Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36](O)=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)O)c3c2)c1=O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)NS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
1,1'-Carbonyldiimidazole (1.17 g, 0.00722 mol) is added to a solution of {{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methoxy}acetic acid (1.50 g, 0.00361 mol) in tetrahydrofuran. The mixture is stirred one hour at reflux and cooled to room temperature. Methylsulfonamide (0.755 g, 0.00794 mol) is added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 ml, 0.00794 mol). The resultant mixture is stirred overnight at room temperature, poured into 10% hydrochloric acid, and filtered. The resultant white solid is triturated in tetrahydrofuran, and filtered to give the title compound as an off-white solid (1.00 g, 56.2%, mp >240° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C1CCC(N=C=NC2CCCCC2)CC1.CS([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[NH:43])[NH2:42])=[CH:37][C:36]=1[C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)=[O:32]>N1C=CC=CC=1>[C:10](=[O:11])([OH:32])[OH:12].[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[NH:43])[NH2:42])=[CH:37][C:36]=2[C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Product: O=C(O)O
Reaction time: 0.5 h

Procedure:
To a solution of 11.6 g of 4-guanidinobenzoic acid hydrochloride in 180 ml of dried pyridine, while being cooled in ice, was added 13.2 g of DCC. After 30 minutes of stirring, 18.0 g of 4-amidino-2-benzoylphenol methanesulfonate was added, and the mixture was further stirred overnight at room temperature. A white solid substance precipitated from the reaction mixture was collected by filtration, washed with acetone, and dissolved in water. The aqueous solution was freed from the water-insoluble DCU by filtration and added to a saturated aqueous sodium bicarbonate solution, while being cooled in ice and stirred. The precipitated pale yellow crystals were collected by filtration, washed with water, then with acetone, and dried to yield 4-amidino-2-benzoylphenyl 4-guanidinobenzoate carbonate.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[CH2:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[CH:18])[CH3:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[CH3:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[C:15]#[C:14][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](CC)(CC)CC)c(C)c1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-bromo-3-methylbenzoate (from the previous step) (1.0 eq.), triethyl(ethynyl)silane (1.1 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 60° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% ethyl acetate in hexane to give ethyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate as a yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:8][C:9]=2[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 95° C. for 5d. The title compound, 200.0 mg (99%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: Cn1nc(Cl)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nc(Cl)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 68.7 %

Procedure:
In the same manner as in Example 259 and using 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (59 mg, 0.37 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (130 μL, 1.5 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (100 mg, 71%) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][CH2:7][SH:8].[F:9][C:10]([F:24])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>C(O)C>[F:24][C:10]([F:9])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17]([S:8][CH2:7][CH2:6][CH2:5][NH2:4])[N:16]=1
Reactant: NCCCS
Reactant: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C

Procedure:
Sodium hydride (50% w/w dispersion in oil; 0.57 g.) was added to ethanol (10 ml.) portionwise. To the resulting solution was added 3-aminopropanethiol hydrochloride (0.75 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]6-chloropyrazine (0.5 g.) was added in one portion and the mixture heated under reflux on the steam bath overnight. The mixture was cooled, evaporated, water (10 ml.) added and the mixture extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated to yield an oil, which was chromatographed eluting with methanol/methylene chloride/ammonia 10:40:1 v/v/v to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine as a pale yellow solid (0.39 g.) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.CS(C)=O.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[CH:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)(c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(CC=O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a 0° C. solution of tert-butyl 2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate (428 mg, 1.4 mmol), dimethyl sulfoxide (4.0 mL, 56.4 mmol) and diisopropylethylamine (1.3 mL, 7.2 mmol) in 8 mL CH2Cl2 was added SO3.pyr (1.4 g, 8.8 mmol) and the reaction mixture was stirred for 2 h. After the addition of saturated aqueous NaHCO3, the solution was extracted with CHCl3, and passed through a plug of silica gel flushing with 2:1 hex:EtOAc to provide tert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226 mg, 53%) as a clear oil. 1H NMR (400 MHz, CDCl3), δ 9.60 (br. s, 1H), 7.54-7.44 (br., 2H), 7.42-7.37 (m, 2H), 7.30 (m, 1H), 4.25-4.01 (br., 1H), 3.80-3.23 (m, 5H), 3.00-2.81 (m, 2H), 2.73 (br., 1H), 1.47 (br., 9H); ESI-MS 328 (M+H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:30]([Cl:33])(=[O:32])[CH3:31].Cl>O.C1COCC1>[ClH:33].[Br:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:22][CH2:21][N:20]([C:30](=[O:32])[CH3:31])[CH2:19]2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)=[N:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: Cc1csc(Nc2ncc(Br)cc2OC2CCNC2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2cc(Br)cnc2Nc2nc(C)cs2)C1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A mixture of N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride (prepared according to Example 62; 70 mg, 0.16 mmol), triethylamine (0.11 mL, 0.82 mmol), and THF (2 mL) was stirred at room temperature. Acetyl chloride (0.009 mL, 0.16 mmol) was added and stirred at room temperature for 30 minutes. Water (15 mL) was added and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)ethanone hydrochloride (16 mg, 22.56% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.60 (bs, 1H), 8.11 (m, 1H), 7.82 (m, 1H), 6.90 (m, 1H), 5.28 (m, 1H), 3.81 (m, 1H), 3.59 (m, 3H), 2.33 (s, 3H), 2.25 (m, 2H), 1.97 (m, 3H); Mass spectrum (apci) m/z=399.1 (M+H—HCl).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:25]([S:39](Cl)(=[O:41])=[O:40])=[CH:24]2.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:31])=[O:32])[C:25]([S:39]([N:17]1[CH2:18][CH2:19][N:14]([C:12]3[S:13][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[CH:8]=4)=[CH:10][N:11]=3)[CH2:15][CH2:16]1)(=[O:41])=[O:40])=[CH:24]2
Reactant: Cc1cc(-c2cnc(N3CCNCC3)s2)ccn1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2cnc(N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5n4S(=O)(=O)c4ccccc4)CC3)s2)ccn1
Reaction time: 3 h

Procedure:
A saturated solution of hydrochloride in methanol (12 ml) was added to 1-(t-butoxycarbonyl)-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine (400 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated under reduced pressure, whereby 1-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained as a white solid. In a solution of the resulting hydrochloride in methylene chloride (12 ml) was dissolved 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (522 mg), followed by the addition of diisopropylethylamine (538 μl) at room temperature. After stirring for 3 hours, a saturated aqueous solution (50 ml) of sodium bicarbonate was added to the reaction. mixture to separate it into layers. The water layer was extracted with methylene chloride (2×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=7:1), whereby the title compound (240 mg) was obtained as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[OH-:24].[Na+].OO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([NH2:23])=[O:24])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(Cn2cc(C#N)cn2)cc1-c1cccc(Cl)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(Cn2cc(C(N)=O)cn2)cc1-c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile (Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50° C., until the starting material dissolved. Sodium hydroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) and hydrogen peroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) were added and the reaction stirred at 50° C. for 2 h. Water was added (5 mL), and the mixture was filtered and washed with water (3×5 mL) to afford the title compound as a solid (25.0 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=13.69 Hz, 2H), 7.80 (d, J=14.48 Hz, 2H), 7.65-7.37 (m, 5H), 6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H). [M+H]=343.33.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:20]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:32].[Ca+2].[OH-:34]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8](=[O:34])(=[O:32])[C:7]=2[CH:20]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2
Reaction time: 24 h

Procedure:
2 G. 3-cyano-8-nitrodibenzo[b,f]thiepin is dissolved in 600 cc. chloroform and 12 g. m-chloroperbenzoic acid added. The solution is stirred for 24 hours. Excess powdered calcium hydroxide is added, the mixture filtered through celite, the filtrate evaporated to dryness and the residue chromatographed on silica gel. Elution with 5% ethyl acetate in benzene afforded 1.36 g. (61%) of pure sulfone.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH:31](O)[C:30]3[CH:34]=[C:35]([S:37]([NH2:40])(=[O:39])=[O:38])[S:36][C:29]=3[S:28]2(=[O:42])=[O:41])=[CH:23][CH:22]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:43]([N:45](CC)CC)[CH3:44].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N)C>C1COCC1>[CH2:43]([NH:45][CH:31]1[C:30]2[CH:34]=[C:35]([S:37]([NH2:40])(=[O:39])=[O:38])[S:36][C:29]=2[S:28](=[O:41])(=[O:42])[N:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:1][Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][CH:23]=2)[CH2:32]1)[CH3:44]
Reactant: CC(C)(C)[Si](OCCc1ccc(N2CC(O)c3cc(S(N)(=O)=O)sc3S2(=O)=O)cc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCNC1CN(c2ccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 5 °C
Reaction time: 4.5 h
Yield: 43.4 %

Procedure:
The product from Step D (1.77 g, 2.75 mmol) was dissolved in dry THF (15 mL) containing triethylamine (1.54 mL, 11 mmol) and cooled to 5° C. p-Toluenesulfonyl chloride (1.05 g, 5.5 mmol) was added and the mixture stirred at 5° C. for 4.5 hr. An excess of ethylamine was condensed into the reaction mixture which was stirred at ambient temperature for 18 hr and then evaporated to dryness. The residue was suspended in water and this mixture was extracted with ethyl acetate (2×50 mL). the combined extracts were dried (NaSO4) and purified by column chromatography (silica, 3.5% ethanol/methylene chloride) to provide 0.8 g (44%) of a solid: mp 66° C.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[CH:24](O)=O.Cl>CCOCC>[ClH:1].[ClH:1].[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:24])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@@H]1COc1cncc(-c2ccccc2)c1

Procedure:
To 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine from Example 52 (150 mg, 0.59 mmol) was added formalin (38%, 5.0 mL) and formic acid (88%, 2.5 mL), and the mixture was refluxed for 16 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CHCl3, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3/MeOH 10:1.5 to afford the base. The salt was prepared by treatment with HCl in Et2O, as described above, to give the title compound. mp. 89-90° C. MS (CI/NH3) m/z 269 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.05-2.29 (m, 2H), 2.38-2.47 (m, 1H), 3.07 (s, 3H), 3.23-3.32 (m, 1H), 3.64-3.82 (m, 1H), 3.92-4.00 (m, 1H), 4.44 (dd, J=7.7, 11.0 (1H), 4.61 (dd, J=3.0, 11.2, 1H), 7.51-7.62 (m, 3H), 7.70-7.74 (m, 2H), 7.88 (s, 1H), 8.36 (br s, 1H), 8.56 (br s, 1H). Anal. Calcd for C17H20N2OCl.2 HCl.0.5 H2O: C, 58.29; H, 6.62; N, 8.00. Found: C, 58.16; H, 6.76; N, 8.18. [α]25D=+9.2° (c 0.39, MeOH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C@@H:11]1[NH:16][C:15](=O)[CH2:14][O:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([C@H:11]1[CH2:12][O:13][CH2:14][CH2:15][NH:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[C@H]1COCC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1COCCN1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added drop wise a solution of (S)-2-amino-4,5-dimethylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a drop wise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-tert-butylmorpholin-3-one (2.0 g, 74%) as a light yellow solid. To ice-cold THF (9 mL) was added lithium aluminum hydride (1.0 M solution in THF, 26.0 mL, 26.0 mmol). Once the addition was complete, a solution of (S)-5-tert-butylmorpholin-3-one (2.0 g, 13.0 mmol) in THF (8.0 mL) was added drop wise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to his was slowly added H2O (1.2 mL), then 15% aqueous solution of NaOH (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-tert-butylmorpholine (1.7 g, 97%) as a light yellow oil. 1H NMR consistent.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(CCCC)C2CCCCC2)CCCCC1.C(=O)CCCCCCC.C1(N([CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]CCCC)[CH:56]([O:59][CH3:60])[O:57][CH3:58])C2CCCCC2)CCCCC1>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:56]([O:57][CH3:58])[O:59][CH3:60])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCC(C(OC)OC)N(C1CCCCC1)C1CCCCC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CCCCCCCC=O
Agent: CCCCN(C1CCCCC1)C1CCCCC1
Product: CCCCCCC(C(OC)OC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 70 %

Procedure:
The product was prepared by above general procedure and the same chemicals except employing dibenzylamine (1a′) (98 mg, 0.5 mmol), and octanal (2c′) (96 mg, 0.75 mmol). After 24 h, the crude product was purified by flash column chromatography (silica gel; ethyl acetate or diethyl ether/hexane=1:100) to afford the desired product 3c as a light yellowish oil (0.129 g, 70% yield); Rf=0.77 (hexane:ethyl acetate=3:1); 1H NMR (CDCl3, 400 MHz) δ 7.37-7.35 (m, 4H), 7.30-7.26 (m, 4H), 7.23-7.18 (m, 2H), 4.37-4.36 (d, J=5.03 Hz, 1H), 3.81-3.65 (m, 4H), 3.35 (s, 3H), 3.32 (s, 3H), 2.73-2.68 (m, 1H), 1.59-1.36 (m, 3H), 1.25-1.17 (m, 5H), 1.15-1.08 (m, 2H), 0.88-0.85 (t, J=7.07 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 140.8 (C×2), 129.0 (CH×4), 128.0 (CH×4), 126.6 (CH2×2), 107.5, 57.4, 54.8, 54.5 (CH2×2), 54.3, 31.9, 29.4, 26.9, 26.5, 22.7, 14.1 ppm; FTIR (neat): v=3015, 1215, 754, 700, 494 cm−1; HRMS (ESI, m/z): calcd for C24H36NO2+ [M+H]+ 370.2746, found: 370.2743.