Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[O:5][C:6]1[C:7](=[O:45])[N:8]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][C:22]([NH:26]CC4C=CC(OC)=CC=4)=[CH:23][CH:24]=3)[N:19](CC3C=CC(OC)=CC=3)[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[NH2:26][C:22]1[N:21]=[C:20]2[NH:19][N:18]=[C:17]([CH2:16][N:8]3[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:6]([O:5][C:4]4[CH:46]=[C:47]([Cl:49])[CH:48]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:45])[C:25]2=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(Cl)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ccc2c(Cn3ccc(C(F)(F)F)c(Oc4cc(Cl)cc(Cl)c4)c3=O)n[nH]c2n1
Reaction time: 4 h

Procedure:
3-(3,5-dichlorophenoxy)-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridine-3-yl}methyl)-4-(trifluoromethyl)pyridine-2(1H)-one (0.900 g, 12.7 mmol) dissolved in TFA (10 mL) was placed in an oil bath at 75° C. After 4 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with 50% aqueous sodium carbonate (50 mL). The aqueous was back extracted with ethyl acetate (100 mL) and the combined organic extracts were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting solid was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 12.60 (s, 1H), 8.00-7.90 (m, 1H), 7.65-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.12-7.00 (m, 2H), 6.65-6.55 (m, 1H), 6.42-6.25 (m, 3H), 5.40-5.30 (s, 2H). LRMS (M+1)=469.77.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH2:32].[F:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]([CH3:50])[C:40]([C:42]2[CH2:43]N(C)[C:45](=[O:48])[C:46]=2[OH:47])=[O:41])=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]([CH3:50])[C:40]([C:42]2[CH2:43][N:32]([CH2:31][CH2:30][C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[C:45](=[O:48])[C:46]=2[OH:47])=[O:41])=[CH:36][CH:35]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccc(Cl)cc2Cl)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2,4-dichloro-phenyl)-ethylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 2.99 (s, 3), 3.03 (t, 2, J=7), 3.74 (t, J=7), 4.06 (s, 2), 4.60 (s, 2), 7.03–7.37 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 31.76, 34.67, 42.95, 49.48, 51.61, 109.74, 115.76, 115.93, 127.53, 129.27, 129.32, 129.53, 131.63, 131.78, 131.80, 133.57, 134.14, 134.65, 152.19, 161.44, 163.40, 165.24, 165.98.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1C=CC=C[CH:10]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C=C>>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:20])[CH:9]=[CH2:10]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Agent: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate salt, crude 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester was deprotected after 2 hours. Flash column chromatography with 0.5% TFA/7% MeOH/CHCl3 gave 2.46 g (87%) of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt as a colorless foam. 1H NMR (CD3OD): δ 5.96 (ddt, 1H, J=5.6, 10.6, 17.1 Hz), 5.35 (ddd, 1H, J=1.6, 3.1, 17.1 Hz), 5.25 (ddd, 1H, J=1.2, 2.5, 10.3 Hz), 4.66 (ddd, 2H, J=1.2, 1.3, 5.9 Hz), 4.34 (dd, 1H, J=5.6, 7.8 Hz), 4.21 (s, 1H), 3.03 (dd, 1H, J=5.6, 17.4 Hz), 2.94 (dd, 1H, J=7.5, 17.4 Hz), 2.71 (d, 3H, J=5.0 Hz), 1.46 (s, 9H), 0.99 (s, 9H). IR (KBr): 3413, 2966, 1672, 1656, 1207, 1143 cm−1. HRFABMS: Calculated for C14H25N3O4Na (M+Na+): 322.1743. Found: 322.1747. Anal. Calculated for C14H25N3O4.2.5F3COOH.0.5CHCl3: C, 36.36; H, 4.38; N, 6.52. Found: C, 36.34; H, 4.25; N, 6.51.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=C)[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2].[OH2:19]>CC#N.[O-]S([O-])(=S)=O.[Na+].[Na+].C(Cl)Cl>[CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=[O:19])[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=C1CC(c2cc(C(=O)OCC)nn2C(C)C)C1
Reactant: O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC(=O)C2)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Compound 8c (6.45 g, 26.0 mmol) was dissolved in a mixture of MeCN (77 mL) and water (13 mL) and cooled in an ice-bath. To this solution RuCl3×H2O (0.19 g, 0.86 mmol) was added, followed by portion-wise addition of NaIO4 (19.35 g, 90.9 mmol). An exotherm was observed during this addition. The obtained thick slurry was stirred at rt for 45 min. The reaction mixture was diluted with Na2S2O3 aq. sol. (10%, 260 mL), water (50 mL) and DCM (100 mL). The phases were separated and the aq. phase was extracted with DCM (2×70 mL). The combined organic phases were washed with Na2S2O3 aq. sol. (10%, 50 mL), water (100 mL), brine (100 mL) and dried over anh. Na2SO4. The crude product (6.5 g) was purified on silica, eluting with hexanes/MTBE to give pure product as an oil that solidified upon storage at −20° C. Yield: 5.8 g (78% over two steps). 1H-NMR (DMSO-d6), δ (ppm): 6.78 (s, 1H), 4.57 (h, J=8.0 Hz, 1H), 4.26 (q, J=8.0 Hz, 2H), 3.85-3.75 (m, 1H), 3.58-3.45 (m, 2H), 3.35-3.25 (m, 2H), 1.39 (d, J=8.0 Hz, 6H), 1.28 (t, J=8.0 Hz, 3H).
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.[CH3:8][C:9]1[C:13]2[C:14]([O:25]C)=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:12]=2[O:11][CH:10]=1.O.Cl>N1C2C(=CC=CC=2)C=CC=1>[CH3:8][C:9]1[C:13]2[C:14]([OH:25])=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:12]=2[O:11][CH:10]=1
Reactant: COc1ccc(C(=O)c2cccs2)c2occ(C)c12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1coc2c(C(=O)c3cccs3)ccc(O)c12
Reaction time: 1 h

Procedure:
A solution of freshly prepared pyridinium hydrochloride (4.84 g, 41.9 mmol) and 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran (2.30 g, 8.38 mmol) in quinoline (10 mL) was heated to reflux for 2.5 hours. The mixture was cooled, an additional portion of pyridinium hydrochloride added (2.42 g, 20.9 mmol) and reflux was resumed for one hour. After cooling the reaction mixture was poured into water (200 mL) and acidified with 2N HCl. The resulting mixture was extracted with chloroform (5×50 mL) and the combined organic extracts were washed with water (50 mL), dried (Na2SO4), and concentrated. Chromatographic purification by preparative HPLC using 25% ethyl acetate in hexane as eluant afforded 3-methyl-4-hydroxy-7-(2-thienoyl)benzofuran compound 3 along with recovered starting material. A sample of the desired product was recrystallized from ether/hexane. 1H NMR d 2.45 (3H, s), 6.24 (1H, br s), 6.45 (1H, d, J=8 Hz), 7.17 (1H, dd, J=4 Hz, 4 Hz), 7.37 (1H, s), 7.61 (1H, d, J=8 Hz), 7.67 (1H, d, J=4 Hz), 7.75 (1H, d, J=4 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[F:24].[ClH:27].Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1.C(NC(=O)OC1C(C)=C2N(C=1)N=CN=C2OC1C=CC(N[C:93]([NH:95][C:96](=[O:105])[CH2:97][C:98]2[CH:103]=[CH:102][C:101]([F:104])=[CH:100][CH:99]=2)=[O:94])=CC=1F)C>>[ClH:27].[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:93]([NH:95][C:96](=[O:105])[CH2:97][C:98]2[CH:103]=[CH:102][C:101]([F:104])=[CH:100][CH:99]=2)=[O:94])=[CH:19][C:18]=1[F:24]
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Reactant: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12
Agent: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Yield: 13 %

Procedure:
4-(6-(3-(Dimethylamino)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (12 mg, 0.03 mmol) was converted to the title compound (2.5 mg, 13%) in a manner similar to the preparation of Compound E of Example 31, except that 2-(4-fluorophenyl)-acetyl isocyanate (0.10 mL, 0.04 mmol, Compound C of Example 4) was used instead of benzenesulfonyl isocyanate. 1H NMR (CD3OD) δ 10.77 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.40-7.23 (m, 5H), 7.11-7.02 (m, 3H), 4.15-4.12 (m, 2H), 3.71 (s, 2H), 3.41-3.36 (m, 2H), 2.97 (s, 6H), 2.44 (s, 3H), 2.31-2.22 (m, 2H); HRMS(ESI), 539.2218 (M+H)+ calc, 539.2218 (M+H)+ found.
Reaction SMILES: [Na].[S:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]1.[N:12](OCCC(C)C)=[O:13]>CO>[OH:13][N:12]=[C:7]([C:5]1[CH:4]=[N:3][S:2][CH:6]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)CCON=O
Reactant: COC(=O)Cc1cnsc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=NO)c1cnsc1
Yield: 61 %

Procedure:
A solution of sodium (1.01 g.) in absolute methanol (10 ml.) was dropwise added over 15 minutes with stirring and ice-cooling to a solution of methyl 2-(isothiazol-4-yl)acetate (6.30 g.) and isopentyl nitrite (10.6 g.) in absolute methanol (63 ml.). The mixture was stirred for 30 minutes at the same temperature and for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was poured into a mixture of ethyl acetate (50 ml.) and water (50 ml.) The aqueous layer was separated and the ethyl acetate layer was extracted twice with 1N aqueous solution of sodium hydroxide (20 ml. and 10 ml.). The extracts and the aqueous layer separated above were combined, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with ethyl acetate (70 ml. and 50 ml.). The extracts were washed with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 2-hydroxyimino-2-(isothiazol-4-yl)acetate (anti isomer) (4.55 g.), mp 110° to 112° C.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]1[CH:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(O)C1CCc2ccc3ccccc3c2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2ccc3ccccc3c2O1
Yield: 63.5 %

Procedure:
A mixture of intermediate (9-a) (7 g), ethanol (160 ml) and sulfuric acid was stirred and refluxed for 1 hour. The reaction mixture was evaporated and the oily residue was taken up in water. After treating with sodium hydroxide, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 5 g (63.5%) of ethyl 3,4dihydro-2H-naphto[1,2-b]pyran-2-carboxylate (interm. 10-a).