Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:7](=[O:9])[CH:6]3[O:1][CH:2]([CH2:3][CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:18][CH2:19]1
Reactant: O=C1OC(=O)C2CCCC1O2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: ClCCl
Product: O=C1C2CCCC(O2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
Tetrahydropyran-2,6-dicarboxylic anhydride (3.0 g., 19 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (4.98 g., 21 mmole) were combined and stirred for 30 minutes in 200 ml. of methylene chloride. The solvent was removed in vacuum and replaced with 300 ml. of xylene. The mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was again removed in vacuum and the residue was column chromatographed on 100 g. of silica with a gradient elution beginning with chloroform and ending with 5% ethanol in chloroform. The relevant fractions were combined and evaporated and the product crystallized from isopropanol with the addition of 4N isopropanolic HCl and ether. A second crystallization from isopropanol gave 1.9 g. of the title compound as the dihydrochloride, hemihydrate; m.p. 232°-233° C. (d).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8]([NH:20][C:21](=[O:41])[C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:25]([O:36][CH2:37][CH2:38]Br)=[C:24]([Br:40])[CH:23]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N[C@H](C(O)=O)[C@@H](C)O>C1COCC1.CCOC(C)=O.CS(C)=O>[CH2:8]([NH:20][C:21]([C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:25]([O:36][CH2:37][CH2:38][N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[C:24]([Br:40])[CH:23]=1)=[O:41])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Reactant: c1nnn[nH]1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCn2cnnn2)c(-c2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.7 %

Procedure:
To a solution of 1H-tetrazole (28 mg, 0.4 mmol) in 1 mL anhydrous THF at 0° C. was added NaH (10 mg, 0.421 mmol). The reaction mixture was stirred for 10 min at 0° C. after which point a solution of N-dodecyl-3-bromo-4-(2-bromoethoxy)-5-(3-methoxyphenyl)benzamide (160 mg, 0.276 mmol) in 2.5 mL anhydrous THF was added. The reaction mixture was stirred at 0° C. for 10 min then allowed to warm up to room temperature for one-half hour. Then 700 μL of DMSO was added and the reaction was then heated at 65° C. overnight. Thr reaction was quenched and diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and the solvent removed in vacuo to give a brown-yellow oil. The crude material was subjected to flash column chromatography (25% EtOAc:75% Hexanes to 40% EtOAc:60% Hexanes to 50% EtOAc:50% Hexanes) to yield 40 mg, 25% of a white solid. mp 100-1° C. ; 1H NMR (DMSO-d6) δ 0.88 (t, J=6.80 Hz, 3H); 1.25-1.37 (m, 18H); 1.60 (quintet, J=7.14 Hz, 2H); 3.43 (q, J=7.14 Hz, 2H); 3.84 (s, 3H); 3.96 (t, J=4.86 Hz, 2H); 4.57 (t, J=4.86 Hz, 2H); 6.01 (t, J=5.00 Hz, 1H); 6.93-6.95 (m, 3H); 7.27-7.32 (m, 1H); 7.64 (d, J=2.20 Hz, 1H); 7.94 (d, J=1.98 Hz, 1H); 8.68 (s, 1H); IR 3330, 2900, 2840, 1625, 1600, 1520, 1460, 1310, 1300, 1235, 1175, and 1030 cm−1; mass spectrum [(+)ESI] m/z 586/588 [M+H]+; Anal Calcd. For C29H40BrN5O3: C, 59.38; H, 6.87; N, 11.94; Found: C, 59.46; H, 6.68; N, 11.77.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:40]([OH:42])[CH3:41]>>[CH2:40]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)[CH3:41]
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCO
Agent: [Li]CCCC
Product: CCOc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and ethanol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=507 (M++1); Rt=4.85 min. 1H-NMR 400 MHz (CDCl3): δ 1.36-1.40 (t, 3H), 4.28-4.38(dd, J=9 Hz, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13]Cl)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-:19]>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][I:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCI
Yield: 49.4 %

Procedure:
To a solution of (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (4.53 g, 17 mmol) in acetone (50 mL) was added NaI (7.67 g, 51 mmol). The mixture was heated to reflux for 12 h. The solution was diluted with H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluted with PE:EA=100:1 to 50:1, to give (S)-iodomethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (3 g, 49%) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 6.06-6.05-7.30 (d, J=2.2, 1H), 5.86-5.85 (d, J=2.0, 1H), 4.97-4.95 (d, J=4.0, 1H), 4.25-4.22 (m, 1H), 2.20-2.18 (m, 1H), 1.46 (s, 9H), 1.01-1.00 (d, J=3.6, 3H), 0.94-0.93 (d, J=3.4, 3H).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])N.[ClH:21]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:21][C:8]1[CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]([O:13][CH2:14][C:15]#[CH:16])=[C:6]([Cl:5])[CH:7]=1
Reactant: C#CCOc1cc(N)cc(Cl)c1OCC#C
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1cc(Cl)cc(Cl)c1OCC#C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (1.33 g) was added to a solution of 3-chloro-4,5-dipropargyloxyaniline (4.47 g) in acetic acid (30 ml) and 35% hydrochloric acid (4 ml) at 0° C., followed by stirring at the same temperature for 1 hour. The resultant solution was poured into 35% hydrochloric acid (20 ml) containing copper chloride (2.35 g) at room temperature, and stirring was continued at 60° C. for 30 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography using toluene as an eluent to give 1,3-dichloro-4,5-dipropargyloxybenzene (3.60 g) as white crystals. m.p. 61°-63° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:36][CH3:37])([OH:35])[CH2:33][CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][C:16]=2[CH3:41])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:9]2[C:10]([O:13][CH3:14])=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:42])=[O:4])[CH:8]=2)=[C:16]([CH3:41])[CH:17]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:33][CH3:34])([OH:35])[CH2:36][CH3:37])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)ccc3OC)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)O)ccc3OC)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.193 mL, 0.193 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-6-methoxy-2′-methyl-biphenyl-3-yl)-acetic acid methyl ester (Example 177-(1); 35.0 mg, 0.064 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (31.0 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[CH3:28])[CH2:8][CH2:9][OH:10])=O.FC1C=CC=C(F)C=1C(NC(C1C=CC(Cl)=CC=1)CCO)=O>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[C:4]1[O:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH3:28])[N:6]=1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1C(CCO)NC(=O)c1c(F)cccc1F
Agent: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1C1CCOC(c2c(F)cccc2F)=N1
Yield: 64.2 %

Procedure:
The procedure is as for Example 85, but 5.0 g (10.8 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(3-methyl-4'-trifluoromethoxybiphenyl-4-yl)-1-propanol are employed instead of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol. 3.1 g (64.5%) of 2-(2,6-difluorophenyl)-4-(3-methyl-4'-trifluoromethoxybiphenyl-4-yl)-5,6-dihydro(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22](OC)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: OCc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a suspension of methyl 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (15.0 g, 39.9 mmol) was added lithium aluminum hydride (3.03 g, 79.8 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was poured into crashed ice, neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product of [1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (13.7 g). To a solution of the above crude product in triethylamine (43.6 mL), dimethylsulfoxide (200 mL), and dichloromethane (40 mL) was added sulfur trioxide-pyridine complex (43.8 g, 275 mmol), and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a pale yellow powder (11.6 g, 33.5 mmol, 84% in 2 steps).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)C1CCNCC1
Product: COc1cc(N2CCC(C(=O)O)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and piperidine-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.CN.C(Cl)CCl.[CH2:18]([N:20](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH3:18])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cc1F
Reaction time: 24 h
Yield: 31.4 %

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH2Cl2(15 mL) was stirred under N2 for 24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to give the title compound as a white solid (0.27 g, 32%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[N:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:25]=[N:24][CH:23]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 42.1) and pyrimidin-5-ylboronic acid to afford an off-white solid. UPLC-MS (Condition 1) tR=2.09 min, m/z=361.0 [M+H]+, m/z=359.0 [M−H]−; 1H-NMR: (400 MHz, DMSO-d6) δ ppm: 7.41 (d, J=8.56 Hz, 1H) 7.90 (d, 1H) 8.72 (t, J=2.20 Hz, 1H) 9.16 (dd, 1H) 9.23 (dd, 1H) 9.29 (s, 1H) 9.32 (s, 2H) 10.67 (s, 1H).
Reaction SMILES: C[O-].[Na+].C(O)C.Cl.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][CH:9]=1.[SH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>CO>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][S:16][CH2:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: OCC(O)CS
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: OCC(O)CSCc1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium methoxide (3.24 g., 60 mmoles) was dissolved in 36 ml. of absolute ethanol under a nitrogen atmosphere and the stirred solution cooled in an ice bath. With continued cooling, finely divided 4-picolyl chloride hydrochloride (5.07 g., 30 mmoles), slurried in approximately 35 ml. of absolute ethanol, was added over 15 minutes, followed by a solution to 3-mercapto-1,2-propanediol (3.24 g., 30 mmoles) in 6 ml. of absolute alcohol added dropwise over approximately 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight (16 hours). The reaction mixture was clarified by filtration through diatomaceous earth; the insolubles and the diatomaceous earth were extracted with ethanol, the original filtrate combined with the extract, and the whole concentrated to an oil (5.83 g.). Vacuum distillation, which appeared to produce considerable degradation, gave approximately 2.0 ml. of reasonably pure product (b.p. 230° C./0.3 mm.). The distillate was taken up in cold methanol, a solid impurity removed by filtration, and purified 4-(2,3-dihydroxy-1-propylthiomethyl)pyridine recovered by evaporating the filtrate to an oil (2.15 g.; ir (film): 2.97, 3.46, 3.50, 6.21, 7.05, 9.40 and 12.25μ).
Reaction SMILES: [Li]CCCC.[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](Cl)=[O:29])=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:8]2[C@H:7]([CH3:6])[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]2=[O:18])=[O:29])=[CH:24][CH:25]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Temperature: -78 °C
Yield: 48.1 %

Procedure:
nBuLi (1.6M in hexanes, 20 mL, 32 mmol) was added to a stirred solution of (4R,5S)-4-Methyl-5-phenyl-oxazolidin-2-one (5.2 g, 29 mmol) in THF (60 mL) at −78 C under N2. The solution was stirred at −78° C. for 10 mL and then 3-(4-Chlorophenyl)-propionyl chloride (6.0 g, 29 mmol) was added and the solution allowed to warm to room temperature over 1 hour. The solution was quenched with saturated aqueous NH4Cl, extracted into DCM (2×200 mL), dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography on silica (50% EtOAc/hexanes) to give (4R,5S)-3-[3-(4-Chlorophenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one (4.8 g, 48%.) 1H NMR (CDCl3, 400 MHz) δ 7.44-7.35 (3H, m), 7.30-7.24 (4H, m), 7.19 (2H, d, J 8.0 Hz), 5.64 (1H, d, J 7.4 Hz), 4.77-4.71 (1H, m), 3.34-3.17 (2H, m), 2.98 (2H, t, J 7.7 Hz), 0.88 (3H, d, J 6.7 Hz.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:36]([CH3:38])[CH3:37])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CC(C)Br
Product: COc1ccc(CC2c3c(OC(C)C)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with isopropyl bromide
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:21][CH:20]=1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C)C2=O)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-methoxyaniline in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.67 (bs, 1H), 7.27-7.22 (m, 1H), 7.18-7.10 (m, 4H), 6.78-6.73 (m, 2H), 6.57-6.52 (m, 2H), 3.65 (s, 3H), 3.20 (s, 3H); Mass Spectrum: M+H+ 345.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][C:19](=[O:21])[CH3:20])=[C:10]([O:22][CH3:23])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>[Cl-].[Zn+2].[Cl-]>[C:24]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19](=[O:21])[CH3:20])=[C:10]([O:22][CH3:23])[CH:9]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(NC2CCCCC2)c2ccccc2c1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc(N(C(C)=O)C2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A solution 5.0 g of 4-(cyclohexylamino)-1-acetoxy-2-methoxynaphthalene in 75 ml of acetic anhydride is stirred with 500 mg of zinc chloride in at 160°-170° C. for 2 hours. The reaction is cooled, filtered and evaporated under reduced pressure. The residue is taken up in 300 ml of diethyl ether and washed with 100 ml of water and then with 100 ml of brine. The organic solvent is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is crystallized from 120 ml of 2:1 diethyl ether-hexane to yield 4-(N-acetylcyclohexylamino)-1-acetoxy-2-methoxynaphthalene, m.p. 137°-139° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17]([OH:19])=O.[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:17]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)[C:6]=4[C:2]=3[CH3:1])=[O:19])=[CH:41][CH:42]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25]
Reactant: Cc1c(C(=O)O)oc2cccc(N3CCOCC3)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(N5CCOCC5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid (97 mg, 0.37 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (268 mg, 0.74 mmol), BOP (327 mg, 0.74 mmol), N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 184 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester, obtained as an off-white solid.