Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:23]O>CO>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:23])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Reactant: OO
Solvent: CO
Product: COc1ccc(S(=O)C(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and 30% H2O2 (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C. and quenched with saturated Na2SO3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl3 and washed with H2O. The organic layer was dried over MgSO4, filtered and concentrated. The title compound was isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; 1H NMR (300 MHz, CDCl3): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[NH:23][C:24]([CH3:27])=[N:25][CH:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[NH:23][C:24]([CH3:27])=[N:25][CH:26]=1
Reactant: Cc1ncc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)[nH]1
Solvent: CO
Product: Cc1ncc(SCc2c(Cl)ccc3c2CCNCC3)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(2-methyl-3H-imidazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (306 mg, 0.602 mmol) in methanol (20 mL) and bubble the resulting solution with hydrogen chloride gas for 5 min. Cap the flask and stir at room temperature overnight. Concentrate the mixture in vacuo. Purify the crude product by chromatography on silica gel (40 g) eluting with a step gradient of DCM/(chloroform:methanol:concentrated NH4OH) [100:0 (5 min), 19:1 (5 min), 9:1 (5 min), 4:1 (5 min), 3:2 (5 min), 1:1; flow rate: 28 mL/min] to provide 7-chloro-6-(2-methyl-3H-imidazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (193 mg, 100%). MS (ES+) m/z: 308 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=O)[NH:6]2.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH:22][C:12]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[O:14])[CH2:18][CH2:17]1
Reactant: CC1(C)CCC(N)CC1
Reactant: O=C(O)c1cc2c(F)cc(F)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(NC(=O)c2cc3c(F)cc(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.36 mmol×4 batches) and 4,4-dimethylcyclohexylamine.HCl (I-6b: 4.6 g, 28.10 mmol, for each batch) in dry DMF (75 mL) was cooled to 0° C. and HATU (11.62 g, 30.57 mmol, for each batch) was added followed by DIPEA (22 mL, 127.9 mmol, for each batch) drop-wise and the mixture was stirred under inert atmosphere at room temperature for 17h. Ice-cold water (50 mL) was added to the reaction mixture with vigorous stirring. The precipitated solid was collected by filtration and dried thoroughly. The crude compound obtained from combining all the batches was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 30%-40% ethyl acetate in hexanes as eluent to afford 23 g of off-white solid. It was triturated with ether/hexanes (3:7) in five cycles to afford 20.6 g (66.2%) of 4,6-difluoro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide (2A) as an white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:16][NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(O)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of methyl 4-(4-hydroxyphenyl)butyrate (4.93 g, 0.025 mol) and hydrazine hydrate (25.4 g, 0.254 mol) in methanol (64 mL) was heated under reflux for an hour. It was then cooled down to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the titled compound as a white crystal (3.30 g, 67%). 400 MHz 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 8.89 (s, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.32 (s, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.2 Hz, 2H), 1.71−1.67 (m, 2H); Mass (M−H−)=193.27.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C@H:5]1[CH2:10][NH:9][C@H:8]([CH3:11])[CH2:7][N:6]1[CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[C:17]([CH3:27])([CH3:26])[CH2:16]1)=[O:14].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[ClH:1].[CH3:27][C:17]1([CH3:26])[C:18]2[C:23](=[CH:22][C:21]([C:24]3[NH:30][N:29]=[N:28][N:25]=3)=[CH:20][CH:19]=2)[N:15]([C:13](=[O:14])[CH2:12][N:6]2[CH2:7][C@@H:8]([CH3:11])[NH:9][CH2:10][C@@H:5]2[CH2:4][O:3][CH3:2])[CH2:16]1
Reactant: COC[C@H]1CN[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(C#N)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC[C@H]1CN[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(-c3nnn[nH]3)cc21
Yield: 4.6 %

Procedure:
A stirred solution of 1-{2-[(2R,5R)-2-(methoxymethyl)-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-2,3-dihydro-1H-indole-6-carbonitrile hydrochloride (25 mg, 0.06 mmol) in DMF (1 mL) was treated with sodium azide (9.0 mg, 0.13 mmol) and ammonium chloride (4.0 mg, 0.06 mmol), and heated under reflux under nitrogen. After 16 h the mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC, basic method then treated with a saturated solution of HCl in EtOAc followed by concentration to dryness in vacuo to give the title compound (1.2 mg, 4%). 1H NMR (Me-d3-OD): 8.86-8.78 (1H, m), 7.77 (1H, d), 7.33 (1H, d), 3.95 (1H, d), 3.88 (1H, d), 3.78 (1H, d), 3.68 (1H, d), 3.62-3.46 (2H, m), 3.39-3.33 (3H, m), 3.33 (3H, s), 3.13 (1H, d), 3.07-2.91 (2H, m), 1.49-1.35 (6H, s), 1.29 (3H, d). MS: [M+H]+=400.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[CH:3]=[CH2:4].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1.CCOCC.[O-2].[O-2].[Mn+4]>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:4][CH2:3][C:2]1([OH:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[O:19]1)[CH3:21]
Reactant: CCNCC
Reactant: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCN(CC)CCC1(O)CCCC(CCCC(C)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
41.3 G. of 3,7-dihydroxy-11-tertiarybutoxy-dodec-1ene produced in Example 121 was dissolved in benzene solution and added to a slurry of 320 g. of activated manganese dioxide in 1600 ml. of benzene containing 120 ml. of diethylamine. The reaction mixture was stirred at room temperature for 20 hours and filtered free of solids. Removal of the solvents in vacuo gave a pale brown oil. The oil was dissolved in ether and extracted with aqueous 1N hydrochloric acid. Sodium hydroxide was added to the acid extract. Extraction into ether and evaporation of the solvent affords 2-[2'-diethylaminoethyl]-6-[4-t-butoxypentyl]-2-tetrahydropyranol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12.C[Si]([N:30]=[C:31]=[O:32])(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:31]([NH2:30])=[O:32])[CH2:17][CH2:18]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12
Reactant: Clc1ccccc1-c1cc(NCC2CCNCC2)n2ncc(Br)c2n1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine (57 mg, 0.136 mmoles) (prepared as described in Example 460, Step B above) was dissolved in anhydrous dichloromethane (1.2 mL) and trimethylsilylisocyanate (0.091 mL, 0.679 mmoles) was added. The mixture was stirred at 25° C. for 2.5 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30×2.5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid amide (53.7 mg, 86%): FABMS: m/z 463.1 (MH+); HRFABMS: m/z 463.0647 (MH+). Calcd. for C19H21N6OBrCl: m/z 463.0649; δH (d6-DMSO) 1.09 (2H, m, CH2), 1.63 (2H, m, CH2), 1.87 (1H, m, CH), 2.60 (2H, m, CH2), 3.53 (2H, bm, CONH2), 3.91 (2H, d, CH2), 6.52 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.33 (1H, s, H2) and 8.52 ppm (1H, m, NH); δC (d6-DMSO)CH2: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1, 158.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24](Br)[CH3:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:12]3[C:11](=[O:27])[CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=[N:13]3)=[CH:19][CH:20]=2)[CH3:25])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Br)c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1
Product: CC(c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(1-{4-[2-(4-Benzyloxy-6-oxo-6H-pyridazin-1-yl)-acetyl]-phenyl}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester is prepared following example 1.1b from 200 mg (0.47 mmol) 5-benzyloxy-2-{2-[4-(1-bromo-ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one (preparation 30c) and 262 mg (1.40 mmol) piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(C(F)(F)F)S([S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])(=O)=O)C=CC=CC=1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:23])[CH:10]([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Reactant: O=S(=O)(N(c1ccccc1)C(F)(F)F)S(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NC(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of 8.30 g (0.026 mol) of rac.-2-acetamido-3-[3-hydroxyphenyl)propanoic acid benzyl ester and 10.0 g (0.028 mol) of N-phenyl-N-trifluoromethyl 1,1,1-trifluoromethyl sulfonyl sulfonamide in 110 mL of freshly distilled dichloromethane was cooled in an ice bath and 4.10 mL (0.029 mol) of triethylamine was added dropwise. The resulting mixture was stirred 1 hour at 0° C. and was allowed to warm to room temperature over 2 hours. The mixture was diluted with 250 mL of ethyl acetate and was washed with successive 50 mL portions of water, 1N sodium hydroxide, 1N hydrochloric acid, water, and brine and was dried over magnesium sulfate. Filtration and concentration afforded an oil which was purified by preparative chromatography on a Waters Prep 500 liquid chromatograph fitted with two Prep-Pak silica gel cartridges, eluting with 40% ethyl acetate-hexane to give 10.02 g (85%) of rac.-2-acetamido-3-[3-[(trifluoromethylsulfonyl)oxy]phenyl]propanoic acid benzyl ester.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:52]=[CH:51][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:51][CH:52]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixture of 2.3 g of diphenylmethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy) propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate, 18.5 ml of anisole and 37 ml of trifluoroacetic acid was stirred at room temperature for 3 hours and then distilled under reduced pressure to remove the solvent. The resulting residue was suspended in a mixed solvent of 15 ml of ethyl acetate and 13 ml of water, followed by adding thereto 0.55 g of sodium hydrogencarbonate, and the resulting mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated, adjusted to pH 3.5 with a saturated aqueous sodium hydrogencarbonate solution, and then concentrated to a volume of about 10 ml under reduced pressure. The resulting concentrate was purified by a reversed phase column chromatography (eluent: 25% aqueous acetonitrile solution) to obtain 0.82 g of 3-[4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][C:22]([CH3:24])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:22]([CH3:24])[CH3:21])[NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.11 mL acetone in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.26 g. MS (ES+): 350 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([N:17]4[CH2:22][CH2:21][C:20]([CH2:29][C:30]([CH3:32])=[CH2:31])([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[O:19][C:18]4=[O:33])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][C:3]1=[O:34].C1([SiH3])C=CC=CC=1.CC([OH:45])C.C(Cl)Cl>[Co]>[OH:45][C:30]([CH3:32])([CH3:31])[CH2:29][C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][C:18](=[O:33])[N:17]([C:14]2([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:34])[CH:4]=4)=[CH:13][CH:12]=3)[CH2:16][CH2:15]2)[CH2:22][CH2:21]1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccn(C)c(=O)c4)cc3)CC2)C(=O)O1
Reactant: CC(C)O
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: Cn1ccc(-c2ccc(C3(N4CCC(CC(C)(C)O)(c5ccccc5)OC4=O)CC3)cc2)cc1=O
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 3-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 0.048 mmol) in 2:1 2-Propanol/CH2Cl2 (1.5 mL) was added cobalt catalyst A (catalytic amount, c.a. 1 mg), followed by addition of phenylsilane (100 μL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction was complete. The mixture was quenched with 3% aq HCl, filtered, and purified by prep HPLC to afford the title compound (6.8 mg, 30%). LC-MS Method 1 tR=1.37 min., m/z 473 (M+1); 1H NMR (CD3OD) δ 7.69(d, 1H), 7.54(d, 2H), 7.42-7.39(m, 5H), 7.13(d, 2H), 6.74(s, 1H), 6.69(d, 1H), 3.59(s, 3H), 3.25(m, 1H), 2.89(m, 1H), 2.67-2.50(m, 2H), 2.19(s, 2H), 1.36-1.20(m, 3H), 1.25(s, 3H), 1.09(m, 1H), 0.95(s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C([O:13][C:14]([C:16]1[C:17](=[O:33])[O:18][C:19]([CH3:32])([CH3:31])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)=O)C.Cl>C(Cl)Cl>[CH3:31][C:19]1([CH3:32])[O:18][C:17](=[O:33])[C:16]([C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:13])=[C:20]1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reactant: C1CCNCC1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)N2CCCCC2)=C1c1ccc(S(C)(=O)=O)cc1
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a room temperature solution of piperidine (284 mg, 3.33 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2M in hexane, 1.7 mL, 3.4 mmol). After 15 min, the product from Step 1 (310 mg, 0.92 mmol) was added in one portion and the mixture was heated to reflux for 20 h. The resulting solution was cooled and poured into 1M HCl (gas evolution). The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (80% EtOAc/Hex) provided 175 mg of the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([OH:19])=[O:18].CI>O1CCCC1.O.C(OCC)C.CCCCCC>[Cl:13][C:14]1[C:15]([F:25])=[C:16]([C:20]([CH3:1])=[C:21]([F:24])[C:22]=1[F:23])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)O
Reaction time: 0.25 h

Procedure:
A 1.69 M hexane solution (14 ml) of n-butyllithium was added dropwise to a solution of diisopropylamine (3.6 ml) in tetrahydrofuran (15 ml) at -65° C. in a nitrogen gas stream, and the mixture was stirred at the same temperature for 15 minutes. A solution of 3-chloro-2,4,5-trifluorobenzoic acid (2.1 g) in tetrahydrofuran (15 ml) was added dropwise to the reaction mixture at -60° C., and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (1.9 ml) was added dropwise at -70° C., and the resultant mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. Diethyl ether and water were added to the reaction mixture to conduct liquid separation. A water layer was collected, to which 12N hydrochloric acid was added to acidify the water layer. The water layer was then extracted with diethyl ether. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.3 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][N:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][N:20]=1)(=[O:15])=[O:14]
Reactant: Cc1cc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (269.5 mg), 2-amino-5-bromo-3-methylpyridine (187 mg) and 4-dimethylaminopyridine (100 mg) in pyridine (5 ml) was heated at 85° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (50 ml) was added. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 5-(dimethylamino)-N-(5-bromo-3-methyl-2-pyridyl)-1-naphthalenesulphonamide as a foam (135) mg); NMR (CDCl3): 2.2(s, 3H), 2.9(s, 6H), 7.15 (d, 1H), (7.4-7.8(m, 4H), 8.4(d, 1H), 8.5(d, 2H); mass spectrum (+ve CI): 420 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([O-:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)[O-])CCOCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.7 %

Procedure:
To a solution of Methyl 4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate (6.47 g, 17.5 mmol, Step 10) in MeOH (32 mL), 5 N NaOH aq (10 mL) was added at room temperature (exothermic). The resulting solution was stirred at 60° C. for 7 h, then cooled to 5˜10° C. in ice-cold bath. To this solution, 5 N HCl aq (10 mL) was added and the resulting solution (pH value was ca.6) was concentrated. To the residue, 2-propanol (80 mL) was added. This solution was concentrated. To the residue, 2-propanol (80 mL) was added and it was concentrated again. The residue was diluted with EtOH (80 mL) and the mixture was stirred at room temperature for 2 h. It was filtered through a celite pad (5.0 g) to remove NaCl. The Celite pad was washed with EtOH (20 mL) and the combined filtrate was concentrated. To the residue, CH3CN (40 mL) was added and it was concentrated. During this procedure, the formation of white precipitate was noticed. To the residue CH3CN (40 mL) was added and the resulting suspension was stirred at room temperature for 2 h. This mixture was filtered and obtained solid was washed with CH3CN (10 mL), then dried under reduced pressure to give 4.1 g (65%) of the titled compound as white powder.