OC1CCNC1
Product: NC(=O)C1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with isonipecotamide. A yellow solid 126 was obtained (0.024 g, 47%). 1H-NMR (CDCl3, 400 MHz) δ 1.90–1.99 (m, 2H), 2.08–2.14 (m, 2H), 2.58–2.65 (m, 1H), 3.38–3.45 (m, 2H), 4.28–4.34 (m, 6H), 5.55 (br s, 1H), 5.97 (br s, 1H), 6.93–6.98 (m, 3H), 7.05 (dd, J=2.0 Hz, 8.2 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.21 (d, J=6.6 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[CH3:39])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccccc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.099 g of 14-bromobutoxy)-2-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=6.34.
Reaction SMILES: B(F)(F)F.CCOCC.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-].[CH3:18][C:19]1([CH:25]=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Na+].[Cl-]>C(Cl)Cl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:25]([C:19]1([CH3:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC1(C=O)CCOCC1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C1(C)CCOCC1
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a solution of BF3.OEt2 (0.350 mL, 2.50 mmol) and ethyl diazoacetate (0.390 mL, 3.42 mmol) was added a solution of 4-methyl-tetrahydro-pyran-4-carboxaldehyde (350 mg, 2.73 mmol) in CH2Cl2 (15 mL). After 20 min, the mixture was poured into half-saturated aq. NaCl and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Chromatography (EtOAc/hexanes) afforded the title compound (461 mg, 79%) as a colorless oil. MS (ESI): mass calcd. for C11H18O4, 214.1; m/z found, 215.2 [M+H]+. 1H NMR (mixture of tautomers; CDCl3): 12.5 (s, 0.5H), 5.05 (s, 0.5H), 4.25-4.17 (m, 2H), 3.76-3.53 (m, 2H), 5.52 (s, 3H), 2.05-1.92 (m, 2H), 1.56-1.47 (m, 2H), 1.26-1.22 (m, 3H), 1.38-1.34 (m, 3H).