Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].N([O-])=[O:19].[Na+]>O>[OH:19][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(O)ccc1C
Reaction time: 1 h

Procedure:
A 0° C. solution of sulfuric acid (89 g, 908 mmol) in water (700 mL) was added to a flask containing methyl 5-amino-2-methylbenzoate (50 g, 303 mmol) in an ice-water bath. The resulting mixture was stirred until the mixture become a cloudy solution. A solution of sodium nitrite (21 g, 303 mmol) in cold water (200 mL) was added dropwise and stirring was continued for 1 h at 0° C. then at 100° C. for another 1 h. The reaction was cooled and the solid collected by filtration, and rinsed with water. The resultant dark red solid was re-dissolved in MeOH (500 mL). Charcoal (2 g) was added and the reaction was heated at reflux for 1 h. The mixture was filtered and concentrated. Chromatography over silica eluting with 0-50% EtOAc/hexane afforded the title compound as white solid. LC-MS: calculated for C9H10O3 166.17, observed m/e: no ionization (Rt 0.89/2 min). NMR (CDCl3): 7.48 (1H, s), 7.15 (1H, d); 6.95 (1H, d), 6.04 (1H, s); 3.95 (3H, s); 2.53 (3H, s).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[CH2:47]([S:54](Cl)(=[O:56])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][S:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:56])=[O:55])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (80 mg, 0.153 mmol) in dichloromethane (4 mL) was added pyridine (24 μL, 0.307 mmol) followed by benzylsulfonyl chloride (32 mg, 0.169 mmol). The mixture was stirred at room temperature for 16 h and concentrated. The solvent was removed under reduced pressure and the crude was dissolved in methanol (4 mL) and acetic acid (1 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 5% MeOH/dichloromethane as an eluent at afford the desired product as a yellowish solid (52 mg, 0.120 mmol, 79%). 1H NMR: 3.16 (t, 2H, J=63.4 Hz), 4.28 (t, 2H, J=6.4 Hz), 4.36 (s, 2H), 6.92 (t, 1H, J=6.8 Hz), 7.02 (s, 1H), 7.11 (d, 3H, J=7.2 Hz), 7.19 (s, 2H), 7.28-7.31 (m, 5H), 7.41 (s, 1H), 7.62 (s, 1H), 8.04 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.C(S)CC1C=CC=CC=1>CO>[SH:4][C:5]1[N:9]([C:2]#[N:3])[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1
Reactant: Brc1nsc2nc3ccccc3n12
Agent: SCCc1ccccc1
Solvent: CO
Product: N#Cn1c(S)nc2ccccc21
Yield: 85.9 %

Procedure:
To a suspension of 500 mg of 3-bromo-1,2,4-thiadiazolo [4,5-a]benzimidazole in 50 mL methanol was added 790 μL of phenethyl mercaptan. The solid rapidly dissolves. After completion of the reaction, the solvent was evaporated and the residue purified by chromatography to give 296 mg of 2-mercapto-1-benzimidazolecarbonitrile: 1H NMR (DMSO-d6) δ12.85 (br s, 1H, SH), 7.5-7.2 (m, 4H, 4×ArH) ppm; IR (KBr) ν 2259, 1509, 1459, 1303, 1189, 752 cm-1 ; MS m/z 175 (M+), 150 (M+ -CN)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH:14]=[CH2:15])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[O:24]1[CH:14]([CH:13]([O:12][C:11]2[CH:17]=[CH:18][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)[CH3:16])[CH2:15]1
Reactant: C=CC(C)Oc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C1CO1
Reaction time: 140 h
Yield: 87.9 %

Procedure:
A solution of (3R and 3S)-3-[4-(tert-butoxycarbonyl)phenoxy]-1-butene (3.78 g, 15.2 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with 3-chloroperoxybenzoic acid (4.8 g, 28.0 mmol) and the resulting mixture was stirred for 140 hours. The mixture was then diluted with toluene, washed with 5% sodium thiosulfate, sodium bicarbonate and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 2%) gave 3.53 g (87%) of the title material as an oil. 1H NMR indicated a 6:4 diastereoisomeric mixture which was used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: COc1cc(O)ccc1-c1nc2cnccc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2cnccc2[nH]1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-c]pyridine and methanesulfonic acid chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].Cl.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[Na+].[I-]>C(#N)C>[ClH:15].[ClH:15].[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]4[CH3:14])[CH2:34][CH2:33]3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Reactant: c1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2cn(-c3ccccc3)c3ccccc23)CC1
Temperature: 75 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g), 1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (7.80 g), N,N-diisopropylethylamine (9.65 g), NaI (350 mg) in acetonitrile (250 ml) was heated at 75° C. for 17 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.80 g of crystals, m.p. 217°-219° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:35]2[CH2:34][CH2:33][N:32]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=4)[CH2:26][CH2:27]3)[CH2:37][CH2:36]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1nccc(N2CCC(CN3CCNCC3)CC2)n1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCC(CN3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonylchloride (367 mg) in methylene chloride (5 ml) was added dropwise over 5 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine trihydrochloride (625 mg) and triethylamine (1.04 ml) in dichloromethane (20 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1-2% methanol in dichloromethane. Filtration from ether gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidyimethyl]piperazine (358 mg), as a solid, mp 135-136° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[ClH:27]>O>[ClH:27].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CCCOCCCCCBr)cc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: COc1ccc(CCCOCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
1-[3-[(5-Bromopentyl)oxy]propyl]-4-methoxybenzene (2.0 g) was added to benzylamine (6 ml) at 120° under nitrogen. The solution was stirred for 2 h at 120° then added (hot) to 2N hydrochloric acid (50 ml) and water (25 ml). The resulting precipitate was collected by filtration, washed with 2N hydrochloric acid, water and ER then dried at 50° under vacuum to give the title compound as a white solid (1.79 g) m.p. 118°-121°. The following compound was prepared in a similar manner:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1>C(#N)C.O1CCCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1-c1ccno1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1-c1ccno1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a solution of (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.30 g, 1.0 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.207 g, 1.5 mmol), potassium iodide (0.033 g, 0.20 mmol) and 4-chloro-2-isoxazol-5-yl-phenol (0.215 g, 1.1 mmol). The resulting mixture was stirred for 18 hours at ambient temperature. The reaction was diluted with tetrahydrofuran (10 mL), filtered and concentrated in vacuo to give the title compound (0.465 g).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C1OC1C>C(#N)C>[CH:10]1[C:9]2[CH:8]=[CH:7][C:1]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: C(=Cc1ccccc1)c1ccccc1
Agent: CC1CO1
Agent: II
Solvent: CC#N
Product: c1ccc2c(c1)ccc1ccccc12
Reaction time: 0.17 h

Procedure:
In a photoreaction container, argon was infused into a solution of 4.0 g (10.0 mmol) of stilbene in 7 L of acetonitrile at room temperature while stirring. After 10 minutes, 2.5 g (10.0 mmol, 1.0 eq.) of iodine and 28 mL (400.0 mmol, 40 eq.) of propylene oxide were added, followed by irradiation of light at room temperature while stirring. After 72 hours of irradiation, the disappearance of the raw materials was confirmed, and the resulting reaction liquid was concentrated. The residual product was dissolved in 500 mL of chloroform, followed by washing with 1 L of saturated sodium thiosulfate and 500 mL of brine. The organic layer was dried over magnesium sulfate, and then the solvent was distilled under reduced pressure to give a solid. The solid was collected by suction filtration using a Büchner funnel and a filtering flask, which was then washed with 50 mL of methanol twice. The solid was dried under reduced pressure at 60° C. to give 2.6 g (64%) of light brown powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].Cl.Cl[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[N:45][CH:46]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH2:40][C:41]4[CH:46]=[N:45][C:44]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:43][CH:42]=4)[N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: ClCc1ccc(N2CCOCC2)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccc(N5CCOCC5)nc4)c4cc(F)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (80 mg, 0.16 mmol) was combined with DMF (8 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 19 mg, 0.48 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(5-(Chloromethyl)pyridin-2-yl)morpholine hydrochloride (60 mg, 0.24 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 58 mg (53%) of 2-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=675.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[OH:44]O.O>C(#N)C.[Cl-].[Ta+5].[Cl-].[Cl-].[Cl-].[Cl-]>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30]([CH3:31])=[O:44])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:2]([F:1])([F:42])[F:43]
Reactant: OO
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(SC)nc3)C2=O)c1
Agent: [Ta+5]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(S(C)=O)nc3)C2=O)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 70 %

Procedure:
To a solution of 3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methyl-5-(6-(methylthio)pyridin-3-yl) imidazolidine-2,4-dione (10 mg, 0.0159 mmol) in acetonitrile (640 tantalum chloride (0.6 mg, 0.00159 mmol) and 30% hydrogen peroxide solution (71 μL) were added under ice-cold conditions, and the resultant mixture was stirred under ice-cold conditions for 1 hour and then stirred at room temperature for 9 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and the title compound (7.2 mg, yield 70%) was obtained as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.S(Cl)([Cl:16])=O>>[F:1][CH:2]([F:13])[C:3]1[C:7]([C:8]([Cl:16])=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F

Procedure:
9.1 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid and 75.5 ml of thionyl chloride are refluxed for 1.5 hours. After cooling down, the reaction mixture is evaporated under vacuum to yield 10 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil. GC-MS; observed m/z: Molecular ion: (M+)=212; fragments: (M+.-Cl)=177 and (M+.-F)=193.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:12][C:13]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(O)(C)C>[Cl:12][C:13]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][C:14]=1[C:15]([C:5]1[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[C:6]=1[OH:7])=[O:16]
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: Cc1c(Cl)ccc(C(=O)Cl)c1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)c(C)c1Cl
Yield: 49.8 %

Procedure:
11.2 g (0.1 mole) of 1,3-dimethyl-5-pyrazolone and 9.6 g (0.13 mole) of calcium hydroxide were suspended in 165 ml of isopropanol, and with stirring, the suspension was heated under reflux for 30 minutes. The reaction mixture was cooled, and 22.4 g (0.1 mole) of 2,4-dichloro-3-methyl-benzoyl chloride was added dropwise. After the addition, the mixture was heated under reflux for 10 hours. The solvent was distilled off from the reaction mixture, and 40 ml of water was added. The mixture was acidified with 65 ml of 2 N hydrochloric acid, and extracted with 100 ml of chloroform twice. The extracts were washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from toluene to give 14.9 g of colorless crystals (yield 49.8%; melting point 148.9°-149.5° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([Si:21]([O:24][CH2:25][CH2:26]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:21]([O:24][CH2:25][CH2:26][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]([Cl:26])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:26][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 57.3 %

Procedure:
A mixture of (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 80 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 122 mg) and DIPEA (0.134 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give the titled compound as solid (90 mg). NMR 10.34 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.94 (s, 1H), 4.96-5.34 (m, 1H), 2.25 (s, 3H), 1.56 (d, 3H); m/z 350.
Reaction SMILES: [P:1]([O:5][CH2:6][C@@H:7]1[C@@H:11]([O:12][P:13]([O:16][CH2:17][C@@H:18]2[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([N:25]3[CH:33]=[N:32][C:31]4[C:26]3=[N:27][CH:28]=[N:29][C:30]=4[NH2:34])[O:19]2)([OH:15])=[O:14])[CH2:10][C@H:9]([N:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][C:36]2=[O:42])[O:8]1)([OH:4])([OH:3])=[O:2].C([N+](CCCC)(CCCC)CCCC)CCC.P(OC[C@@H]1[C@@H](OP(OC[C@@H]2[C@@H](O)[C@@H](O)[C@H](N3C=NC4C3=NC=NC=4N)O2)(O)=O)C[C@H](N2C=CC(N)=NC2=O)O1)(O)(O)=O.[CH3:102][N:103]([CH2:110][C:111](OCC#N)=[O:112])[C:104](=[O:109])[CH2:105][CH2:106][CH:107]=[CH2:108]>O1CCCC1>[CH3:102][N:103]([CH2:110][C:111]([O:23][C@H:22]1[C@@H:21]([OH:24])[C@H:20]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:19][C@@H:18]1[CH2:17][O:16][P:13]([O:12][C@H:11]1[CH2:10][C@H:9]([N:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][C:36]2=[O:42])[O:8][C@@H:7]1[CH2:6][O:5][P:1]([OH:4])([OH:3])=[O:2])([OH:15])=[O:14])=[O:112])[C:104](=[O:109])[CH2:105][CH2:106][CH:107]=[CH2:108]
Reactant: C=CCCC(=O)N(C)CC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N(C)CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (Compound 1h) (1.00 g, 1.57 mmol) was dissolved in buffer A (1 l), a solution of cyanomethyl 2-(N-methylpent-4-enamido)acetate (Compound SP704) (2.00 g, 9.51 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was lyophilized, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.5% aqueous trifluoroacetic acid solution/acetonitrile) to afford the title compound (Compound SP705) (139 mg, 11%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-:18].[K+].Cl>OCCOCCO.C(OCC)C>[CH2:1]([C:3]1[C:8]([C:9]([OH:18])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1c(C(N)=O)cccc1-c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: OCCOCCO
Solvent: CCOCC
Product: CCc1c(C(=O)O)cccc1-c1ccccc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
A stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.1 g, 0.0093 mole) and potassium hydroxide (26.3 g, 0.4 mole) in 175 ml of 2-hydroxyethyl ether was heated at 163° for approximately 18 hours. The reaction mixture was cooled and diluted with 150 ml of ice water. The solution was acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was isolated by filtration and dissolved in diethyl ether; the ethereal solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.2 g) as a solid.