Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: Oc1ccc2c(c1CNc1ccccc1)CCCO2
Yield: 26 %

Procedure:
A mixture of 6-hydroxy-dihydrobenzopyran- 5-carboxaldehyde (206 mg, 1.16 mmol) and aniline (108 mg, 1.16 mmol) in benzene (6 mL) was heated to reflux for 30 minutes under nitrogen. After cooling the mixture was passed through a short column of silica gel and the eluate concentrated to an orange solid (119 mg). This material was taken up in methanol (10 mL) and hydrogenated at 40 psi using 10% Pd/C (12 mg) as catalyst. After filtration and concentration the crude product was purified by chromatography over silica gel (Hexane/ethyl acetate, 85/15, an eluant) to afford 6-hydroxy-5-phenylaminomethyl-3,4-dihydrobenzopyran (77 mg, 26%) m.p. 105°-107° C.
Reaction SMILES: ClC1C(NC)=C(N)C=C(Cl)N=1.[Cl:12][C:13]1[C:18]2[N:19]([CH3:24])[C:20]([CH3:23])(O)[NH:21][C:17]=2[CH:16]=[C:15]([Cl:25])[N:14]=1.CO.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)=O>[Cl:12][C:13]1[C:18]2[N:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:17]=2[CH:16]=[C:15]([Cl:25])[N:14]=1
Reactant: CN1c2c(cc(Cl)nc2Cl)NC1(C)O
Agent: CNc1c(N)cc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2cc(Cl)nc(Cl)c2n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
2,6-dichloro-N3-methylpyridine-3,4-diamine 2.45 (0.15 g, 0.78 mmol) was dissolved in AcOH (5 mL) and heated in a sealed tube at 100° C. After 48 hr, LC/MS indicated full conversion to desired intermediate 4,6-dichloro-2,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-2-ol 2.46. Reaction mixture was evaporated under reduced pressure and re-dissolved with MeOH (3 mL), 4-methylbenzenesulfonic acid (220 mg, 1.2 mmol) was added and mixture heated at 120° C. in a microwave reactor. After 20 min, LC/MS indicated full conversion to desired product. Solvent was removed under reduced pressure, and solids were diluted and extracted with ethyl acetate and water. The organic layer was washed with water and brine. Organic phase was then dried over MgSO4, and evaporated under reduced pressure to obtain 4,6-dichloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridine 2.47 that was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]3[N:13]([CH:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:17][C:18]([O:20]CC)=[O:19])[CH:14]=[N:15][C:11]=3[CH:10]=2)=[O:7])=[CH:4][CH:3]=1>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]3[N:13]([CH:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[N:15][C:11]=3[CH:10]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc(N)cc3)ccc21
Agent: Cl
Product: Nc1ccc(C(=O)Nc2ccc3c(c2)ncn3C(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A solution of ethyl 3-{5-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (50 mg, 117 μmol) was dissolved in hydrochloric acid (25 mL of a 5N solution), and stirred at room temperature for 110 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.27 min, MH+ 401].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])=[C:6]([C:8](=O)[CH2:9]Cl)[CH:7]=1.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]([CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH:9]=[CH:8]2
Reactant: CN1CCC[C@H]1CNc1ccc(Br)cc1C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@H]1Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.7 %

Procedure:
To an ice cold solution of compound 101 (402 mg, 1.052 mmol) in 95% ethanol (20 mL) was added 1M sodium hydroxide (1.052 mL, 1.052 mmol) followed by sodium borohydride (19.9 mg, 0.526 mmol) and the mixture stirred under ice cooling for 45 minutes. The reaction was quenched with ice cold H2O (5 mL), diluted with dichloromethane, transferred to a separatory funnel and the organic layer separated. The aqueous layer was further extracted with dichloromethane (twice) and the combined organic layers washed with brine, dried over sodium sulfate and concentrated to residue. The residue was taken up in anhydrous dioxane (20 mL) and heated to reflux for 2.5 hours. After cooling to room temperature the reaction was treated with ice-cold 2N potassium carbonate, diluted with dichloromethane, transferred to a separatory funnel and the organic layer separated. The aqueous layer was further extracted with dichloromethane (twice) and the combined organic layers washed with water (twice), brine, dried over sodium sulfate concentrated under reduced pressure and the residue purified via chromatography on silica gel (MeOH:CH2Cl2, 3:97) to yield compound 102 (110 mg, 35.7%) as a yellow oil. 1H NMR (DMSO-d6) δ 1.42-1.50 (m, 1H), 1.50-1.60 (m, 2H), 1.62-1.71 (m, 1H), 2.09-2.14 (m, 1H), 2.17 (s, 3H), 2.50-2.57 (m, 1H), 2.90-2.96 (m, 1H), 4.05 (dd, 1H, J=14.1, 6.3 Hz), 4.23 (dd, 1H, J=14.0, 5.1 Hz), 6.41 (d, 1H, J=3.0 Hz), 7.22 (dd, 1H, J=8.9, 1.9 Hz), 7.42-7.49 (m, 2H), 7.71 (d, 1H, J=2.0 Hz); ESI-MS (m/z, %): 293/295 (MH+, 100%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][N:40]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:7]([C:8](=[O:21])[NH:9][C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=4)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)Cl)cc3)sc2n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(OC)nc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Title compound E, 4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl chloride (120 mg, 0.2499 mmol) was dissolved in dichloromethane. To this was added a solution of piperidine-4-carboxylic acid ethyl ester (38 μL, 0.2499 mmol) and diisopropylethylamine (87 μL, 0.4998 mmol) in dichloromethane. The reaction was stirred at room temperature for 1 hour, then concentrated. The residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a yellow oil. The crude was then purified via column chromatography 10-90% ethyl acetate in hexanes to afford the desired product as a yellow foam (107 mg, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.07 Hz, 3 H) 1.10-1.22 (m, 2 H) 1.50 (d, J=2.78 Hz, 2 H) 1.49 (br. s., 1 H) 1.63 (dd, J=14.91, 7.83 Hz, 2 H) 1.62 (br. s., 1 H) 1.81 (dd, J=13.64, 3.79 Hz, 3 H) 1.95 (t, J=7.07 Hz, 2 H) 1.91 (d, J=7.83 Hz, 1 H) 2.21-2.31 (m, 2 H) 2.53 (td, J=11.43, 2.91 Hz, 2 H) 3.61-3.71 (m, 3 H) 4.00 (s, 3 H) 4.09 (q, J=7.07 Hz, 2 H) 6.80 (d, J=8.84 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.74-7.84 (m, 3 H) LC/MS 601.3 (M+1) 599.4 (M−1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:16])[CH2:9][CH2:10][CH:11](OC)[O:12]C)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:16])[CH2:9][CH2:10][CH:11]=[O:12])[CH:3]=1
Reactant: COC(CCC(=O)c1cc(Br)ccn1)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCCC(=O)c1cc(Br)ccn1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-pyridin-2-yl)-4,4-dimethoxy-butan-1-one (2) (crude from Step 2, 11 g, 38.2 mmol) in 100 of CH2Cl2 at room temperature is added trifluoroacetic acid (10.9 g, 95.4 mmol) and the reaction mixture is stirred overnight. The reaction is concentrated, the residue dissolved in ethyl acetate (150 mL) and washed with water 3 times. The organic layers are combined, dried over Na2SO4 and the solvent evaporated. The residue is purified by flash column chromatography (30% EtOAc in hexanes) to give 4-(4-bromo-pyridin-2-yl)-4-oxo-butyraldehyde (3) as an yellow oil. (4.16 g, 45%): MS ES+244.04.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.Cl[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]2[CH:20]=[C:21]([C:26]3([O:32][CH3:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([F:25])[CH:24]=2)=[CH:14][CH:13]=1)[CH3:11]>>[F:25][C:23]1[CH:22]=[C:21]([C:26]2([O:32][CH3:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:20]=[C:19]([S:18][C:15]2[CH:14]=[CH:13][C:12]([CH:10]([O:8][N:7]=[C:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH3:11])=[CH:17][CH:16]=2)[CH:24]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: ON=C1CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C4CCOCC4)cc3)c2)CCOCC1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 1, tetrahydropyran-4-one oxime was reacted with 4-{3-[4-(1-chloroethyl)-phenylthio] -5-fluorophenyl}-4-methoxytetrahydropyran to give tetrahydropyran-4-one O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)-phenylthio]-α-methylbenzyl}oxime as an oil in 74% yield.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:31][CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCc1ccncc1
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCC(=O)NCCc2ccncc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 4-pyridine ethanamine according to procedure A and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[2-(4-pyridinyl)ethyl]hexanamide, the title compound, mp 80°-83° (from methylene chloride-ether) in 58% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([CH2:9][C:10](OCC)=[O:11])#[C-:8]>CO>[N+:7]([CH2:9][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11])#[C-:8]
Reactant: C1CCNCC1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
48.7 g (570 mmol) of dry piperidine were added to 25.8 g (228 mmol) of ethyl isocyanoacetate in 200 ml of dry methanol, and the mixture was stirred at room temperature overnight. It was subsequently evaporated to dryness and crystallized from ether/isopropanol to give 33 g (=95% of theory) of pure N-isocyanoacetylpiperidine as beige solid.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH2:36][CH2:35][C:32]5[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=5)[CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCN(CCc4ccccc4)C3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (51.8 mg, 0.132 mmol) in 1,2-dichloroethane was treated portionwise with phenacetaldehyde (0.2 mL, 0.2 mmol) and acetic acid (0.2 mL, 4 mmol), stirred for one hour at ambient temperature under nitrogen, treated with sodium triacetoxyborohydride (49.1 mg, 0.232 mmol), stirred for 2.5 hours, treated with sodium triacetoxyborohydride (37.5 mg, 0.177 mmol), stirred for 2.5 hours, poured into 1.0 N sodium hydroxide and extracted with chloroform. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 100% chloroform and 0.05-0.2% ammonium hydroxide/0.5-2.0% methanol in chloroform to yield 3-(1-naphthylsulfonyl)-5-{[1-(2-phenylethyl)pyrrolidin-3-yl]oxy}-1H-indazole as a light yellow semi-solid, 24.6 mg (36.5% yield). The semi-solid was dissolved in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 82° C. for 12 hours to give the title product as a brown foam, 24.6 mg, Mass spectrum (+ES, [M+H]+) m/z 498. 1HNMR (500 MHz, DMSO-d6): δ14.24 (d, 1H, J=4.88 Hz), 10.59-10.90 (m*, 1H), 8.77-8.79 (m, 1H), 8.59-8.60 (m, 1H), 8.31 (d, 1H, J=8.24 Hz), 8.07 (d, 1H, J=8.09 Hz), 7.75-7.78 (m, 1H), 7.60-7.68 (m, 3H), 7.24-7.37 (m, 6H), 7.15-7.19 (m, 1H), 5.25-5.31 (m*, 1H), 3.74-4.02 (m*, 2H), 3.31-3.55 (m*, 4H), 3.01-3.04 (m, 2H), 2.08-2.63 ppm (m*, 2H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:26](=[O:28])[CH3:27])=[N:15][C:16]=2[C:17]2[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:34]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:26](=[O:28])[CH3:27])=[N:15][C:16]=2[C:17]2[CH:22]=[C:21]([S:23]([CH3:24])=[O:34])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cc1F
Solvent: C1COCCO1
Product: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(S(C)=O)nc(C)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(5-(5-fluoro-6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (52 mg, 0.130 mmol) and 3-chloroperoxybenzoic acid (44.8 mg, 0.260 mmol, Aldrich, St. Louis, Mo.) in dioxane (1 mL) was stirred at room temperature for 2 h. The mixture was taken on directly to the next step without work-up.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[C:21]([CH3:33])[N:20]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.CCOCC.[OH-].[OH-].[Pd+2]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[C:21]([CH3:33])[N:20]=[C:19]([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:34])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)nc(C)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)nc(C)n1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
3-[6-(2-Methoxy-phenyl)-2-methyl-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXVII) (0.270 g, 0.586 mmol) was taken in methanol (5 ml) to which 10% Pd(OH)2 (0.125 g) was added and the mixture was stirred overnight under an atmosphere of hydrogen. The reaction was monitored by TLC. After completion, the reaction mixture was filtered through a celite bed and concentrated to get a viscous oil which was stirred in ether to precipitate a white solid. Filtration provided 0.160 g of piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-2-methyl-pyrimidin-4-yl]-amide (compound #22A).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.[O-:24][CH2:25][CH3:26].[Na+]>O1CCCC1>[CH2:25]([O:24][C:17]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:26]
Reactant: CC[O-]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2cccnc2Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncccc1-c1ccc([C@@H](C)N)cc1
Yield: 90 %

Procedure:
To a solution of (R)-1-(4-bromophenyl)ethylamine (1.0 g, 5 mmol) in methanol (10 ml) was added sodium hydrogen carbonate (1.26 g, 15.0 mmol) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The reaction mixture was sonicated for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.8 g, 6.0 mmol, 120%) as a white solid. To a solution of (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.73 g, 2.4 mmol) in 1,2-dimethoxyethane (10 ml) was added tetrakis (triphenylphosphine) palladium (0.14 g, 0.12 mmol), 2-chloropyridine-3-boronic acid (0.77 g, 4.9 mmol) and 2 M sodium carbonate. The reaction mixture was heated to reflux for 16 h and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was chromatographed over silica gel eluting with 3:1 heptane/ethyl acetate and the solvent removed under reduced pressure to give (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.56 g, 1.7 mmol, 71%) as an off white solid. A mixture of (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (100 mg, 0.3 mmol), sodium ethoxide (61 mg, 0.9 mmol) and tetrahydrofuran (5 ml) was heated under reflux under an argon atmosphere for 16 h. The solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) chromatography to give (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (66 mg, 0.27 mmol, 90%) as a yellow gum. To a solution of (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (13 mg, 0.05 mmol) in dichloromethane (1 ml) was added triethylamine (17 mg, 0.16 mmol) followed by 2-(trifluoromethoxy)benzenesulfonyl chloride (17 mg, 0.065 mmol). The reaction mixture was stirred for 16 h and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6 mg, 0.013 mmol, 26%). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, 1H), 8.13 (dd, 1H), 7.81 (dd, 1H), 7.63 (m, 2H), 7.39 (m, 4H), 7.24 (d, 2H), 7.05 (m, 1H), 4.48 (q, 1H), 4.36 (q, 2H), 1.35 (d, 3H), 1.29 (t, 3H) ppm; MS (ESI) m/z: 467 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2].F[C:18]1C=CC([N+]([O-])=O)=CC=1C#N.CC(S)C.C1C=C(Cl)C=C(C(OO)=O)C=1>>[CH:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[C:8]#[N:9])(=[O:4])=[O:5])([CH3:18])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)S
Agent: O=C(OO)c1cccc(Cl)c1
Product: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6A, 2-fluoro-5-nitrobenzonitrile (2.50 g, 15.6 mmol) was reacted with isopropylthiol and oxidized with mCPBA to afford 9A (3.04 g, 91%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J=7.03 Hz, 6 H), 3.55-3.76 (m, 1 H), 8.38 (d, J=8.35 Hz, 1 H), 8.63 (dd, J=8.79, 2.20 Hz, 1 H), 8.74 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[CH:18]=[CH2:19])=[CH:5][CH:4]=1.[O:20]=[C:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1>C1COCC1.C(Cl)Cl>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C@@:21]3([OH:20])[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]3)=[CH:4][CH:5]=2)=[C:10]([CH:18]=[CH2:19])[CH:11]=1
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cc(N(C)C)ccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
Magnesium (62 mg, 2.55 mmol) was stirred in a round bottom flask under N2 for 15 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-N,N-dimethyl-2-vinylbiphenyl-4-amine (735 mg, 2.432 mmol) in THF (20 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (699 mg, 2.432 mmol) in DCM (20 mL) at r.t. and stirred for 1 hr and then quenched with sat. NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (330 mg, 0.646 mmol, 27% yield) as a yellow foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 0.99-1.11 (m, 2H) 2.34-2.52 (m, 1H) 2.62-2.81 (m, 1H) 3.00-3.07 (m, 6H) 3.68-3.81 (m, 1H) 3.82-3.89 (m, 3H) 4.17-4.34 (m, 3H) 4.49-4.68 (m, 1H) 5.19 (dd, J=11.04, 1.25 Hz, 1H) 5.70 (dd, J=17.57, 1.25 Hz, 1H) 6.67-6.80 (m, 2H) 6.96 (d, J=2.26 Hz, 1H) 7.16-7.22 (m, 1H) 7.34 (m, 2H) 7.49 (m, J=8.28 Hz, 2H). LCMS: rt=1.71 min. [M+H]+=511; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)=[C:23]=[O:24].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:15]1([C@@H:14]2[O:21][C:23](=[O:24])[N:22]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH2:12][CH2:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(N2CC[C@H](c3ccccc3)OC2=O)c1
Yield: 6.1 %

Procedure:
To a solution of (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (100 mg, 0.327 mmol) and 1-isocyanato-3-methylbenzene (44 mg, 0.327 mmol) in CH2Cl2 (2 mL) was added DBU (149 mg, 0.981 mmol) and the reaction mixture was refluxed overnight. After the solvent was removed under reduced pressure, the residue was separated by preparative HPLC to give (R)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (5.34 mg, 6%:). LC-MS (10-80) tR=2.439 min, m/z=268; 1H NMR (CDCl3): 2.30-2.34 (m, 5H), 3.63-3.68 (m, 1H), 3.80-3.86 (m, 1H), 5.49 (dd, 1H), 7.09-7.45 (m, 9H).