Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Si:7]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CC=CC1
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Yield: 96.6 %

Procedure:
By using 2.2 g of 3-cyclopentenol prepared according to the method described in J. Org. Chem., 25, 26-29 (1960) and 9.2 g of t-butyldiphenylsilyl chloride and by the same procedures as in (1) of the intermediate preparation example 1, there was obtained 8.15 g of 3-cyclopenten-1-yl (t-butyldiphenylsilyl) ether. Yield 97%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>C(OC(C)C)(C)C>[CH3:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:3]([O:2][CH3:1])=[C:4]([CH:5]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[C:7]=1[CH3:14]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C)c(OC)c(C=O)c1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Product: COc1cc(C)c(OC)c(C=C(C)[N+](=O)[O-])c1C
Yield: 99 %

Procedure:
A mixture of 2,5-dimethoxy-3,6-dimethyl-benzaldehyde (4.0 g, 20 mmol), ammonium acetate (1 g, 13 mmol) and nitroethane (25 ml) was heated under reflux for 4 hours. The reaction mixture was diluted with diisopropyl ether, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:isopropyl ether=95:5) and then recrystallized from methanol to obtain 5.1 g of the title compound.
Reaction SMILES: O.[C:2](=[O:5])([O-])[O-:3].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]#[N:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:47]([C:17]1[CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=2)[N:21]2[N:22]=[C:23]([NH:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:2]([OH:3])=[O:5])=[O:35])[N:24]=[C:20]2[N:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=2)[C:18]=1[CH3:46])#[N:48]
Reactant: O=C([O-])[O-]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(NC(=O)c3ccccc3C(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 55 °C
Yield: 96.1 %

Procedure:
Water (0.5 ml) and potassium carbonate (8.1 mg, 59 mmol) were added to a solution of 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25.0 mg, 45.3 μmol; Example 3) in ethanol (3.4 ml). In a closed pressure-proof glass tube, the reaction mixture was heated at 55° C. For complete conversion, more potassium carbonate was added in two separate portions (5 mg, 36 mmol in total), and the mixture was once more heated at 55° C. 1 N hydrochloric acid (180 μl, 180 mmol) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (24.8 mg, 96% of theory).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH:36][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(N)n3)ccc2n1CC1CCOCC1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(NC(=O)C4CCC4)n3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cyclobutanecarbonyl chloride (30 mg, 30 uL, 0.26 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazol-3-amine (37 mg, 0.087 mmol) (see Example 21 for preparation) and DIPEA (34 mg, 46 uL, 0.26 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 14.3 mg (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.56 (m, 4 H), 1.59 (s, 9 H), 1.76-1.88 (m, 1 H), 1.91-2.01 (m, 1 H), 2.06-2.18 (m, 2 H), 2.17-2.27 (m, 2 H), 2.26-2.37 (m, 1 H), 3.10-3.24 (m, 1 H), 3.25-3.35 (m, 2 H), 3.84-3.95 (m, 2 H), 4.41 (d, J=7.62 Hz, 2 H), 6.87 (d, J=2.93 Hz, 1 H), 7.88 (d, J=8.9 Hz, 1 H), 7.92 (dd, J=8.8, 1.5 Hz, 1 H), 8.18 (d, J=2.93 Hz, 1 H), 8.25 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=499.8; Anal. Calcd for C25H33N5O4S+0.80 TFA+0.20 EtOAc+0.10H2O (612.68): C, 54.11; H, 5.86; N, 11.43. Found: C, 54.12; H, 5.92; N, 11.34.
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[S:13])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: S=c1[nH]c(=S)c2[nH]cnc2[nH]1
Yield: 202.6 %

Procedure:
8.41 g (21 mmoles) of 2-thioxanthine are refluxed with 5.60 g (25.2 mmoles) of phosphorus pentasulfide in 80 ml of pyridine. After 5.5 hours 27.7 ml (55.4 mmoles) of 2N NaOH were added at 5-10° C. The solid was filtered off and washed with pyridine. The filtrate was evaporated in vacuo to dryness, the residue is suspended in 200 ml of water with little tetrahydrofuran (THF) for crystallization, the suspension is concentrated and the solid at pH 8 collected and washed. Redissolution in 100 ml of 0.5 N NaOH, treatment with charcoal (20%), filtration and acidification to pH 6 yielded the solid crude dithioxanthine 7.84 g (89.6%). Crystallization from chloroform and suspension in hot methanol gave 5.31 g (60.7%) of dithioxanthine with mp 241-3° C. The mother liquors were combined (2.36 g) and filtered with chloroform through 60 g of silicagel in a column: 1.73 g (19.8%) were isolated as a second crop.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:22]=1[CH2:23]Cl.Cl>O.C(#N)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:22]=1[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)c(CNc2cccc(S(=O)(=O)O)c2)c(C)c1
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A mixture of 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid, 83.0 g (0.61 mole) of sodium acetate trihydrate, 33.7 g (0.20 mole) of 2,4,6-trimethylbenzyl chloride, 225 ml of water and 150 ml of acetonitrile was refluxed for 4 hrs, then acidified by the dropwise addition of 40 ml of conc. HCl over 30 minutes during which time approximately 100 ml of acetonitrile was distilled off. The resulting mixture was vacuum filtered while hot (80° C.) and a grayish-white powder obtained which was then slurried in 300 ml of hot (65° C.) water for 20 minutes and vacuum filtered. The slurrying process was repeated with water and then with 300 ml of boiling methanol for 20 minutes. Vacuum filtration followed by drying in vacuo at about 60° C. afforded 24.85 g (40.7% yield) of purified 3-(((2,4,6-trimethylphenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:27][CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@H:28]2[CH2:27][CH2:26][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:30][CH2:29]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CC[C@H](Nc2nc(Cl)ncc2Cl)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@H](N(CC#N)S(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
trans-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-N-cyanomethyl-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white solid (60 mg, 40%). m.p.=159-162° C.; LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.37 (d, 1H, J=8.0 Hz), 7.25 (s, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.81 (s, 1H), 5.03 (d, 1H, J=7.2 Hz), 4.24 (s, 2H), 4.0-3.81 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.38 (s, 3H), 3.09 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.67 (m, 6H), 2.40-2.29 (m, 2H), 2.13-2.03 (m, 2H), 1.87-1.72 (m, 2H), 1.54-1.38 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=1)=O>C(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:17](=[O:16])[CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=[CH:23][N:22]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C(=O)c1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluorophenylacetonitrile (11.13 g, 82 mmol) was dissolved in absolute ethanol (100 ml) and sodium ethoxide (2wt % in EtOH) (46 ml, 123 mmol) was added in one portion. The resulting brown solution was stirred for 10 min. at room temperature. A solution of 2-chloropyridine-4-carboxylic acid methyl ester (14.1 g, 82 mmol) in absolute ethanol (100 ml) was then added to the reaction over 3-5 min. The reaction mixture was then refluxed for 2 h during which time the color turned to dark brown. The reaction mixture was concentrated in vacuo and water (100 ml) was added to the resulting residue. The pH of the reaction mixture was adjusted to 3 using 10% hydrochloric acid. The product was extracted with ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(2-chloropyridin-4-yl)-2-cyano-2-(4-fluorophenyl)ethanone as a dark brown solid which was used without further purification (22.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[S:27]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2)(=[O:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1,1-dimethylethyl 6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.146 g; 0.586 mmol) and Et3N (0.17 mL; 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Tf2O (0.11 mL; 0.67 mmol (dropwise over 2 min. The mixture was stirred overnight, gradually warming to room temperature, diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum which slowly solidified. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.87 (t, J=5.7 Hz, 2H), 3.66 (br. t, J=5.5 Hz, 2H), 4.59 (s, 2H), 7.04-7.12 (m, 2H), 7.18 (d, J=8.4 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-hydroxy)-2-(S)-(t-butoxycarbonylamino)propionate (58 g, 196 mmol), dry methylene chloride (150 ml), p-toluenesulfonyl chloride (43.35 g, 227.4 mmol), 4-(dimethylamino)pyridine (2.4 g, 19.6 mmol) and pyridine (30 ml, 371 mmol) were combined and stirred at room temperature overnight. The reaction solution was concentrated in vacuo to a pale yellow oil. The oil was stored in vacuo overnight, then the white solid that formed was isolated to give 75.33 g of crude product. The product was triturated in petroleum ether (approximately 200 ml) to yield methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate: n.m.r.: (CDCl3, 90 MHz): δ7.72, 7.31 (2x dd, 4, aromatic protons), 5.26 (m, 1, nitrogen proton), 4.48 (m, 1, C-2 proton), 4.32 (m, 2, C-3 protons), 3.68 (s, 3, methyl protons of methyl ester), 2.44 (s, 3, methyl protons of toluene moiety), 1.40 (s, 9, protons of t-butyl moiety); i.r. (CHCl3): 3435, 3019, 1753, 1711, 1502, 1369, 1351, 1250, 1215, 1190, 1177 cm-1 ; m.s.: 279, 210, 172, 91, 41;
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[N:13]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][C:12]1[N:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1

Procedure:
tert-butyl-N-(1-{[4-chloro-6-(pyridine-2-amido)pyridin-2-yl]carbamoyl}ethyl)carbamate K56 (27 mg, 64 μmol) in DCM:TFA=9:1 (3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 12 mg (58%). HPLC-MS: M+H=320; tR=1.57 min (METHOD—1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]([S:10][C:11]#[N:12])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(Cl)ncc1F
Yield: 68 %

Procedure:
In 50 ml of formic acid, a reaction of 10.0 g of 2,4-dichloro-5-fluoropyrimidine and 5.8 g of potassium thiocyanate was conducted at room temperature (20° C.) for 5 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 68.0% yield of 2-chloro-5-fluoro-4-thiocyanopyrimidine, m.p. 103°-104° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=3)[CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.CS(O[C@H:36]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([F:54])[CH:48]=1)[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])(=O)=O>CC1CCCO1>[Si:40]([O:39][CH2:38][CH2:37][C@@H:36]([N:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)[N:23]=2)=[CH:25][C:26]1=[O:30])[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([F:54])[CH:48]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC1CCCO1
Product: CC(C)(C)[Si](C)(C)OCC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (0.91M in THF, 0.202 mL) was added to a cooled to 0° C. suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (40 mg, 0.147 mmol) in 2-methyltetrahydrofuran (4 mL). The mixture was agitated 15 minutes, and (S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl methanesulfonate (81.6 mg, 0.206 mmol) in 2-methyltetrahydrofuran (1 mL) was added. The mixture was then heated to 75° C. and agitated overnight. The reaction was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate (5 mL). The organic layer was washed with water (2×) and evaporated. Purified by chromatography on silica gel, eluted with 50-75% ethyl acetate/hexanes to give (R)-1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.056 g, 0.0977 mmol, 66.5% yield) as thick oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Cl)=[CH2:12].C1COCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])[CH:11]=[CH2:12]
Reactant: Cc1cccc(C=O)c1O
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C)c1O
Temperature: 17.5 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxy-3-methylbenzaldehyde (48.78 g, purity: 40.7%, 0.146 mol) was dissolved in toluene (100 ml), and the mixture was added to a reactor under a nitrogen atmosphere. After the mixture was cooled to 0° C. in ice-water, a solution of vinyl magnesium chloride in THF-toluene (1.77M, 182 ml, 0.32 mol, THF:toluene=1:1 (v:v)) was added thereto over 15 minutes such that the temperature of the mixture did not exceed 25° C. After the mixture was stirred at 15-20° C. for 2 hours, it was cooled to 0° C. A 20% aqueous ammonium chloride solution (250 ml) was added thereto. After the mixture was stirred at 25° C. for 1 hour, the solution was separated. The organic layer was concentrated to obtain 32.36 g (purity: 73.5%, 0.145 mol) of 2-(1-hydroxy-2-propenyl)-6-methylphenol as an orange-colored oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@H:15]4[CH2:17][C@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:53][C@@H:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:55][OH:56]>CN(C=O)C>[F:59][C:58]([F:61])([F:60])[CH2:57][C@H:54]([NH:53][C:18]([C:11]1[C:12]2[CH2:13][C@@H:14]3[CH2:17][C@@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:55][OH:56]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@H]2C[C@H]2C3)c1
Reactant: N[C@H](CO)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@H]2C[C@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To a solution of (1aS,5aS)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (75 mg, 0.282 mmol) and triethylamine (0.118 mL, 0.845 mmol) in DMF (1 mL) was added HATU (118 mg, 0.310 mmol). The reaction was stirred at 23° C., for 5 min, then was added (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (55.6 mg, 0.310 mmol). The reaction was stirred at 23° C. for 30 min, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound (86 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.7, 3.2 Hz, 1H), 1.27 (td, J=8.1, 4.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 3H), 2.77-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.6, 6.1 Hz, 1H), 3.88 (d, J=2.9 Hz, 2H), 4.33-4.41 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (t, J=0.8 Hz, 1H), 8.62 (dd, J=5.1, 0.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.CN(C=O)C.[Pd]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH:11][C:14](=[O:16])[CH3:15])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1O

Procedure:
A solution of 1-(4-hydroxy-3-nitro-phenyl)-ethanone (10 g) in methanol, DMF (50 ml) and acetic anhydride (10 ml) was hydrogenated using 10% Pd—C (0.45 g) for 2 h at 30 psi. The catalyst was filtered off. The filtrate was concentrated (5 ml) and treated with EtOAc (100 ml) to obtain the title compound, which was filtered, washed with EtOAc (10 ml) and dried. Yield, 9.1 g (85%); mp, >215° C.; MS (EI): 193 (M+), 151, 136, 108.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[OH:7].C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[OH:7][C@@H:3]1[CH2:4][O:5][CH2:6][C@H:2]1[NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1COC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1COC[C@H]1O)OCc1ccccc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of the crude trans-4-aminotetrahydrofuran-3-ol (from Step 1), sodium carbonate (7.68 g, 72.5 mmol), tetrahydrofuran (100 mL) and water (100 mL) was cooled to 0° C. and stirred vigorously. Benzyl chloroformate (9.48 mL, 66.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo. The aqueous residue was diluted with water (50 mL) and extracted with ethyl acetate (3×70 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes, gave benzyl trans-4-hydroxytetrahydrofuran-3-ylcarbamate as a white solid (8.43 g, 59% yield for 2 steps). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.51 (5 H, m), 5.11 (2 H, br. s.), 4.92 (1 H, br. s.), 4.32 (1 H, br. s.), 3.93-4.17 (3 H, m), 3.50-3.80 (2 H, m), 2.69 (1 H, br. s.); MS (ES+) m/z: 238.1 (M+H); LC retention time: 2.595 min (analytical HPLC Method H).