Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11](O)[CH2:12][CH3:13]>>[CH:11]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH:2]([CH2:4][CH3:5])[CH3:1])=[O:6])[OH:3])([CH2:12][CH3:13])[CH3:10]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCC(C)O
Product: CCC(C)OC(=O)CC(O)C(=O)OC(C)CC
Temperature: 102 °C

Procedure:
Di-sec-butyl-DL-malate was prepared using a procedure similar to Example 3. This compound was isolated as a bottoms product. To the reaction flask, DL-malic acid (80.23 g), 2-butanol (220 mL) and Amberlyst® 15 ion exchange resin (11.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 102° C., one phase started to collect in the Dean-Stark trap. The reaction was maintained at 102° C. for 4 hr. During this time, the water/alcohol azeotrope was removed as fresh alcohol was added. The product was dissolved in diethyl ether, separated from the catalyst via filtration over a bed of silica, washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Di-sec-butyl-DL-malate was obtained as a low viscosity, clear light yellow liquid with no detectable odor (46 g, 31% yield) after pumping on the sample in vacuo to remove residual 2-butanol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[OH-].[Li+]>CS(C)=O.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:3]([CH:6]=1)[C:4]#[N:5])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Temperature: 25 °C

Procedure:
Combine 2-amino-5-isopropyl-benzonitrile (3.19 g, 20 mmol), 1-fluoro-2-nitro benzene (2.1 mL, 20 mmol) and lithium hydroxide (1.68 g, 40 mmol) in DMSO (40.0 mL) and heat at 55° C. for 19 hours. Cool to ambient temperature and dilute with water (200 mL). The title compound precipitates as 4.56 g of an orange solid: mp 91–96° C.; mass spectrum (ion spray) m/z=280 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](OCC)=[O:12].CC[O-].[Na+].Cl>CCO.O>[OH:12][CH:11]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: CCOC=O
Reactant: O=C1Cc2ccccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a slurry of oxindole (1.33 g, 10.0 mmol) and ethyl formate (2.42 mL, 30.0 mmol) was added 4.85 mL of 21 wt. % NaOEt in EtOH. The thick solution was stirred for 30 min at room temperature and then heated at reflux for 30 min. The solution was acidified to pH=3 with 10% aqueous HCl and 5 mL H2O was added. The solid which formed was filtered and rinsed with H2O to give the title compound (1.34 g, 83%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[NH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:6]
Reactant: CC(C)(CO)C(=O)O
Reactant: CCOC(=O)C(N)C(=O)OCC
Product: CCOC(=O)C(NC(=O)C(C)(C)CO)C(=O)OCC
Yield: 88 %

Procedure:
Diethyl N(β-hydroxypivaloyl)aminomalonate was prepared (method B) from β-hydroxy pivalic acid and diethyl aminomalonate in 88% yield. The compound was isolated as an oil. NMR 1.13-1.3 (12H, m), 3.5 (2H, br s), 4.16-4.4 (4H, q), 5.1-5.16 (1H, d), 7.6-7.7 (1H, d).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH:12](O)[C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)(C)C(O)I
Reactant: O=C(O)c1cccnc1S
Product: CC(C)(C)CSc1ncccc1C(=O)O
Yield: 16 %

Procedure:
2-Mercapto-nicotinic acid (0.5 g, 3.2 mmol) and 1-iodo-2,2-dimethyl-propanol were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.12 g, 16%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[Br:29])[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Sn](Cl)Cl.C(O)C>O>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([Br:29])=[C:20]([CH:25]=1)[CH2:19][N:15]1[C@@H:14]([CH3:30])[C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:31])([F:32])[F:1])[CH:4]=2)[O:17][C:16]1=[O:18]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(N)ccc1Br
Temperature: 20 °C
Reaction time: 36 h

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (614 mg, 1.17 mmol), tin(II) chloride dehydrate (1.314 g, 5.823 mmol) and ethanol (3 mL) was stirred at 20° C. for 36 h. Reaction crude was worked up with water. The resulting mixture was extracted with EtOAc and dried over Na2SO4. The titled compound was obtained as a glassy material after SiO2 purification (Biotage 40+M, gradient, 0% to 35% EtOAc in hexanes). LC-MS: 499.05 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.77 (s, 2H), 7.31 (d, J=8.5, 1H), 6.77 (d, J=2.7, 1H), 6.54 (dd, J=8.5, 2.7 Hz, 1H), 5.69 (d, J=8.0 Hz, 1H), 4.77 (d, J=15.3, 1H), 4.29 (d, J=15.3 Hz, 1H), 4.05-4.12 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11]C[O:9]1)C)[CH2:3][OH:4].[C:14](Cl)(=O)CCC.Cl>N1C=CC=CC=1>[C:8]([O:7][CH2:5][C@H:2]([CH3:1])[C@@H:3]([OH:4])[CH3:14])(=[O:9])[CH2:13][CH2:12][CH3:11]
Reactant: CCCC(=O)Cl
Reactant: C[C@H](OC1CCCCO1)[C@@H](C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)OC[C@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
3.76 g (0.02 tool) of (2S,3S)-2-methyl-3-tetrahydropyranyloxybutanol was dissolved in 30 ml of pyridine. Thereto was dropwise added 2.56 g (0.024 mol) of butyryl chloride at room temperature. The mixture was stirred for 30 minutes at room temperature. 2 N hydrochloric acid was added to the reaction mixture. The mixture was extracted with ether. The ether layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to purification by chromatography to obtain 3.70 g (yield: 71.7%) of a desired compound. 3.40 g (0.013 mol) of the compound was dissolved in 50 ml of methanol. Thereto was added 10 g of Amberlist 15. The mixture was stirred overnight at room temperature. The Amberlist 15 was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to purification by silica gel column chromatography (developing solvent: chloroform) to obtain 1.51 g (yield: 66.8%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](/[N:11]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=S)Nc1cccc(Br)c1
Solvent: CCOCC
Product: CN(C)/C=N/C(=S)Nc1cccc(Br)c1
Temperature: 100 °C

Procedure:
(3-Bromophenyl)thiourea (2.1 g, 9.1 mmol) was suspended in N,N-dimethylformamide dimethyl acetal and was heated to 100° C. for 2 d. The cooled mixture was diluted with ether and filtered and the solid washed with ether to give the title compound (2.42 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.Cl[C:54]([O:56][CH3:57])=[O:55]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:54]([O:56][CH3:57])=[O:55])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cl
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)OC)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 6.9 μL (0.089 mmol) of methyl chloroformate. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 54 mg (98%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.28 (m, 6H), 6.99 (d, 1H), 6.89 (s, 1H), 6.71 (dd, 1H), 5.54 (d, 1H), 5.30 (d, 1H), 4.93 (m, 2H), 4.17-3.50 (m, 11H), 3.25-2.60 (m, 12H), 1.60-1.12 (m, 6H), 0.89 (s, 3H), 0.81 (s, 3H). MS(ESI): 677(M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M192) (216 mg, 0.396 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (37 mg, 22%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:2]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=[O:1]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(CO)ccn23)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
To a solution of 1-[3-(7-Hydroxymethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (1.42 g, 3.90 mmol) and NMO (1.38, 11.7 mmol) in CH2Cl2 (30 ml) with sieves (3 g) at 0° C. was added TPAP (0.14 g, 0.38 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, before being filtered to remove the sieves. The organic layer was washed with H2O (×2), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by silica column chromatography (0-60% MeOH in Et2O) to afford the product (0.2 g). MS: [M+H]+=363
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[C:8]=1[CH3:11])=[O:19]
Reactant: COc1ccc2occ(C)c2c1
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2) above, 5-chlorovaleryl chloride (1.74 mL) and nitromethane (40 mL) was added aluminum chloride (2.47 g) at 0° C., and the mixture was stirred for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title object compound (2.63 g, 76%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:27])[N:11]([O:28]CC3C=CC=CC=3)[C:10]2=[O:36])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:27])[N:11]([OH:28])[C:10]2=[O:36])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Agent: [Pd]
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 87.4 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.06 g) with 1-(3-chloro-4-fluorophenyl)-6-fluoro-3-benzyloxy-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example R-1, 0.12 g, 0.23 mmol) afforded 0.085 g of the title compound as a solid, mp 197-199° C.