Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-:29].[K+].[K+].CS(C)=O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]([NH2:27])=[O:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C(N)=O)CC5)cc4)nc23)cn1
Reaction time: 5 h

Procedure:
1-{4-[8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino]-phenyl}-cyclopropanecarbonitrile is dissolved in methanol before potassiumcarbonate (5 eq.), DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) are added. The mixture is stirred for 5 h and monitored via LCMS MS. DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) ares added and the mixture iss stirred at rt for 16 h. The mixture is concentrated and the crude material purified via column chromatographie. LCMS purity (Method D): 100%, Rt: 1.70 min, observed [M+H]=375.1;
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]([F:27])([F:26])[CH:7]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1>O>[F:5][C:6]([F:26])([F:27])[CH:7]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CCOc1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 50 °C
Yield: 74.5 %

Procedure:
0.082 g of sodium hydroxide was dissolved in 1 ml of water, followed by addition of 3 ml of methanol and 0.22 g of ethyl p-(3-trifluoromethylheptyloxy)-benzoate and 3 hours of stirring at 50° C. After the reaction, water was added, methanol was removed by distillation under a reduced pressure, and 6N-hydrochloric acid was added to precipitate a crystal. The crystal was recovered by filtration, washed with water and dried to obtain 0.15 g (yield: 76%) of p-(3-trifluoromethylheptyloxy)benzoic acid, which showed: [α]D24 +4.2, [α]43525 +8.6 (c 1.00, CHCl3).
Reaction SMILES: NC1C=C(C=C([N+]([O-])=O)C=1C(=O)C1C=CC=CC=1)C(O)=[O:6].N[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]>>[OH:6][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]
Reactant: Cc1ccc(C(=O)c2c(N)cc(C(=O)O)cc2[N+](=O)[O-])cc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Cc1ccc(C(=O)c2c(O)cc(C(=O)O)cc2[N+](=O)[O-])cc1

Procedure:
By replacing in Example 1, step A, 3-amino-4benzoyl-5-nitrobenzoic acid with 3-amino-4-(4'-methylbenzoyl)-5-nitrobenzoic acid and following the procedure described, 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoic acid is obtained as a hemihydrate with a melting point of 249.5°-251° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]4[N:16]=[C:17]([NH:19][C:20]5[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:27])[NH:18][C:9]=4[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[C:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:13]([C:12]2[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=3[C:9]3[NH:18][C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:27])=[N:16][C:10]=3[CH:11]=2)=[O:15])=[CH:41][CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c3nc(C4CC4)oc23)cc1
Yield: 11.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 2-cyclopropyl-7-[(2,6-dichlorophenyl)amino]-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-58, 0.100 g, 0.248 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-tert-butylaniline (0.055 g, 0.369 mmol), THF (5.0 mL) and 60% NaH (0.095 g, 0.744 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.20 (s, 4H), 1.29 (s, 9H), 2.32 (m, 1H), 7.28 (d, J=7.8 Hz, 3H), 7.59 (s, 3H), 7.68 (d, J=8.4 Hz, 2H), 9.36 (s, 1H), 9.90 (s, 1H), 11.55 (s, 1H); MS [M+H]+: 534.32.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21].CCN(CC)CC>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc[nH]1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccc(F)cc1F)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of 2.0 g Et3N in 25 ml of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives β-oxo-α-(2,4-difluorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 169°-171°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
To a stirring solution of DMSO (12.45 ml, 176 mmol) in DCM (150 mL) at −78° C. under an argon atmosphere was added dropwise oxalyl chloride (8.61 mL, 100 mmol). After stirring for 30 minutes at −78° C., a solution of 1-benzhydrylazetidin-3-ol (20 g, 84 mmol) in DCM (75 mL) was added dropwise. The reaction mixture was stirred for 1 h at −78° C. before triethylamine (58.2 ml, 418 mmol) was added. The reaction mixture was allowed to reach 0° C. and was quenched with saturated NH4Cl (150 mL), and then extracted with DCM (3×). The combined organic layers were washed with water, brine, dried on Na2SO4 and concentrated to give crude 1-benzhydrylazetidin-3-one (20.8 g, 105%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:14]#N)=[CH:10][N:11](C)C)=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH2+:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]#[N:11])=[CH:14][N:31]=[C:29]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[N:30]=2)=[CH:4][N:3]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Cl)nc1
Reactant: NC(=[NH2+])Nc1ccc(F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(Nc2ccc(F)cc2)nc1-c1ccc(Cl)nc1

Procedure:
4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine was prepared from 1-(2-chloropyridin-5-yl)-2-cyano-3-dimethylamino propen-1-one (8.0 g, 36 mmol), 4-fluorophenylguanidinium nitrate (8.23 g, 37.8 mmol) and sodium hydroxide (1.49 g, 37.8 mmol) as a yellow solid (7.23 g). δH (d6 DMSO) 10.66 (1H, bs), 9.00 (1H, s), 8.95 (1H, d, J 2.3 Hz), 8.38 (1H, dd, J 8.4,2.5 Hz), 7.80 (1H, d, J 8.4 Hz), 7.77-7.74 (2H, m) and 7.24-7.20 (2H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1C=CC=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]I.C(Cl)Cl.C1C[O:25]CC1>[Cu]I>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:25])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Cu]I
Agent: C[Mg]I
Solvent: ClCCl
Product: CC[C@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a mixture of the benzyl ether above (44 g, 0.268 mol) and CuI (51 g, 0.268 mol) in anhydrous THF (1 L) was slowly added MeMgI (270 mL of a 3 M THF solution, 0.810 mol) at -78° C. The mixture was stirred at -78° C. for 4 hours and was warmed to room temperature. After aqueous work-up (CH2Cl2) and chromatography, 47.0 g of the title compound was obtained: [α]25D +8.2° (c 1.2, CHCl3). IR: 3428. 1H NMR (CDCl3): δ0.94 (3H, t, J=7.5), 1.47 (2H, m), 2.38 (1H, br), 3.32 (1H, dd, J=8.0, 9.3), 3.50 (1H, dd, J=2.9, 9.3), 3.73 (1H, m), 4.54 (2H, s), 7.26-7.36 (5H, m). 13C NMR (CDCl3): δ9.8, 26.1, 71.7, 73.3, 74.3, 127.7, 127.7, 128.4, 138.0. HRMS (EI) calcd for C11H16O2 180.1150, found 180.1145.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5](Cl)=[O:6].[NH2:8][C:9]1[S:13][N:12]=[C:11]([Br:14])[C:10]=1[C:15](=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([C:10]1[C:11]([Br:14])=[N:12][S:13][C:9]=1[NH:8][C:5]([C@@H:3]1[CH2:4][C@H:2]1[CH3:1])=[O:6])(=[O:17])[CH3:16]
Reactant: C[C@@H]1C[C@H]1C(=O)Cl
Reactant: CC(=O)c1c(Br)nsc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1c(Br)nsc1NC(=O)[C@@H]1C[C@H]1C
Yield: 82 %

Procedure:
Add a freshly prepared 1.93M solution of (1R,2R)-2-methyl-cyclopropanecarbonyl chloride (5.52; mol) in dichloromethane over 15; min to a suspension of 1-(5-amino-3-bromo-isothiazol-4-yl)-ethanone (1.17; kg, 4.93; mol) and triethylamine (859; mL, 6.16; mol) in dichloromethane (5.86; L) at room temperature and stir 4; hours. Quench the reaction with water (1; L) and separate the layers. Dry the organic layer over magnesium sulfate, filter, concentrate and purify the residue by short column silica gel chromatography (3500; g of SiO2) gradient eluting from 100:0; to 40:60 using n-hexane and ethyl acetate to give the title compound as a white solid (1230; g, 82%). MS (m/z): 303, 305; (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24]O)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][N:63]4[CH2:67][CH2:66][CH2:65][CH2:64]4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27]
Reactant: C1CCNC1
Reactant: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CN1CCCC1
Yield: 13.4 %

Procedure:
The same procedure as E69 from 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-(hydroxymethyl)-4(1H)-pyrimidinone (53 mg, 0.120 mmol), DIAD (0.035 mL, 0.180 mmol), triphenylphosphine (47.1 mg, 0.180 mmol) and pyrrolidine (25.5 mg, 0.359 mmol) in DMF (2 mL), except that the temperature was up to 50° C., to afford the title compound (8 mg, 13.48% yield). LCMS: rt=3.06 min, [M+H+]=496
Reaction SMILES: C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:3](=[O:4])C1.[CH2:19]([NH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[C:24]=1[NH2:30])[CH:20]=[CH2:21]>C(#N)C>[CH2:19]([N:22]1[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[C:24]=2[NH:30][C:3]1=[O:4])[CH:20]=[CH2:21]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: C=CCNc1ccnc(Cl)c1N
Solvent: CC#N
Product: C=CCn1c(=O)[nH]c2c(Cl)nccc21
Yield: 70 %

Procedure:
A solution of N,N′-disuccinimidyl carbonate (4.46 g) in acetonitrile (400 mL) was added to a solution of N*4*-allyl-2-chloropyridine-3,4-diamine (2.88 g) in acetonitrile. This was then heated under reflux for 70 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (500 mL) and water (300 mL). The organic layer was then washed twice with 100 mL of 1 N hydrochloric acid and then once with 100 mL of saturated aqueous sodium chloride solution. This was then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted by ethyl acetate-dichloromethane (1:1) gave the title compound (2.30 g).
Reaction SMILES: [I-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([C:23]([N:25]2[CH:29]=C[N+](C)=[CH:26]2)=[O:24])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:15]=1.CC[N:33]([CH2:36][CH3:37])[CH2:34]C.[CH2:38](Cl)Cl>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([C:23]([N:25]([CH3:26])[CH2:29][CH:37]([CH3:38])[CH2:36][NH:33][CH3:34])=[O:24])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:15]=1
Reactant: CCN(CC)CC
Reactant: C[n+]1ccn(C(=O)N2CCC(c3cc(F)ccc3F)=CC2c2cccc(O)c2)c1
Reactant: ClCCl
Agent: [I-]
Product: CNCC(C)CN(C)C(=O)N1CCC(c2cc(F)ccc2F)=CC1c1cccc(O)c1
Reaction time: 8 h

Procedure:
To a crude solution of 3-2 (25 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added Et3N (0.02 mL, 0.14 mmol) and amine (11 mg, 0.09 mmol) and the reaction stirred overnight. The reaction was simply concentrated and purification was conducted by reverse phase column chromatography (CH3CN/H2O/0.1% TFA gradient). 1H NMR (300 MHz, CDCl3) rotamers δ 7.30-6.80 (m, 7H), 6.10 (s, 1H), 5.58 (br s, 1H), 4.08 (m, 1H), 3.58 (m, 2H), 3.46 (s, 3H), 3.30 (m, 1H), 2.90 (m, 2H), 2.58 (m, 2H), 2.38 (s, 3H), 1.90 (s, 3H), 1.00 (m, 1H); MS 430.4 observed, 430.5 required (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=2)[C:16]#N)=[N:4][NH:5][C:6](=[O:9])[C:7]=1[CH3:8].[OH-:20].[Na+].Cl.[OH2:23]>>[CH3:1][C:2]1[C:3]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=2)[C:16]([OH:23])=[O:20])=[N:4][NH:5][C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O
Reactant: [OH-]
Reactant: Cc1c(Cc2ccc(F)c(C#N)c2)n[nH]c(=O)c1C
Agent: Cl
Agent: [Na+]
Product: Cc1c(Cc2ccc(F)c(C(=O)O)c2)n[nH]c(=O)c1C
Temperature: 100 °C

Procedure:
To a suspension of intermediate B3 in water (0.35 M) was added NaOH (8 eq.) and the resulting mixture was stirred and heated to 100° C. for 60 min. The mixture was cooled with an ice bath and slowly acidified to pH 2-3 with 6N HCl. The formed light yellow precipitate was filtered off, dried under air stream and then under high vacuum. MS (ES) C14H13FN2O3 required: 276, found: 277 (M+H)+.