Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][C:44]=2[CH3:53])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:39]=[C:40]([C:43]5[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][C:44]=5[CH3:53])[CH:41]=[CH:42][C:37]=4[O:36][CH3:35])=[CH:24][CH:23]=[C:22]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B3OC(C)(C)C(C)(C)O3)c2)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(-n2cccn2)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(-n4cccn4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(1H-pyrazol-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.182 mmol) in THF (0.91 mL) was added methyl 4′-methoxy-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (84 mg, 0.218 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (17.8 mg, 0.027 mmol), and potassium carbonate (2 M in water, 0.273 mL, 0.546 mmol). The system was flushed with nitrogen, capped, and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and the organic was washed with water (2×), brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by column chromatography to yield methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-(1H-pyrazol-1-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (91.4 mg, 0.126 mmol). LCMS calc.=725.2. found=725.3.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH:14]=O)[N:10]([CH2:16][CH:17]=[CH2:18])[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:23])[N:10]([CH2:16][CH:17]=[CH2:18])[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: C=CCn1c(C=O)nc2c1c(=O)n(C)c(=O)n2CCCC
Agent: Cl
Solvent: c1ccncc1
Product: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCC
Temperature: 50 °C

Procedure:
A solution of 3-butyl-1-methyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbaldehyde in anhydrous pyridine (5 ml) was treated with hydroxylamine hydrochloride (63 mg, 0.91 mmol) and heated at 50° C. for 1 hour. The mixture was allowed to cool, concentrated, and treated with acetic anhydride (5 ml) then heated at 100° C. for 2.5 hours and 125° C. for 45 minutes. Again the mixture was allowed to cool then partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound as a yellow residue (230 mg crude, 114%); m/z 288.3[MH+].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.032 g, 0.053 mmol) and 1M NaOH (0.159 ml, 0.159 mmol) in EtOH (2 mL) was refluxed for 4 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0257 g, 0.045 mmol, 84% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.14 (dd, J=8.5, 2.0 Hz, 1H), 7.09-7.04 (m, 1H), 7.01-6.96 (m, 2H), 6.93-6.88 (m, 2H), 6.00 (br. s., 1H), 4.26-4.17 (m, 2H), 3.83 (s, 3H), 3.57 (br. s., 1H), 3.10 (t, J=7.1 Hz, 2H), 2.93 (br. s., 1H), 2.64 (s, 3H), 2.34 (br. s., 1H), 2.21 (s, 3H), 2.16-2.01 (m, 1H), 1.68-1.47 (m, 2H), 1.40-1.28 (m, 2H), 1.25 (s, 9H), 0.88 (br.s., 3H), 0.68 (br. s., 3H). LCMS (M+H)=575.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:34][CH3:35]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid propyl ester was prepared from [(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using propyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 490.4 [M]+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[C:15](OC)([CH3:17])[CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][CH:15]([CH3:17])[CH3:16])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: COC(C)(C)OC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
4,5-difluoro-2-nitroaniline (3.48 g, 20 mmol), 2,2-dimethoxypropane (11.9 mL, 100 mmol), and trifluoroacetic acid (1.6 mL, 21 mmol) were dissolved in toluene (40 mL) and stirred at room temperature for 1 h. A boron-pyridine complex (2.12 mL, 21 mmol) was slowly added. The reaction mixture was stirred for 20 h. The solvent was evaporated in vacuo, and the residue was taken up into water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (30:1) to give 2.42 g (56%) of the title compound as a bright orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:14])[C:8](I)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]=1[C:9]1[O:10][C:11]2[C:6]([C:7](=[O:14])[CH:8]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccc2c(=O)c(I)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)cc(-c3nc4ccccc4[nH]3)oc2c1
Temperature: 0 °C
Yield: 68.6 %

Procedure:
A mixture of 7-methoxy-3-iodochromone (151 mg) prepared in Example 21, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (100.2 mg; yield=68.2%) as white needle crystals. Melting point: 201°-203° C. 1H-NMR(CDCl3, δ ppm): 3.97 (s, 3H, CH3O), 6.52 (br, 1H, H3), 8.17 (d, 1H, H5'), 7.06 (d, 1H, H6), 6.99 (s, 1H, H8), 8.44 (s, 1H, H2'), 7.85 (d, 1H, H4'), 7.46 (m, H5'), 7.46 (m, 1H, H6'), 7.90 (d ,1H, H7').
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:6][N:5]2[CH:17]=1.[CH3:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:17]=[C:2]([C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:3]=2)[N:6]=1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Fc1ccccc1-c1ccc2nc(Cl)cn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ncc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 11.4 %

Procedure:
To a mixture of 2-chloro-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.403 mmol), 2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.605 mmol), Na2CO3 (2.01 mmol) in 2-propanol (3.75 mL) and water (1.25 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0403) mmol). The mixture is heated at 80° C. for 12 hours, then cooled, concentrated under reduced pressure, added sat. aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.016 g, 11%) as a white solid: Rf 0.38 (1:1 EtOAc:hexanes); LCMS (m/z)=350.3 [M+H]+, tR=2.71 min.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50])#[N:42]>O1CCCC1>[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([N:15]1[C:11]([C:10]2[C:5]([C:3]#[N:4])=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:12][C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:14]1)(=[O:51])=[O:50])#[N:42]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) in tetrahydrofuran (2 mL) solution, 15-crown-5 (0.13 mL) and 2-cyanobenzenesulfonyl chloride (151 mg) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was diluted with ice water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→ethyl acetate) to give the title compound as a pale-yellow oil (yield 239 mg, 100%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[NH2:9].[C:10](Cl)(Cl)=[O:11]>ClC1C=CC=CC=1Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[N:9]=[C:10]=[O:11]
Reactant: O=C(Cl)Cl
Reactant: CC1CCCC(C)C1N
Solvent: Clc1ccccc1Cl
Product: CC1CCCC(C)C1N=C=O

Procedure:
The thus formed oxime is thereafter reduced in the presence of a Na--alcohol couple to 2,6-dimethylcyclohexylamine at a temperature in the range 0° to 80° C. at 1-5 atmospheres pressure: ##STR10## Amine is then dissolved in o-dichlorobenzene and in the presence of excess phosgene with the reaction being performed in two temperature stages with the first temperature stage in the range -20° to 20° C. and the second from 20° to 200° C. with pressures ranging from 1 to 15 atmospheres to form 2,6-dimethylcyclohexylisocyanate, thusly: ##STR11##
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[C:9](=O)[CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:21]CO.Cl>C(OCC)C>[CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][C:10]([CH3:21])=[CH:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
2,3,5,7-Tetrahydro-5,5,8,8-tetramethyl-1H-Benz(f)inden-1-one (14.89 g, 58.08 mmol) and NaBH4 (2.21 g, 58.5 mmol) were stirred in diethylether (200 mL) at 0° C. while EtOH (100 mL) was added slowly. This mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. After the reaction period the mixture was poured onto crushed ice and made acidic with HCl. The organic layer was then separated and washed with 1 M HCl (1×100 mL). The volatiles were then removed from the organic layer and the residue refluxed in benzene (300 mL) with p-toluenesulfonic acid (0.12 g) using a Dean-Stark apparatus until no more H2O was evolved. The mixture was then washed with 1 M NaHCO3 (2×100 mL) and the volatiles were removed from the organic layer resulting in the isolation of a yellow oil. Recrystallization from MeOH (0° C.) resulted in the isolation of the desired product as off-white crystals (10.37 g, 74.3 percent yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:20]([CH2:21][O:22][C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32](OCC)=[O:33])=[CH:25][C:24]=4[F:37])=[C:19]([C:38]([F:41])([F:40])[F:39])[S:18][N:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1>>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:20]([CH2:21][O:22][C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:25][C:24]=4[F:37])=[C:19]([C:38]([F:40])([F:41])[F:39])[S:18][N:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc4c(c3)OCO4)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2c(-c3ccc4c(c3)OCO4)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(benzo[d][1,3]dioxol-5-yl)-5-(trifluoromethyl) isothiazol-4-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.28 (d, J=8.1 Hz, 1H), 7.18 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.80 (d, J=9.3 Hz, 2H), 6.03 (s, 2H), 5.20 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 1.82-1.76 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H16F5NO4S, 474.1 (M+H). found 474.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)cc1N
Reaction time: 15 h
Yield: 87.2 %

Procedure:
A solution of 4-fluoro-1-methoxy-2-nitro-benzene (85 g, 0.50 mol) in methanol (300 mL) containing palladium on carbon (10%, 8 g) was stirred for 15 hours under an atmosphere of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness to give the crude product (61.5 g, 0.436 mol, 87%), which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([OH:31])[CH:7]=1.Br[CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:44]=[C:45]([Br:49])[CH:46]=[CH:47][CH:48]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=2)[CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: BrCCCOc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2cccc(Br)c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 70.2 %

Procedure:
A mixture of 1.0 g (1.92 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycine methyl ester, 0.59 g (2.01 mmol) of 3-(3-bromopropoxy) bromobenzene, 0.53 g (3.83 mmol) of potassium carbonate and 0.29 g (1.92 mmol) of sodium iodide in 30 ml of acetone and 6 ml of DMF was stirred at reflux under argon for 65 hours. The solvents were removed at reduced pressure and the residue was treated with methylene chloride and filtered. The filtrate wasconcentrated and crystallized from methylene chloride-methanol to give 0.99g (70%, mp 48°-50°) of N-(2-methoxy-2-oxoethyl)-N-[3-[3-(3-bromophenoxy) propoxy]-5-(octadecyloxy)phenyl]glycine methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3ccncc3)c3ccccc23)cc(OC)c1OC
Yield: 25.6 %

Procedure:
Substantially the same procedure as in Example 59 was repeated using Compound 1 (1.43 g) obtained in Example 1 and isonicotinoyl chloride hydrochloride (1.51 g) to give Compound 61 (0.48 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([C:29](=[O:31])[CH3:30])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:20]([C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][CH:17]=1)[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 126.3 %

Procedure:
To a solution of 6′-[acetyl-(3-chloro-benzyl)-amino]-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-5c (27.1 mg, 0.06 mmol) in methylene chloride (1 mL) was added trifluoroacetic Acid (1 mL). The reaction mixture was stirred at room temperature until the reaction was completed. The reaction mixture was poured into saturated NaHCO3 (20 mL) and extracted with methylene chloride (2×15 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness to yield the title compound 5-A (26.2 mg).
Reaction SMILES: C1O[C@H]1CO.C(NC1C=CNC(=O)N=1)(=O)C1C=CC=CC=1.[CH:22]1[C:28]([NH2:29])=[N:27][C:25](=[O:26])[N:24]([CH2:30][C@H:31]([O:34][CH2:35][P:36]([OH:39])([OH:38])=[O:37])[CH2:32][OH:33])[CH:23]=1>>[CH:22]1[C:28]([NH2:29])=[N:27][C:25](=[O:26])[N:24]([CH2:30][C@@H:31]([O:34][CH2:35][P:36]([OH:39])([OH:38])=[O:37])[CH2:32][OH:33])[CH:23]=1
Reactant: Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Agent: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: OC[C@H]1CO1
Product: Nc1ccn(C[C@H](CO)OCP(=O)(O)O)c(=O)n1

Procedure:
The title compound (R)-HPMPC was prepared from (S)-glycidol (88% ee) and N4 -benzoylcytosine, following the method described for (S)-HPMPC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@@H:25]([OH:29])[C@H:24]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:29][C@@H:25]1[C@@H:26]([CH3:28])[CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:23][C@H:24]1[NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])(=[O:41])=[O:40]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl tert-butoxycarbonyl(4-((3R,4R,5S)-3-((tert-butoxycarbonyl)amino)-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)carbamate (1.0 equiv.) in DCM (0.20 M) was added TEA (1.7 equiv.), followed by MsCl (1.3 equiv.). The capped solution was stirred at rt for 90 mins. The reaction mixture was quenched with NaHCO3(sat.), and extracted with EtOAc. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated to yield (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-yl methanesulfonate in 99% yield. LC/MS (m/z)=601.3 (MH+), Rt=0.83 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH3:9]O>>[CH3:9][N:6]1[C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: CO
Reactant: CC1(C)CCC(=O)N1
Product: CN1C(=O)CCC1(C)C
Yield: 86 %

Procedure:
A solution of 113 g (1 mole) of 5,5-dimethylpyrrolid-2-one and 96 g (3 moles) of methanol was vaporized, and passed over an alumina catalyst at 400° C. Working up the gas mixture in a conventional manner to obtain 1,5,5-trimethylpyrrolid-2-one gives this compound in about 86% yield; boiling point: 236°-238° C.