Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=O.[CH2:9]([O:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH3:10].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:14]#[N:15])=[CH:1][C:2]([CH3:8])([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH3:10]
Reactant: CCOC(=O)CC#N
Reactant: C=CCC(C)(C)C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C=C(C#N)C(=O)OCC

Procedure:
A solution of 2,2-dimethyl-pent-4-enal (5.0 g, 44 mmol), cyano-acetic acid ethyl ester (5.12 mL, 48 mmol), piperidine (1.3 mL, 14 mmol) and acetic acid (4.52 mL, 80 mmol) in 170 mL of toluene was heated under reflux for 18 hours in a flask equipped with a Dean-Stark separator. Several mL of water was collected in the trap. The reaction was cooled and washed with 1N HCl, NaHCO3 and brine, successively. The organic layers were dried over Na2SO4 and concentrated to an oil. This oil was chromatographed eluting with 20% of EtOAc in hexane to give a combination of two lots total 8.3 g (91%). 1H NMR (400 MHz; CDCl3) 1.28 (s, 6H), 1.32 (t, 3H, J=7 Hz),. 2.26 (d, 2H, J=7.6 Hz), 4.27 (q, 2H, J=7.2 Hz), 5.08 (d, 1H, J=12 Hz), 5.10 (d, 1H, J=4 Hz), 5.72 (m, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[CH3:6][O:7][C:8]([CH3:17])(C)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH:13]=[CH2:14]>O1CCCC1.[Cl-].[Cl-].C1([Ti+2]C2C=CC=C2)C=CC=C1>[CH3:17][C:8]1([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]1[CH2:14][CH2:3][CH2:2][CH2:1][CH2:17][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH3:13]
Reactant: C=CC(C)CCCC(C)(C)OC
Reactant: CCC[Mg]Br
Agent: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC1(C)C=CC=C(C)C1CCCCCCCCCC(C)C
Temperature: 25 °C

Procedure:
To a solution of n-propylmagnesium bromide (0.25 mole) in tetrahydrofuran (200 ml) was added 7-methoxy-3,7-dimethyl-1-octene (42.5 g) and biscyclopentadienyl titanium dichloride (1.25 g). After the vigorous reaction subsided, the mixture was heated in an oil bath (75°) for 19 hours. Aliquot quench at this point indicated ~50% conversion. The Grignard exchange product was transferred to a separatory funnel, and added dropwise to p-isopropylbenzyl chloride (21 g) in THF (300 ml) containing cuprous chloride (2.5 g) cooled at 0° to -10° while stirring. On warming to room temperature overnight, the reaction was then quenched with aqueous ammonium chloride and extracted with pentane. The pentane extracts were distilled to give product (2,6-dimethyl-2-methoxy-9-isopropylphenylnonane) (12.5 g; bp 150°-152° /0.25-0.3 torr) contaminated with some p, p'-diisopropylbibenzyl.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:24]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:8]([CH3:7])[CH:9]=2)[O:13][N:26]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCOCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 1 (90 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow solid.
Reaction SMILES: C(N1C(=O)C(N)=C(N)N(CCCC)C1=O)C=C.[NH2:18][C:19]1[NH:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:33])[C:20]=1[N:34]=O.C(N1C(=O)C(N=O)=C(N)N(CCCC)C1=O)C=C>>[CH2:26]([N:22]1[C:21](=[O:33])[C:20]([NH2:34])=[C:19]([NH2:18])[NH:24][C:23]1=[O:25])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N=O
Agent: C=CCn1c(=O)c(N)c(N)n(CCCC)c1=O
Agent: C=CCn1c(=O)c(N=O)c(N)n(CCCC)c1=O
Product: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N
Temperature: 0 °C

Procedure:
This compound was prepared by a method similar to that of Müller et al. as described in Synthesis 1995, 1295. The method used was similar to that used in scheme 1 for the preparation of 3-allyl-5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione except that 6-amino-3-benzyl-5-nitroso-1H-pyrimidine-2,4-dione was used as the substrate for the reaction in place of 3-allyl-6-amino-1-butyl-5-nitroso-1H-pyrimidine-2,4-dione and concentration was continued only until a solid precipitate was observed. This mixture was then cooled overnight at 0° C. and the solids isolated by filtration under an atmosphere of nitrogen to give 3-benzyl-5,6-diamino-1H-pyrimidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na]
Product: Nc1nc(N)nc(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-6-chloro-s-triazine (2.25 g, 15.0 mmol) was added to a solution of sodium (0.43 g, 18.8 mmol) in benzyl alcohol (30 mL) under argon. The suspension was heated in a 130° C. oil bath for 3.5 h. The excess benzyl alcohol was removed under vacuum and the resulting solid was collected with the aid of benzene, and washed with water (100 mL): yield, 1.83 g (56%); mp 184-185° C. (lit. 186-188° C.; Wakabayashi et al., Nippon Dojo-Hiryogaku Zasshi, 41, 193-200 (1970)); UV. (pH 1) 1max 233 nm (sh) (e=0.589×104); (pH 6.9) 238 (sh) (0.111×104)i (pH 13) 240 (sh) (0.073×104) ; 1H NMR d 5.25 (s; 2 H, ArCH2), 6.63 (s, 4 H, NH2, exchange with D2O), 7.30-7.42 (m, 5 H, ArH); MS (EI) calcd. m/z for C10H11N5O 217.0963, found 217.0955.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Si:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([NH2:47])=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[Si:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[S:10])[NH2:47])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](OCCCCC(N)=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCCCC(N)=S)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lawesson's reagent (8.19 g, 20.25 mmol) was heated to reflux in benzene (100 mL) for 1 hr. Cool to just below reflux temperature, and add a solution of 5-{[tert-butyl(diphenyl)silyl]oxy}pentanamide (7.20 g, 20.25 mmol in 50 mL benzene). Stir at room temperature for 2 hrs. Concentrate in vacuo to a chunky oil and purified via silica gel chromatography (eluent: 9:1 Hexane:Ethyl Acetate) to give the product as a yellow-green oil. Yield: 6.50 g (62%) 1H NMR (DMSO-d6) δ7.65–7.60 (m, 4H), 7.49–7.41 (m, 6H), 3.68–3.63 (t, 2H), 2.50–2.44 (t, 2H), 1.80–1.70 (m, 2H), 1.60–1.51 (m, 2H), 1.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:30][CH2:31][OH:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: OCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCO
Temperature: 80 °C
Yield: 25.9 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinoline (500 mg, 1.7 mmol), potassium carbonate (232 mg, 1.7 mmol) and 2-bromoethanol (1181l, 1.7 mmol) in DMF (15 ml) was heated at 80° C. for 5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(2-hydroxyethoxy)-6-methoxyquinoline (160 mg, 26%).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3cncs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3cncs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1

Procedure:
Racemic benzyl 2-benzamido-7a-thiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.173 g, 2.45 mmol) is purified by chiral HPLC: (Column: Chiralpak AS 8×33 cm; eluent: 100% methanol; flow: 400 mL/min at UV 240 nm), to give the title product as the first eluting isomer with Rt=3.43 minutes, (422 mg, 36%, >99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 99.8% methanol with 0.2% isopropylamine; flow: 1.0 mL/min at UV 225 nm). ES/MS (m/e): 479(M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-].[C]>[C:1]([O:5][C:6](=[O:25])[CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Oxalyl chloride (8.7 mL, 99.7 mmol) and several drops of N,N-dimethylformaldehyde (hereinafter DMF) were added to a solution of dichloromethane (40 mL) containing 4-benzyloxybenzoic acid (11.1 g, 48.6 mmol) under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated. The resulting residue was dissolved in dichloromethane (100 mL), and then glycine tert-butyl ester hydrochloride (8.20 g, 48.9 mmol) and N-ethyl-N,N-diisopropylamine (21 mL, 120 mmol) were added thereto under ice-cooling. The mixture was stirred at room temperature for 19 hours, and then water was added thereto to terminate the reaction. The mixture was extracted with dichloromethane twice, and the organic layers were combined and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1 to 2:1, v/v) to give N-[4-(benzyloxy)benzoyl]glycine tert-butyl ester. All the given ester was dissolved in methanol (165 mL), and 20% palladium hydroxide-carbon (926 mg) was added thereto. The mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 3.5 hours. The reaction mixture was filtered through Celite and then concentrated to give 12.2 g of the title compound (colorless crystalline solid, yield: quantitative).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:10]2)=[CH:13][CH:14]=1)#[CH:19]
Reactant: C[Si](C)(C)C#Cc1ccc(C2(OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-benzyloxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate 70, 150.0 mg, 0.47 mmols) in methanol (6 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (115 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].Cl[C:19](OC)=[O:20]>CCOCC>[CH:1]1([C:12]2[C:11]3[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][C:19](=[O:20])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1N
Reactant: COC(=O)Cl
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Product: O=c1nc(C2CCCCC2)c2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a dried round-bottomed flask containing cyclohexylmagnesium chloride (26 mL, 51 mmol) in anhydrous ether (10 mL) was added dropwise a solution of 2-aminobenzonitrile (2.0 g, 17 mmol) in anhydrous ether. The mixture was stirred at rt for 2 h, then cooled to 0° C., and a solution of methyl chloroformate (2.6 mL, 34 mmol) in dry ether (10 mL) was added. The reaction mixture was returned to rt and stirred for 2 d. The reaction was quenched with 1 N hydrochloric acid and stirred for 30 min. The precipitate that formed was collected by vacuum filtration, washed with ethyl acetate and dried to give 4-cyclohexylquinazolin-2(1H)-one (545 mg, 14%) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH:5]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1)[OH:6].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C1C=CN=CC=1.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH:5]([O:6][C:32](=[O:34])[CH3:33])[C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1
Reactant: CCCCc1ncc(C(O)C(Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1ncc(C(OC(C)=O)C(Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 2 h
Yield: 110.2 %

Procedure:
A solution of methyl-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-[(4-pyridyl)methyl]propanoate (3.32 g, 7.5 mmol) dichloromethane (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with dichloromethane and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol methyl-acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (6 g, 16.3 mmol) in methanol (100 ml) was added sodium borohydride (640 mg, 16.9 mmol) under ice-cooling, and the mixture was stirred for 20 min. The reaction solution was poured into 1N hydrochloric acid (50 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (5.1 g, 84%) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:12])([Cl:11])[C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14]>Cl>[CH2:13]([O:9][C:8](=[O:10])[C:7]([Cl:11])([Cl:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:14]
Reactant: O=C(O)C(Cl)(Cl)CCCCCBr
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(Cl)(Cl)CCCCCBr
Temperature: 0 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
19.5 g 5 was dissolved in 300 ml ethanol, saturated at 0° C. with hydrochloric acid gas and stirred for a further 5 hours at 0° C. After removing the major amount of ethanol in a vacuum, the residue was taken up in ether, washed with water, dried over magnesium sulfate and the solvent was removed. 21.2 g (98%) 7-bromo-2,2-dichloroheptanoic acid ethyl ester 6 was obtained as a colourless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1N1CCC(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 73 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 2-chloro-3-nitropyridine (158 mg, 1.0 mmol) to afford the title compound (148 mg), a yellow solid, in 73% yield.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C=O)C.[NH2:11][C:12]1[S:13][C:14]2[C:19](O)=[N:18][C:17]([S:21][C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[N:16][C:15]=2[N:30]=1>O1CCOCC1>[Cl:3][C:19]1[C:14]2[S:13][C:12]([NH2:11])=[N:30][C:15]=2[N:16]=[C:17]([S:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[N:18]=1
Reactant: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
POCl3 (1 mL) was added to DMF (1 mL) in dioxane (6 mL). 2-Amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-ol (1 g, 3.3 mmol) was added to the reaction in one portion. POCl3 (1 mL) was added and the reaction mixture was heated to 80° C. for about 30 min. The reaction was cooled to room temperature and poured onto ice. The resulting mixture was heated at reflux for about 5 h. The mixture was allowed to attain room temperature and was then extracted with EtOAc. The organic layer was passed through a layer of silica gel and concentrated to dryness to give the title compound (1 g, 95% yield).
Reaction SMILES: Br.[CH2:2]([S:4][S:5][CH2:6][CH3:7])[CH3:3].[O-:8][S:9]([O-:12])(=[O:11])=[O:10].[Na+].[Na+]>>[CH2:2]([S:4][S:5][CH2:6][CH3:7])[CH3:3].[OH:11][S:9]([OH:12])(=[O:10])=[O:8].[CH3:2][S:4][S:5][CH3:6]
Reactant: O=S(=O)([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: CCSSCC
Product: CSSC
Product: O=S(=O)(O)O

Procedure:
The HBr catalyzed oxidation of diethyl disulfide was carried out at 110°C. With the same concentrations as above except for a concentraton of 0.0356 M HBr catalyst, the oxidation was complete in 33/4 hours. The yield as the crude sodium sulfonate salt after neutralization was 82% with correction for Na2SO4. The oxidation of diethyl disulfide produced more H2SO4 than that of DMDS. The yields of H2SO4 were 8% with I2 catalysis and 0.6% with HBr catalysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[F:24][C:25]([F:36])([F:35])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][OH:34])[CH2:29][CH2:28]1.[H-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:34][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:25]([F:24])([F:35])[F:36])[CH2:28][CH2:29]2)=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: OCC1CCN(CC(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCN(CC(F)(F)F)CC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (25 mg, 0.075 mmol) and (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methanol (14.70 mg, 0.075 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL) stirred in air at 20° C., was added sodium hydride (approximately 2.98 mg, 0.075 mmol, 60% dispersed in oil) in one charge. The reaction mixture was stirred at 20° C. for 16 hours. The reaction was carefully quenched with methanol (0.5 mL) and water (0.5 mL). The solvent was concentrated in vacuo (Biotage V10) to give the crude product in DMSO (0.5 mL). The residue was taken up in additional DMSO (0.5 mL) and methanol (1 mL) then purified by mass directed autoprep (formic acid modifier). The appropriate fractions were evaporated under a stream of nitrogen to give the required product, 11.5 mg. LCMS [LCMS1] Rt 1.51 min, m/z (ES+) 513 (M+H).
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:29])[CH2:12][CH2:11]1)(C)(C)C.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[O:35]1[C:34]2[CH:39]=[CH:40][C:31]([CH2:30][NH:9][CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=5)[CH:21]=[CH:20][C:19]4=[O:29])[CH2:14][CH2:15]3)=[CH:32][C:33]=2[O:38][CH2:37][CH2:36]1
Reactant: Cc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To 2.0 mL of a methanol solution containing 0.25 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2.0 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added and stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to afford 0.18 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].N#N>C1(C)C=CC=CC=1.C1COCC1>[CH3:9][C:8]1([CH3:10])[C:1]2([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:2]([CH2:4][CH:5]1[CH2:6][CH2:7]2)=[O:3]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: N#N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Yield: 99 %

Procedure:
Thirty (30) g of the compound of Formula II and 0.386 g (2 mole %) of (1S)-(+)-10-camphorsulfonic acid (CSA) was charged in a 500 mL 3 necked round bottom flask equipped with a thermometer, N2 inlet and addition funnel. 111 mL of dry THF was charged to dissolve the 30 g of the compound Formula II, and the (1S)-(+)-10-camphorsulfonic acid at about 20 to 25° C. 2.2 mL of pre formed (R)-MCBS catalyst in toluene (3 mole %) was charged. 39.9 mL of 1M borane THF complex in THF solution was slowly charged over 1.5 hours at a temperature range between about 23 and 28° C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, using the same subsequent procedure as described in Example 1 (i.e. quenching with MeOH, vacuum concentration of the batch, etc., but in appropriate ratios of reagents for this example), the compound of Formula I was obtained. Results varied, but in general, ˜99% yield and ˜94% de were obtained.