Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 4.2 g (10 mmol) of 5-phenylpentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 2.627 g (quant., brown oily substance) of the desired product.
Reaction SMILES: C(N(CC)CC)C.Cl.O(N)C.ClC[C:14]1[N:15](CC(O)(C)C)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1.O>CN(C=O)C>[NH:15]1[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=[CH:14]1
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Agent: CON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc2ccccc2c2[nH]cnc12
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Triethylamine (1.49 g, 2.1 mL, 14.8 mmol) and methoxylamine hydrochloride (0.822 g, 9.84 mmol) were added to a stirring suspension of 2-chloromethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.92 mmol) in DMF (10 mL). The resulting suspension was heated to 50° C. and stirred for 17 hours. The reaction mixture was cooled to room temperature and poured into water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and dichloromethane (3×50 mL). A significant amount of the desired product remained in the aqueous layer thus the organic fractions were combined with the aqueous fraction and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 10-25% methanol in dichloromethane) and triturated with dichloromethane to provide 760 mg of 1-(2-Hydroxy-2-methylpropyl)-2-{[methoxylamino]methyl)}-1H-imidazo[4,5-c]quinolin-4-amine; hydrochloride as a tan solid, mp 255-257° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C-:21]#[N:22].[K+].O>CCOCC.CCOC(C)=O>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([C:21]#[N:22])([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Reactant: C1COCCN1
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1(N2CCOCC2)CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.5 ml of morpholine and then 5.1 g of Na2S2O5 are added to a mixture of 5 g of 1-benzylpiperid-4-one and 1.9 g of potassium cyanide in 50 ml of an EtOH/water mixture (50/50; v/v) and the mixture is heated at 60° C. for 2 hours. A further 2.5 ml of morpholine are added and the reaction mixture is stirred overnight at RT. Water is added and the crystalline product formed is wrung to give 5.5 g of of the expected product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-methylpiperidin-3-ylcarbamate (0.64 g, 2.1 mmol) and 10% Pd/C (0.22 g, 0.21 mmol) in methanol (10 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 18 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-methylpiperidin-3-ylcarbamate (0.43 g, 95%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH2:23][OH:24])[CH3:25])=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(OCCO)cc4)nc3c2)cc1

Procedure:
Compound 223 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-methyl-N-2-hydroxyethylamino)benzamide and 4-(2-hydroxyethyloxy)benzaldehyde. [M+H]+ calcd for C25H26N4O4: 447.21; found: 446.89.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:15][C:14]([NH:13][CH:4]([C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)c2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
tert-Butyl 1-(dimethylamino)-3-(3-hydroxyphenyl)-1-oxopropan-2-ylcarbamate (0.025 g, 0.081 mmol) and methyl 4-fluorobenzoate (Aldrich, Cat. #120707) (0.025 g, 0.16 mmol) were combined in acetonitrile (1.0 mL) with cesium carbonate (0.053 g, 0.16 mmol) in a sealed tube and heated to 100° C. After 4 h., the reaction was allowed to cool, diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude methyl 4-(3-(2-(tert-butoxycarbonylamino)-3-(dimethylamino)-3-oxopropyl)phenoxy)benzoate as a semi-solid. Analytical LCMS (M+H-Boc)+: m/z=342.9.
Reaction SMILES: [CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)=[O:2]>CO.[Pd]>[CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)=[O:2]
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)(NC=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(N)c1)(NC=O)c1ccccc1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of N-formyl-l-(3-nitrophenyl)-2-phenyl-2-propylamine (5.0g, 0.017mol) in methanol (200 ml) was added 10% Pd/C catalyst (0.5g) and the mixture hydrogenated at 50 psi in a Parr apparatus for 3 hours. The catalyst was removed by filtration and the solvent evaporated to a white solid, 4.6 g. This solid was recrystallised from isopropanol (50 ml) to give 2.6 g of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine, mp 114°-115° C. To a stirred solution of sodium nitrate (2.0 g,0.03 mol) in sulphuric acid (15 ml) at 0° C. under nitrogen was added dropwise a solution of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine (7.0 g, 0.027 mol) in acetic acid (75 ml) and the solution was stirred 2.5 hours at a temperature less than 20° C. The above mixture was added to a solution of cuprous chloride (5.3 g, 0.054 mol) in concentrated HCl (50 ml) at 15° C., and the resulting solution was stirred at that temperature for 1 hour. The reaction mixture was poured into water (500 ml), basified with concentrated ammonium hydroxide, and extracted with chloroform (3×200 ml). The combined chloroform extracts were dried over magnesium sulphate and the solvent evaporated to a solid, 7.5 g. Thissolid was recrystallised from isopropanol (20 ml) to provide 3.2 g of N-formyl-1-(3-chlorophenyl)-2-phenyl-2-propylamine, mp 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:15]O>>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)s1

Procedure:
To a solution of 5-methylthiophene-2-carboxylic acid (F-1) (14.0 g, 0.1 mol) in MeOH (250 mL) was added concentrated H2SO4 (2.0 mL). The reaction mixture was stirred under reflux for 60 h. The solvent was removed in vacuo. Ethyl acetate was added to dilute the reaction mixture. Then the organic solution was washed with a saturated aqueous Na2CO3 solution, and dried over Na2SO4. The solvent was removed to afford the title compound (13.4 g).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C[C:11]([N:13](C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[N:13]
Reactant: CC(=O)N(C)C
Reactant: Cc1cccc(F)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 5 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (2.4 L) and degassed under vacuum and purged with N2 three times. Tetrakis was added to the mixture (35 g, 30.3 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (230 g, 974 mmol) and zinc cyanide (68.7 g, 585 mmol) were added and the mixture was degassed under vacuum and purged with N2 three times. The mixture was heated to 80° C. for 16 hrs and allowed to cool to RT. The solution was added to 2.0 L aqueous solution of 1N NH4OH, which was then extracted three times with 1.5 L EtOAc, washed with 2 L brine, dried over Na2SO4, filtered, concentrated and purified by silica chromatography (PE/EA=10:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=[C:7]([N:4]4[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Cc1ccn(-c2cc(N)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4ccc(C)n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (250 mg, 1.036 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.036 mmol) in pyridine (5 mL) was added T3P® (3298 mg, 5.18 mmol) in portions. The mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (280 mg, 0.357 mmol, 34.5% yield). 1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.50-7.43 (m, 3H), 7.41 (d, J=9.0 Hz, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.36 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.CC(C)=O.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:18][C:3]1[CH:4]=[C:5]([OH:17])[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Cl:1])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1cc(Cl)c(O)cc1O)c1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Yield: 41.6 %

Procedure:
To crude N-(5-chloro-2,4-dihydroxyphenyl)benzamide (1 mmol) in acetone (10 mL) potassium carbonate (280 mg, 2 mmol) and benzoylchloride (140 mg, 1 mmol) was added. The mixture was stirred at ambient tempearature over night. The solvent was removed in vacuo and the residue purified by flash chromatography on silica using DCM and methanol in gradient. The pure compound was obtained as a white solid (153 mg, 42%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1.ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:36])[CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ncccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.23 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (166) in tetrahydrofuran (20 mL) were added triphenyl phosphine (66 mg, 0.25 mL) and DTAD (58 mg, 0.25 mmol) at room temperature. A yellow clear solution was formed, which was sonicated for 20 min. It was stirred at room temperature for 24 h. Silica thin layer chromatography was performed (5% methanol in dichloromethane, Rf=0.2). The mixture was concentrated under reduced pressure to get a crude product, which was purified by a preparative thin layer chromatography plate (mobile phase 5% methanol in dichloromethane) to get pure 9-benzyloxy-2-isopropyl-6-(3-phenyl-pyridin-2-ylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (167) (17 mg, 35.23%) as a yellow sticky solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C@@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C@@H:20]([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) and (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride (1:1) (CAN 426844-23-7; 40 mg, 236 μmol) as starting materials and isolated (68 mg, 91%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 348.1721 [MH+].
Reaction SMILES: [CH3:1][S:2]Cl.C(OCC)C.[CH3:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12].O>N1C=CC=CC=1>[CH3:9][N:10]([S:2][CH3:1])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12]
Reactant: CSCl
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CSN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 20 ml of methylsulfenyl chloride and 200ml of ethyl ether was added slowly while keeping the temperature below -30° C. to a solution of 40 g of N-methyl-N'-(3,4-dichlorophenyl)-urea in 500 ml of pyridine and the mixture was stirred for 1 hour at -30° C. After letting the temperature rise to 5° C., the mixture was stirred for 17 hours and the mixture was poured into a mixture of ice and water. The mixture was extracted with methylene chloride and the methylene chloride extract was washed with water and dried. The volatile fractions were removed by distillation under reduced pressure and the residue was crystallized from isopropyl ether to obtain 29.4 g of N-methyl-N-methylthio-N'-(3,4-dichlorophenyl)-urea melting at 93° C. A microanalytical sample was obtained by chromatography over silica gel and elution with a 9-1 benzene-ethyl acetate mixture.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([CH:15]=[O:16])[N:9]2[N:8]=1)=[O:5])[CH3:2].S([CH2:34][N+:35]#[C-:36])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([C:15]3[O:16][CH:36]=[N:35][CH:34]=3)[N:9]2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C=O)n2n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnco3)n2n1

Procedure:
A mixture of the product of Step 2 (40 mg, 0.13 mmol), tosylmethyl isocyanide (28 mg, 0.14 mmol) and K2CO3 (36 mg, 0.26 mmol) were stirred at room temperature in MeOH (5 mL) for a few minutes, then heated at reflux for 0.5 h. All solvent was then removed under reduced pressure, the residue taken up into MeOH/CH2Cl2, and dried onto silica. Purification was carried out by filtration through a plug of silica gel (5% MeOH/CH2Cl2 as eluant) to give the title compound as a solid. LCMS (APCI+) 350.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])C.[BH4-].[Li+].Cl>O1CCCC1>[OH:10][CH:8]1[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:5]([CH2:4][OH:3])[CH2:9]1
Reactant: CCOC(=O)[C@H]1CC(O)CN1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To an ice-cold solution of 286.4 g (0.914 mole) of 4-hydroxy-(4-toluenesulfonyl)-D-proline ethyl ester (5) in 2.8 L of tetrahydrofuran was added 20 g (0.918 mole) of lithium borohydride in one portion. The mixture was stirred at 0° C. for 1 hour and then kept at a temperature below 25° C. overnight. The mixture was cooled to 0° C. and the pH adjusted to 3 with 6N hydrochloric acid (180 ml). The volume was reduced to 500 ml by rotary evaporation, and 1.5 L of water was added. The white precipitate was filtered, washed with cold water (500 ml) dried under reduce pressure to give 223.8 g (90%) of the title compound. M.P. =127° C. [α]D =36.66° (c=1.0, acetone) K.F. -6.55%.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.CO>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([C@@:4]1([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC)cc2)C(=O)O1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(O)cc2)C(=O)O1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one (0.1094 g, 0.30 mmol, 1.0 equiv) in 6 mL of dry CH2Cl2 was cooled to −78° C. At this temperature, BBr3 (1.0 M solution in CH2Cl2, 0.6 mL, 0.60 mmol, 2.0 equiv) was added under N2 atmosphere. After 1 h, the reaction mixture was stirred at an ice bath for further 3 h. After the reaction mixture was cooled with a dry ice—acetone bath, surplus of BBr3 was hydrolyzed with methanol (3 mL). The mixture was then treated with brine, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 ml/min) to afford 0.0669 g (64%) of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.57 min, m/z 356 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.23-7.18 (m, 2H), 7.00-6.96 (m, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.2 Hz, 2H), 5.64-5.54 (m, 1H), 5.34 (q, J=7.0 Hz, 1H), 4.96-4.89 (m, 2H), 2.93-2.88 (m, 1H), 2.50 (d, J=7.0 Hz, 2H), 2.34-2.29 (m, 1H), 2.18-2.03 (m, 2H), 1.36 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −117.48 (m).