Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:37]=[CH:36][C:28]2[N:29]=[C:30](S(C)(=O)=O)[O:31][C:27]=2[CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:30]3[O:31][C:27]4[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][C:28]=4[N:29]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)oc2c1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) were added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00-7.50 (m, 8 H), 7.30 (d, 2 H), 7.05 (d, 1 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.53 min (method 2), m/z 429.17 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.7 %

Procedure:
A solution of tert-butyl [(4-bromophenyl)amino]acetate (intermediate 1, 5.86 g, 20.5 mmol), methanesulfonyl chloride (2.58 g, 1.74 mL, 22.5 mmol), triethylamine (4.15 g, 5.71 mL, 41.0 mmol) and 4-dimethylaminopyridine (260 mg, 2.05 mmol) in dichloromethane (100 mL) was heated at reflux for 14 h. A second portion of methanesulfonyl chloride (2.58 g, 1.74 mmol, 22.5 mmol) was added and heating at reflux continued for a further 48 h. The reaction was cooled to room temperature and extracted with aqueous hydrochloric acid solution (1.0 M; 3×50 mL). The organic phase was dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound as a pale cream solid (2.37 g, 32%). LC/MS: 3.35 min; z/e 381 and 383, calcd (M+18) 381 and 383. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.35 (2H), 4.30 (2H), 3.10 (3H), 1.45 (9H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ncccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccnc1S(N)(=O)=O
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
3-Nitro-pyridine-2-sulfonic acid amide (3 g, 14.77 mmol) and iron powder (5 g, <10 micron) were suspended in ethanol (100 mL). Saturated aqueous ammonium chloride solution (60 mL) was added and the mixture stirred at 105° C. for 1.5 h. Upon cooling to 25° C., ethyl acetate (200 mL) was added and the mixture was shaken vigorously. The entire mixture was filtered through a plug of Celite. The resulting filtrate was diluted with ethyl acetate (100 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The resulting solid was triturated with a 3:1 mixture of hexanes and ethyl acetate (˜10 mL). The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, 3-amino-pyridine-2-sulfonic acid amide (1.95 g, 11.27 mmol, 76%), as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 5.98 (2H, bs), 7.19-7.21 (1H, m), 7.32 (2H, bs), 7.79-7.80 (1H, m), 7.90-7.91 (1H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:13])([F:12])[CH:9]1[O:11][CH2:10]1>>[F:7][C:8]([F:13])([F:12])[CH:9]([OH:11])[CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: FC(F)(F)C1CO1
Product: OC(CN1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a round bottomed flask containing 3.136 g (36 mmol) of morpholine was added 3.362 g (30 mmol) of racemic 1,1,1-trifluoro-2,3-epoxypropane dropwise over 10 min (exothermic). The mixture was stirred at room temperature. After 90 min, the volatiles were removed under reduced pressure to give 5.837 g (98%) of 1,1,1-trifluoro-3-morpholin-4-yl-propan-2-ol as an oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[C:25]([O:35][CH:36]2[O:38][C@H:37]2[CH3:39])=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:10][N:11]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:12]1)[CH2:39][C@H:37]([OH:38])[CH2:36][O:35][C:25]1[C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:33][C:34]=2[CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Reactant: O=[N+]([O-])c1ccc(N2CC(NCc3ccccc3)C2)cc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3cccc4[nH]c5ccccc5c34)C2)cc1

Procedure:
Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine (which was obtained in Example 398) (1.95 g, 6.87 mmol) and (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (Berridge et al., Int. J. RadiaL Appl. Instrum., 1992, 563) (1.64 g, 6.87 mmol) was stirred at reflux in anhydrous methanol for 24 hours. Methanol was removed in vacuo and the desired product was isolated using silica gel flash chromatography to give 3.01 g of product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ2.90 (m, 2H), 3.04 (s, 1H), 3.85 (m, 3H), 3.98 (m, 3H), 4.23 (m, 3H), 6.01 (d, 2H, J=7.26Hz), 6.61 (d, 1H, J=8.10 Hz), 7.06 (d, 1H, J=8.04 Hz), 7.17 (t, 1H, J=2.14 Hz), 7.34 (m, 7H), 7.97 (d, 2H, J=9.12 Hz), 8.14 (t, 2H, J=8.79 Hz); MS (ES) m/z: 522.9 (MH+); Anal. Calcd. for C31H30N4O4: C, 71.25; H, 5.79; N, 10.72. Found: C, 70.77; H, 6.17; N, 9.61.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH2:7]([O:11][C:12]1[CH:19]=[CH:18]C(C#N)=[C:14]([F:20])[CH:13]=1)[CH2:8][CH2:9][CH3:10].[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:22]([C:21]([OH:24])=[O:23])=[C:14]([F:20])[CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(C#N)c(F)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCOc1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of concentrated sulphuric acid (190 ml) and water (190 ml) was added dropwise to a stirred solution of compound 18 (19.0 g, 0.098 mol) in glacial acetic acid (380 ml). The stirred mixture was heated under reflux for 48 h, cooled in a refrigerator for 24 h and the product was filtered off and dried (CaCl2) in vacuo to give pale-yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:9]2C=CC=C[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[CH3:10][CH2:9][CH:7]([OH:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 86.6 %

Procedure:
A Grignard reagent was prepared from 4-(3-benzyloxypropyl)bromobenzene (3.2 g), magnesium (0.25 g), a catalytic amount of iodine and tetrahydrofuran (10.5 mL). To the obtained Grignard reagent solution was added a solution of 2-(methoxymethoxy)benzaldehyde (1.1 g) in tetrahydrofuran (24 mL), and the mixture was stirred at 65° C. for 25 minutes. After cooling to room temperature, a saturated aqueous ammonium chloride solution (10 mL) and water (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water (20 mL) and brine (20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give a diphenylmethanol compound (2.5 g). The obtained diphenylmethanol compound (2.5 g) was dissolved in ethanol (42 mL), a catalytic amount of 10% palladium-carbon powder was added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 7.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/2) to give a phenylpropanol compound (1.6 g). After the obtained phenylpropanol compound (1.6 g) was dissolved in dichloromethane (29 mL), 4-(dimethylamino)pyridine (0.069 g), triethylamine (1.0 mL) and benzoyl chloride (0.79 mL) were added to the solution, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added ethyl acetate (100 mL) and water (30 mL), and the organic layer was separated. The extract was washed with brine (30 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=20/1) to give an ester compound (2.2 g). A mixture of the obtained ester compound (2.2 g), p-toluenesulfonic acid monohydrate (0.21 g) and methanol (28 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-[4-(3-benzoyloxypropyl)benzyl]phenol (1.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc(OCC(=O)c2ccccc2)c(C)c1

Procedure:
Using the method described in Example 1, 2,4-dimethylphenol is reacted with alpha-bromoacetophenone to provide alpha-(2,4-dimethylphenoxy)acetophenone.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:20][CH:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[OH:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: c1ccc2c(C3CO3)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccnc3ccccc23)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.5 mmol) in DMF (5 mL) was added sodium hydride (180 mg, 4.5 mmol) under nitrogen. After stirring at RT for 10 min, 4-(oxiran-2-yl)quinoline (384 mg, 2.25 mmol) was added dropwise under nitrogen into the reaction mixture, which was stirred at RT for 18 h. The progress of reaction was monitored by TLC, LCMS and NMR. The reaction mixture was poured in ice-cold water and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Re-crystallization with diethyl ether yielded 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(quinolin-4-yl)ethanol (140 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.86 (d, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.41 (d, 1H), 7.56 (t, 1H), 7.2 (d, 1H), 6.93-7.01 (m, 2H), 5.57 (t, 1H), 4.2 (dd, 1H), 4.1 (dd, 1H), 3.37 (dd, 2H), 2.83 (m, 1H), 2.71 (bs, 3H), 2.4 (s, 3H), 2.38 (s, 3H). Separation by chiral HPLC provides enantiomers II-90a-b.
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[O:10][CH2:9][C@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[O:7]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][CH2:14][C@H:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:4]4[N:3]=[C:2]([CH3:1])[O:26][C:5]=4[C:6]=3[O:7]2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)O[C@@H](CN[C@H]1CC[C@@H](c2c[nH]c4ccc(F)cc42)CC1)CO3
Temperature: 80 °C

Procedure:
Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthlen-8-ylmethyl ester (0.52 g, 1.39 mmole) and cis-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.60 g, 2.6 mmole) were combined in 10 mL of anhydrous DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 5 hours. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (CH2Cl2 then 1% MeOH/CH2Cl2) afforded 0.26 g of the title compound as a light yellow solid: m.p. 80-82° C.; MS (ESI) m/z 436 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][Sn:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[Sn](C)(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Sn](C)(C)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a suspension of NaH (140 mg, 5.83 mmol) in anhydrous THF (150 mL) under N2 at RT was added dropwise 4-chlorophenol (738 mg, 5.74 mmol). After stirring the mixture at RT for 15 min, (chloromethyl)trimethylstannane (350 mg, 1.64 mmol) in anhydrous THF (5 mL) was added and the reaction was stirred at RT for 18 hours. The mixture was diluted with EtOAc (50 mL) and was washed with aqueous 1.0 N NaOH (3×60 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane, using LC-MS to identify fractions containing the desire product) to afford ((4-chlorophenoxy)methyl)-trimethylstannane 8A (457 mg, 87% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 7.03 (2H, d, J=8.78 Hz), 6.67 (2H, d, J=9.03 Hz), 3.94 (2H, s), 0.00 (9H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5].O.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(OCC)(=O)C>[C:20]([NH:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5])(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)C(N)c1ccccc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(=O)NC(C(C)=O)c1ccccc1

Procedure:
To a mixture of 1-amino-1-phenyl-2-propanone hydrochloride (5.55 g), water (40 ml), ethyl acetate (75 ml) and potassium carbonate (4.55 g) was added dropwise hexanoyl chloride (4.42 g) under ice-cooling and stirring. The mixture was further stirred for an hour with ice-cooling. The ethyl acetate layer was separated, washed with water, diluted hydrochloric acid and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was recrystallized from isopropyl ether to give crystals of 1-hexanoylamino-1-phenyl-2-propanone, yield 5.80 g (78.2%), m.p. 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH:11]=[O:12]
Reactant: COc1ccc(Cl)c(C)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)c(C)c1C=O
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Chloro-3-methylanisole (15.4 g., 0.10 mole) was taken into 200 ml. of methylene chloride and cooled to 0° C. Titanium tetrachloride (37.9 g., 0.2 mole) and then 1,1-dichloromethyl methyl ether (13.8 g., 0.12 mole) were added, each over a 2 minute period. The reaction mixture was stirred at room temperature for 1 hour, poured over 500 ml. of ice and water and the organic layer separated. The aqueous layer was extracted with two portions of fresh methylene chloride and these extracts combined with the original organic layer. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated dryness (15.2 g., 82%), containing two thirds 5-chloro-2-methoxy-4-methylbenzaldehyde [Rf 0.35 (1:1 chloroform:hexane] and one third of the desired isomeric product [Rf 0.28 (1:1 chloroform:hexane]. These two compounds were separated by chromatography on 1 kg. of silica gel, eluting with 1:1 methylene chloride:hexane, collecting 15 ml. fractions and monitoring by tlc. Fractions 115-140 were combined and evaporated to dryness to yield the undesired Rf 0.35 isomer (860 mg., m.p. 86°-88° C.). Fractions 240-310 were combined to yield the desired 3-chloro-6-methoxy-2-methylbenzaldehyde [1.61 g.; m.p. 95°-97° C., pnmr/CDCl3 /delta 2.4 (s, 3H), 3.9 (s, 3H), 6.8 (s, 1H), 7.7 (s, 1H), 10.4 (s, 1H); Rf 0.28 (1:1 methylene chloride:hexane)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31](N)=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:32])=[O:42])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reaction time: 3 h
Yield: 13.9 %

Procedure:
To a solution of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide (70 mg, 0.16 mmol) in CH2Cl2 (10 mL), was added m-CPBA (135 mg, 0.79 mmol), and the reaction mixture was stirred at it for 3 h. After the solvent was removed under reduced pressure, the residue was purified by preparative TLC to afford 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (10 mg, 15%). LC-MS Method 2 tR=0.987 min, m/z=464.17; 1H NMR (CDCl3): 1.51 (m, 3H), 1.92 (m, 1H), 2.12-2.28 (m, 5H), 2.43 (m, 1H), 2.95 (m, 1H), 5.56 (m, 1H), 5.65 (m, 1H), 5.31 (m, 1H), 6.95 (m, 2H), 7.08 (m, 2H), 7.15 (m, 1H), 7.20 (m, 1H), 7.25 (m, 2H), 7.56 (m, 1H), 7.24 (m, 1H), 8.35 (m, 1H), 8.65 (m, 1H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N+:12]([CH2:15][C:16]([O-])=[O:17])([O-:14])=[O:13]>ClCCl>[N+:12]([CH2:15][C:16]([O:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17])([O-:14])=[O:13]
Reactant: OCCSc1ccccc1
Reactant: O=C([O-])C[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: O=C(C[N+](=O)[O-])OCCSc1ccccc1

Procedure:
This compound was prepared according to a known process (British Pat. No. 835,521 Spec.). Namely, a solution of β-phenylthioethylalcohol (50g) in dichloromethane (15ml) was saturated with dry hydrogen chloride at 0° C. and to the resulting solution was added, in three portions, dipottassium nitroacetate (27.5g). During the addition, hydrogen chloride was passed into the well stirred mixture while the temperature was allowed to rise to 10° C. Then the gas supply was stopped and the reaction mixture was stirred for 4 hours at less than 10° C. After stirring for 20 hours at 0° C., excess β-phenylthioethyl-alcohol was removed under reduced pressure and the remaining solution was kept to cool, the crystals precipitated was washed with water and then with n-hexane, giving β-phenylthioethyl nitroacetate (11.1g), m.p. 22.0°-24.0° C..
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:33])[C:6]([C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:30][CH:31]=[CH2:32])=[C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:11]2=[N:12][C:13]=1[CH3:14])=[O:7])[CH3:3].[BH4-].[Na+]>C(O)C>[CH2:2]([O:4][C:5](=[O:33])[CH:6]([C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:30][CH:31]=[CH2:32])=[C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:11]2=[N:12][C:13]=1[CH3:14])[OH:7])[CH3:3]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(=O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a stirred solution of [4-(2-Allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-oxo-acetic acid ethyl ester hydrochloride (1.1 g, 2.56 mmols) in ethanol (20 mL) was added sodium borohydride (145 mg, 1.5 eq, 3.84 mmols), and the reaction was stirred at room temperature for 5 minutes. The reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and hydrochloric acid (aqueous, 1 N, 30 mL). The organics were separated, washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give crude [4-(2-allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-hydroxy-acetic acid ethyl ester as a pale orange gum 1.1 g (91% yield). LCMS (2 min acidic) 1.53 min 52-81% pure by UV, ES+/AP+ 452. HNMR (CDCl3)>80% pure 7.02 (d, J=7.4 Hz, 1H) 6.81-6.85 (m, 1H) 6.79 (s, 1H) 5.86 (m, 1H) 5.18 (s, 1H) 5.08-5.17 (m, 2H) 4.47-4.51 (m, 2H) 4.08-4.22 (m, 2H) 2.81 (t, J=6.2 Hz, 2H) 2.63 (s, 3H) 2.43 (s, 3H) 1.71-1.87 (m, 4H) 1.53-1.64 (m, 2H) 1.17-1.21 (m, 3H).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccn2)CC1
Temperature: 150 °C

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (5.0 g, 25.0 mmol) (Aldrich) and 2-bromopyridine (1.98 g, 12.50 mmol) (Aldrich) were combined in a sealed tube and heated at 150° C. for 12 hours. The mixture was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48 (m, 9H), 1.88–2.02 (m, 2H), 3.20–3.48 (m, 2H), 3.52–3.70 (m, 4H), 3.72–3.83 (m, 2H), 6.45–6.59 (m, 2H), 7.47 (m, 2H), 8.11–8.18 (m, 1H); MS (DCI/NH3) m/z 278 (M+H)+.