Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[N:4]=1>[Pd].CO>[CH3:13][O:12][C:7]1[C:8]([NH2:9])=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[N:6]=1
Reactant: COc1nc(N2CCC(OC)CC2)nc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nc(N2CCC(OC)CC2)nc(OC)c1N
Reaction time: 3 h
Yield: 108.9 %

Procedure:
To a 1 L Atlantis reactor, under nitrogen, was added 20% palladium on carbon (6.16 g, 5.79 mmol, 15% by weight), 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)-5-nitropyrimidine (41.1 g, 137.8 mmol) and methanol (390 mL). The reactor was sealed and purged with nitrogen (3×) and then hydrogen (3×). The mixture was hydrogenated at 50 psi (H2) for 3 h. After purging with nitrogen, the catalyst was removed by filtration, and the filter cake was rinsed with additional methanol (150 mL). The filtrate was concentrated to afford 40.25 g of 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-amine as a viscous orange oil that was used without further purification. 1H NMR (400 MHz, CDCI3) δ 4.17-4.29 (m, 2H) 3.92 (s, 6H) 3.39 (s, 3H) 3.34-3.47 (m, 1H) 3.19 (ddd, J=13.0, 9.0, 3.0 Hz, 2H) 2.76 (br. s., 2H) 1.87-2.00 (m, 1H) 1.43-1.68 (m, 2H). LCMS m/z=269.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][N:17]=5)[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ncn(-c2ccc(F)c(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.10 g, 0.44 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1 eq) and HATU (0.19 g, 1.3 mmol, 3 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-(3,4-difluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.046 g, 0.11 mmol, 25%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH3:18][C:15]([CH3:19])([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[C:16]#[CH:17]
Reactant: C#CC(C)(C)Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)(C)Oc1cc(C(=O)OC)ccc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (5.41 g), 3-chloro-3-methyl-1-butyne (10 ml), cesium carbonate (19.4 g), and DMF (54 ml) was stirred at 80° C. for one hour. 3-Chloro-3-methyl-1-butyne (5 ml) was further added to the mixture followed by stirring at 90° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and with a saturated saline and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 and 7/1) to give Compound IIao-a (2.31 g, 31%) as a brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([OH:21])[C:19]#[CH:20]>ClCCl.[Cu]I>[NH2:1][C:2]1[C:7]([C:20]#[C:19][C:18]([CH3:22])([OH:21])[CH3:17])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol), copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol) in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (2×50 mL). The organic phase was then treated with 1 M HCl (80 mL). The layers were separated and the organic layer was extracted with 1 M HCl (20 mL). The combined product containing aqueous layers were washed with dichloromethane (2×10 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water, 18 g). The resulting suspension was stirred at 20° C. for 2 hours and the crystals were then filtered off and washed with water (2×20 mL). The wet crystals were dried at 50° C./<30 mbar affording 6.99 g (82%) of 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted mass with a purity of 99.5% (HPLC, area%). 1H NMR (400 MHz, CDCl3): δ ppm 1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][S:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]4[C:16]5[C:8](=[CH:9][CH:10]=[C:11]6[C:15]=5[S:14][CH:13]=[N:12]6)[NH:7][C:6]4=[O:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:37]=2)[CH:33]=[N:34]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Yield: 16 %

Procedure:
The title compound was prepared in 16% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(1H-indazol-6-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.9 (s, 1H), 11.1 (d, 1H), 10.9 (s, 1H), 10.4 (s, 1H), 9.3 (s, 1H), 8.1(d, 1H), 8.0 (s, 1H), 7.8 (d, 1H), 7.8 (d, 2H), 7.7 (d, 1H), 7.6 (d, 2H), 7.3 (s, 1H), 7.1 (d, 1H), 6.9 (d, 1H); APCI−MS m/z 487 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[C:11]([F:21])[CH:10]=2)=[CH:5][CH:4]=1.I[CH3:34].[H-].[Na+].O>CN(C=O)C>[F:21][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([F:15])[C:12]=1[C:16]([CH3:20])([CH3:19])[CH2:17][O:18][CH3:34])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: CI
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(F)c(C(C)(C)CO)c(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)c1c(F)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a solution of 2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol (1.31 g, 2.97 mmol) and iodomethane (0.278 mL, 4.45 mmol) in DMF (10 mL) was added sodium hydride (60%, oil, 0.154 g, 3.86 mmol) at 0° C., and the mixture was stirred at 0° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→40% ethyl acetate/hexane) to give 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline (1.000 g, 2.195 mmol, 74.0%) a yellow oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[C:1]([Cl:14])(=[O:11])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-anisic acid (77 g, 0.55 mol) to 100 mL SOCl2 and stir overnight at room temperature. Evaporate the excess SOCl2 to give p-anisoyl chloride. Add (2R,3R)-(+)-tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 170° C. for an hour. Allow the mixture to cool to 100° C. and add 200 mL toluene. Cool the mixture to room temperature and add another 100 mL toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL acetone and 20 mL water for two hours. Then add 200 mL water and evaporate the acetone. Add another 200 mL water and collect the precipitate, rinse with water and dry. Reflux the product in 200 mL toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL warm toluene and dry to give (2R,3R)-(−)-di-(p-anisoyl)tartaric acid.
Reaction SMILES: [CH:1]#[C:2][CH:3](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:4].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:1]#[C:2][CH:3]([O:17][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])[CH3:4]
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)Oc1ccccc1O

Procedure:
A solution of 247 parts of p-toluenesulphonic acid-1-butin- 3-yl ester in 200 parts by volume of acetone is dropped at 50°C into a suspension of 110 parts of pyrocatechol, 152 parts of anhydrous potassium carbonate and 166 parts of potassium iodide in 100 parts by volume of acetone. The mixture is refluxed for 2 days, then filtered and evaporated. The residue is taken up in 500 parts by volume of ether, washed with water and with 450 parts by volume of sodium hydroxide solution of 20 % strength. The alkaline extract, together with the partially precipitated sodium salt of the product, is acidified with semidilute hydrochloric acid while being cooled with ice. The product is obtained by extracting this solution with chloroform and evaporating the extract. For purification it is distilled under a high vacuum. Boiling point: 63° to 66°C under 0.07 mm Hg. The distillate crystallises; it melts at 52° to 54°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH3:12])[C:13](=[O:15])[CH:14]=[C:7]2[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)cc(O)c2cc(Cl)ccc21

Procedure:
5-Chloro-N-methyl anthranilic acid (15g; 0.081 mole) was dissolved in acetic acetic acid (41 ml) and acetic anhydride (41 ml) and the dark mixture refluxed for 12 hours. After cooling the red solution was poured onto crushed ice, basified with 2.5N sodium hydroxide solution and filtered free of tar. The filtrate on acidification to pH5 gave the carbostyril as a yellow solid, m.p. (AcOH) 317°-318°C (Found; C, 57.39; H, 3.98;N, 6.83; Cl, 16.69; C10H8NClO 2 requires C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[N+:7]([O-:12])[C:6]([C:13]([NH2:15])=[O:14])=[C:5]([CH2:16]Br)[N+:4]=2[O-:18].[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[SH:25]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[N+:7]([O-:12])[C:6]([C:13]([NH2:15])=[O:14])=[C:5]([CH2:16][S:25][C:21]1[N:20]([CH3:19])[CH:24]=[CH:23][N:22]=1)[N+:4]=2[O-:18]
Reactant: Cn1ccnc1S
Reactant: Cc1cccc2c1[n+]([O-])c(CBr)c(C(N)=O)[n+]2[O-]
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1[n+]([O-])c(CSc1nccn1C)c(C(N)=O)[n+]2[O-]

Procedure:
Methyl 3-bromomethyl-2-quinoxalinecarboxamide-1,4-dioxide (0.24 moles) was suspended in 1 liter of chloroform with stirring and N-methyl-2-mercaptoimidazole (0.24 moles) was added as a solid. A complete solution resulted within 10 minutes. The solution was stirred overnight at room temperature during which time the desired product crystallized as the hydrobromide. The product was collected by filtration and dried. Yield, 96 grams (91%); m.p. 148°-52° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O.CCOCC>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 2,5-dibromopyridine (20 g, 84 mmol) in DMSO (84 mL) is added (25 wt %) sodium methoxide (21.2 mL, 93 mmol). The resulting solution is heated to 80° C. and stirred for 45 min then cooled to 20° C., diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether in hexanes) to give 14.6 g of title compound as a colorless oil. 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.66 (d, J=9 Hz, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 8.20 (d, J=3 Hz, 1H). MS (EI) m/z 187/189 (M+, Br).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4].[CH3:34]I.O>CN(C=O)C>[CH2:3]([N:5]([CH3:34])[C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:16][CH:17]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4]
Reactant: CI
Reactant: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)c1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82 %

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) in DMF (5 ml) was stirred under ice-cooling for 5 min. and methyl 2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.95 g) was added to the mixture, followed by stirring for 10 min. To the mixture was added methyl iodide (0.2 ml) and the mixture was stirred for 20 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crude crystals, which were recrystallized from ethyl acetate hexane to afford colorless needles (0.88 g, 82%), m.p. 66–69° C.
Reaction SMILES: CS(C)=O.[OH-].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(Cn2ccnc2)cc1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Dimethyl sulphoxide (20 mL; dried over 4 A molecular sieve) was added to potassium hydroxide (2.24 g, 0.04 mol, crushed pellets) and the mixture was stirred for 5 min. Imidazole (0.5718 g, 0.0084 mol) was then added and the mixture was stirred for 2 h. 4-Bromobenzyl bromide (3.25 g, 0.013 mol) was added and the mixture was cooled briefly and stirred for a further 1 h before water (20 mL) was added. The mixture was extracted with ether (3×100 mL) and each extract was washed with water (3×50 mL). The combined ether layers were dried over CaCl2 and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CHCl3:MeOH (30:1) plus 0.05% formic acid as eluent to give the sub-title product (1.275 g, yield: 53%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH2:26][F:27])[C@H:22]1[CH2:21][S:20][C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:18]2.[OH-].[Na+]>C(O)C>[NH2:14][C:10]1[CH:11]=[C:12]([F:13])[C:7]([F:6])=[C:8]([C@:17]23[CH2:25][O:24][C@H:23]([CH2:26][F:27])[C@H:22]2[CH2:21][S:20][C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[N:18]3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Reaction time: 16 h

Procedure:
Tin(II) chloride dihydrate (2.06 g) was added to a suspension of tert-butyl ((4aS,5S,7aS)-7a-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, obtained in Preparation Example 2-(29), (1.17 g) in ethanol (20 ml) at RT. The mixture was stirred for 16 h at the same temperature (the solid gradually dissolved and the reaction color became yellow). The resultant mixture was poured into 2N sodium hydroxide solution and the organic was extracted with EtOAc. The organic layer was washed sequentially with water and brine, then dried over MgSO4. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (gradient from 20% to 60% EtOAc in heptane) acetate to afford the targeted compound (1.09 g) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.51 (s, 9H), 2.69-2.73 (m, 1H), 3.07-3.15 (m, 2H), 3.69 (bs, 2H), 3.84-3.85 (m, 1H), 4.49-4.67 (m, 4H), 6.34-6.36 (m, 1H), 6.44 (ddd, J=11.2, 6.4, 2.8 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:34][C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:34][C:35]([OH:37])=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)O
Yield: 80 %

Procedure:
17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester (0,054 g, 0.08 mmol) was dissolved in THF (2 ml). 10% Palladium on Charcoal was added and the mixture was hydrogenated at 1 atm and RT over the week-end. The dry reaction mixture was dissolved in EtOAc and filtered 3 times to remove the carbon. The filtrate was concentrated to give 17-[(2-tert-Butoxycarbonyl-ethyl)-carboxymethyl-carbamoyl]-heptadecanoic acid tert-butyl ester in 80% yield (37 mg).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][NH:63][CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:70])[F:69]>CN(C=O)C>[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][N:63]([C:6]([C:4]5[N:3]=[CH:2][O:1][CH:5]=5)=[O:8])[CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:69])[F:70]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: O=C(O)c1cocn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cocn5)C4)c3C2)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To the oxazole-4-carboxylic acid (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11-2.39 (m, 2 H) 2.80-3.01 (m, 2 H) 3.22-4.29 (m, 11 H) 5.59-5.80 (m, 1 H) 7.72-7.94 (m, 1 H) 8.10-8.29 (m, 1 H) 8.41-8.55 (m, 1 H) 8.57-8.77 (m, 2 H) LCMS: [M+H]+=491.1, Rt(1)=1.69 min.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.[Li]CCCC.[C:22]([C:26]1[CH:33]=[CH:32]C(C#N)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([C:26]1[CH:33]=[CH:32][C:16]([C:15]2[NH:3][C:4](=[O:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CC(C)(C)c1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a stirred solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (10 ml) was added n-BuLi (2.82 ml, 4.52 mmol, in hexane) at −78° C. and stirred for 1 h. Then to this 4-(tert-butyl)benzonitrile (0.72 g, 4.52 mmol) was added at same temperature and allowed to warm to room temperature and continued the stirring for another 1 h at room temperature. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOac (2*100 ml). The organic phase was washed with brine, dried on Na2SO4, and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (0.72 g, 46.7%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.26(s, 1H), 8.11-8.09 (d, J=8 Hz, 1H), 7.73-7.71 (d, J=8 Hz, 2H), 7.52-7.50 (d, J=8 Hz, 2H), 7.06 (s, 1H), 7.05-7.03 (d, J=8 Hz, 1H), 6.82 (s, 1H), 3.89 (s, 3H), 1.32 (s, 9H); MS: MS m/z 308.2 (M++1).