Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of sodium carbonate (0.903 g), tetrakis(triphenylphosphine)palladium(0) (0.246 g), 4-(trifluoromethoxy)phenylboronic acid (1.14 g) and 3-bromopyridin-2-amine (0.737 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.069 g) as a pale-yellow solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([CH3:31])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[N:15]1.O.NN>C(O)C>[NH2:3][C@H:12]([CH3:31])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[N:15]1
Reactant: C[C@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 58 %

Procedure:
(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.199 g, 0.469 mmol) was mixed with ethanol (15 ml). Hydrazine hydrate (0.227 ml, 4.69 mmol) was added and the mixture was refluxed for 3 h. After cooling to RT the precipitate was filtered and washed with ethanol. The filtrate was purified with CombiFlash using DCM and methanol as eluents. Drying in the vacuum afforded 0.080 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 3.21-3.29 (m, 2H), 4.01-4.03 (m, 2H), 7.05 (d, 1H), 7.88 (d, 2H), 8.18 (d, 1H), 8.26-8.28 (m, 1H), 8.31 (s, 1H).
Reaction SMILES: O[C:2]1([C:27]([F:30])([F:29])[F:28])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:27]([F:28])([F:29])[F:30])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH:5][CH3:6].N1C=CC=CC=1.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[N:5]([CH3:6])[C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: CNc1ccc(Cl)c(Cl)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)c(Cl)c1

Procedure:
Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.
Reaction SMILES: CN(C)C=O.[C:6](=[O:26])([O:22][CH:23](Cl)[CH3:24])[O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13].[CH2:27]([O:29][C:30]1[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:33]2[C:72]([C:76]([OH:78])=[O:77])=[CH:73][CH:74]=[CH:75][C:32]=2[N:31]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:27]([O:29][C:30]1[N:34]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)[N:51]=[N:50][N:49]=3)=[CH:40][CH:41]=2)[C:33]2[C:72]([C:76]([O:78][CH:23]([O:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13])=[O:26])[CH3:24])=[O:77])=[CH:73][CH:74]=[CH:75][C:32]=2[N:31]=1)[CH3:28]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A N,N-dimethylformamide (20 mL) solution of (4R,5R)-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (2.94 g, 8.89 mmol) was added to a stirred N,N-dimethylformamide (20 mL) suspension of 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (7.46 g, 10.9 mmol) and cesium carbonate (3.95 g, 12.1 mmol). The solution was stirred at 70° C. for 2 hours. Water (100 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J=1.6, 7.3 Hz, 1H), 7.76 (dd, J=1.0, 7.9 Hz, 1H), 7.58 (dd, J=1.0, 7.9 Hz, 1H), 7.45 (dt, J=1.7, 7.4 Hz, 1H), 7.42 (dt, J=1.7, 7.4 Hz, 1H), 7.32 (t, J=7.4 Hz, 3H), 7.29 (dd, J=1.5, 7.4 Hz, 1H), 7.24 (t, J=7.8 Hz, 6H), 7.17 (t, J=7.9 Hz, 1H), 6.98 (d, J=8.2 Hz, 2H), 6.92 (d, J=8.2 Hz, 6H), 6.85 (q, J=5.4 Hz, 1H), 6.78 (d, J=8.2 Hz, 2H), 5.56 (s, 2H), 5.12-5.22 (m, 2H), 4.58-4.68 (m, 2H), 4.06-4.20 (m, 2H), 1.64-1.94 (m, 4H), 1.41-1.46 (m, 6H), 1.33 (d, J=6.4 Hz, 3H); LC-MS: m/z 999.5 (M+Na).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:92][CH2:91][CH2:90][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:89][CH2:88][CH2:87][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:83]([O:85][CH3:86])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75]C(OC(C)(C)C)=O)=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].C(OC(C)C)(C)C.[F:107][C:108]([F:113])([F:112])[C:109]([OH:111])=[O:110]>>[NH:1]1[CH2:92][CH2:91][CH2:90][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:89][CH2:88][CH2:87][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:83]([O:85][CH3:86])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[C:109]([OH:111])([C:108]([F:113])([F:112])[F:107])=[O:110]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Reaction time: 0.5 h

Procedure:
Stage 2.7 330 mg of Boc-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe are dissolved in 1.7 ml of 95% strength trifluoroacetic acid and left to stand for 30 minutes at 25°. Then, 14 ml of diisopropyl ether are added, the whole is stirred for 30 minutes at 0°, filtered and dried in a high vacuum over KOH, yielding H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OMe×5 TFA; Rf (D)=0.17; Rf (K)=0.20.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][SH:25])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:9].[ClH:1].[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][S:25][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: SCCN1CC=C(c2ccccc2)CC1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCSCc2cccnc2)C1
Temperature: 80 °C
Yield: 29.1 %

Procedure:
A solution of 3-picolyl chloride hydrochloride (2.50 g) and 3,6-dihydro-4-phenyl-1(2H)-pyridineethanethiol hydrochloride (3.90 g) (Example A) in 100 mL of dimethylformamide is treated with triethylamine (7.4 ml) and the mixture is heated at 80° C. for 8 hours. The solvent is evaporated in vacuo, and the residue is partitioned into chloroform/sodium bicarbonate solution. The organic extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 2% methanol in chloroform) to yield 1.7 g of the title compound as an oil, which is converted into its hydrochloride salt (hydrogen chloride gas in diethyl ether) and recrystallized from ethanol/acetonitrile; mp 218°-220° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[Li+].[OH-].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Temperature: 45 °C

Procedure:
Phenylmethyl 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 64; 444 mg, 0.92 mmol) was dissolved in tetrahydrofuran (4 ml) and LiOH (66.6 mg, 2.78 mmol) and water (1 ml) were added. The solution was heated at 45° C. for 90 minutes. 2M Hydrochloric acid (1.39 ml, 2.78 mmol) was added and the solvent was removed in vacuo. The solid was partitioned between 2M HCl (5 ml) and ethyl acetate (40 ml), and the organic layer separated, dried (MgSO4) and the solvent removed in vacuo to give the title compound as a brown solid. 374 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:18]4[CH2:23][CH2:22]N(C)[CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:26])[N:10]([OH:27])[C:9]2=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:18]4[CH2:23][CH2:22][CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:26])[N:10]([OH:27])[C:9]2=[O:28])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2)c(=O)n1O

Procedure:
1-(4-Fluorophenyl)-6-fluoro-3-hydroxy-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione, trifluoroacetate;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (112 mg, 0.472 mmol) and K2CO3 (326 mg, 2.36 mmol) in acetone (3 mL) was added p-anisoyl chloride (0.066 mL, 0.472 mmol). The reaction vessel was sealed and heated to 80° C. for 4 days. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 15 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 9 mg (5%) of 5-hydroxy-2-(4-methoxy-phenyl)-7-morpholin-4-yl-chromen-4-one. Me is CH3—.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]([C:17]1[C:26]([O:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[C:19]([C:36]#[C:37][CH2:38]OS(C)(=O)=O)[N:18]=1)=[O:16]>C(#N)C>[CH3:13][O:14][C:15]([C:17]1[C:26]([O:27][C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[C:19]([C:36]#[C:37][CH2:38][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=1)=[O:16]
Reactant: C1CCNCC1
Reactant: COC(=O)c1nc(C#CCOS(C)(=O)=O)c2cccnc2c1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc(C#CCN2CCCCC2)c2cccnc2c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of piperdine (207 μL, 2.09 mmol) and potassium carbonate (296 mg, 2.14 mmol) in dry acetonitrile (10 mL) was pipetted in 5-(3-methanesulfonyloxy-prop-1-ynyl)-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (230 mg, 0.522 mmol) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated, filtered, and purified on the Gilson auto-prep running a 95-50% H2O (0.1% TFA)/CH3CN (0.09% TFA) gradient over 30 minutes to obtain the desired compound as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][N:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][N:23]=1)=[O:8]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Product: CN(C)C(=O)c1ccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)nc1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.510 mmol) and 6-chloro-N,N-dimethylnicotinamide (94 mg, 0.510 mmol) as starting materials.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (APCI) m/z 405 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:35])(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42]>C(Cl)Cl>[C:16]([NH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH2:43])(=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Yield: 76.3 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (2.27 g) was added to a solution of 2.82 g of oleic acid and 1.62 g of o-phenylenediamine in 50 ml of methylene chloride with stirring under ice cooling. The mixture was stirred at room temperature for one night. After completion of the reaction insoluble matter was filtered, followed by removal of the solvent by evaporation. The residue obtained was purified by silica gel column chromatography to obtain 2.84 g of the objective compound (yield: 76%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1.C1C=C([O:23]O)C(C(O)=O)=C(C(O)=O)C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1)=[O:23]
Reactant: CSc1cc(F)cc(C(=O)c2nccs2)c1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 144.4 %

Procedure:
To a solution of sulfide from Step 1 (0.76 g, 2.99 mmol) in MeOH (1.5 mL) and CH2Cl2 (6 mL) at 0° C. was added the magnesium salt of monoperoxyphthalic acid (1.11 g, 1.80 mmol). The mixture was stirred at 0° C. for 1.25 h and then sat. aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with H2O and dried over anhydrous MgSO4. Evaporation of the solvent and chromatography using toluene:EtOAc (25:75) gave 0.70 g of the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:24]C(=O)OCC1C=CC=CC=1)[C:9]1[NH:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:12][N:13]=1>CO.[Pd]>[NH2:24][C@H:8]([C:9]1[NH:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:12][N:13]=1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:1])=[O:35]
Reactant: NC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CCCCC[C@H](N)c1ncc(-c2ccc3ccccc3c2)[nH]1
Reaction time: 2.5 h

Procedure:
A solution of the amide (ZZ5) (1 eq.) in MeOH was cooled at 0° C. under N2, then Pd/C (10% wt) was added. After two vacuum-H2 cycles the mixture was stirred 2.5 hr under an H2 atmosphere. The catalyst was filtered off and washed with MeOH then the solvent was removed under reduced pressure. The crude was used as such in the following reaction. MS (ES) C20H24N4O requires: 336, found: 337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:32][O-:33].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:33][CH3:32])[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C[O-]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)n5)CC4)nc23)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2CCC(Nc3nc4c(-c5ccc(F)cc5Cl)cccn4n3)CC2)n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 190b) (71 mg, 0.155 mmol) in MeOH (1.5 mL) was added sodium methoxide solution (30% in MeOH, 35 L, 0.186 mmol) and the reaction mixture was stirred in a sealed tube under Argon at 60° C. for 18 hours and then heated in the microwave to 150° C. for 30 minutes. The mixture was then evaporated.
Reaction SMILES: C([O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:16]2[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:34][CH:33]=3)[N:15]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]propenoate (10.0 g), 5% palladium-carbon (20.0 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred for 1 hour under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 3-[3-(4-fluorophenyl)-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (7.15 g, yield 88%) as a colorless oily substance.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[OH:4])#[CH:2].I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[C:1]#[C:2][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)SCCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)SCCC3(C)C)cc1
Yield: 57.1 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 2 g (8.6 mmol) of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol with 2.25 g (8.6 mmol) of methyl 4-iodobenzoate, 1.8 g (57%) of the expected ester was obtained in the form of an yellow oil.