Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCc1cc(C)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.20 (3H, t, J=7.6 Hz), 2.35 (3H, s), 2.68 (2H, q, J=7.6 Hz), 5.21 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.07 (1H, s), 7.27 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 7.96-7.97 (1H, s), 8.66 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C19H18N4O, 319; Found, 319.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 339 (M+H+, 45), 257 (100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:9][C:6]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:4]([F:20])[C:3]([CH2:2][N:1]2[C:31](=[O:32])[C:30]3[NH:29][CH:28]=[N:27][C:26]=3[N:25]=[CH:24]2)=[CH:8][CH:7]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.15 g, 0.422 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.098 g, 0.464 mmol) and phenol (0.052 g, 0.548 mmol) in DCM (2 mL) to give 0.070 (34%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.15 (t, 1H), 5.28 (s, 2H).
Reaction SMILES: [C:1]([N:8]([CH3:28])[C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:30]1([C:36]2([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:25](=[O:26])[NH:41][CH2:40][C:36]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][CH2:38][CH2:39]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: NCC1(c2ccccc2)CCC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of Boc-NMe-Tyr(OBn)-OH (0.90 g, 2.3 mmol) and C-(1-phenyl-cyclobutyl)-methylamine hydrochloride (synthesized according to the method in Bridges, A. J., Hamilton, H. W., Moos, W. H., Szotek, D. L., N6−substituted Adenosines, U.S. Pat. No. 4,755,594) (0.46 g, 2.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.97 g, 5.6 mmol) in methylene chloride (10 mL) was treated with DIEA (0.86 mL, 5.1 mmol). The suspension was stirred at room temperature overnight. The resulting solution was concentrated. The residue was taken up in ethyl acetate. The solution was washed with 0.5 M HCl, saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The oil was chromatographed (CH2Cl2:CH3OH 50:1) to give the desired product (1.07 g, 2.02 mmol; 87% yield). MS-APCI 529 (m+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[N:43]2[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[N:43]2[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1
Yield: 60.9 %

Procedure:
A solution of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.590 g, 0.97 mmol), cesium carbonate (1.95 g, 5.98 mmol) and tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 1.16 mmol) in dimethylacetamide (10 ml) was heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography. Elution with 5 to 7% methanol in dichloromethane gave tert-butyl (2S)-2-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.332 g, 61% yield) as a light brown solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2].S(Cl)([Cl:33])=O>CN(C)C=O.C(OCC)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:33])=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)O)cc3)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)Cl)cc3)ccc2c1
Yield: 99.3 %

Procedure:
A solution of 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoic acid (3.1 g, 7.6 mmol) and thionyl chloride (1.1 ml, 15.2 mmol) in dimethylformamide (30 ml) was stirred overnight at room temperature, then the suspension was diluted with diethyl ether and the solid was filtered and dried yielding 3.2 g of crude 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoyl chloride. This compound was added as solid to a solution of hydroxylamine hydrochloride (0.6 g, 8.5 mmol) and sodium bicarbonate (1.2 g, 14 mmol) and 1N sodium hydroxide (8.5 ml, 8.5 mmol) in water (30 ml) and THF (40 ml). The mixture was stirred at room temperature for 2 hours, then the mixture was saturated with sodium chloride and the organic phase was separated and the aqueous phase was extracted with THF. The combined organic phases were dried foyer anhydrous sodium sulphate and the solvent was removed under reduced pressure. Crude was dissolved in hot THF (150 ml) and the insoluble material was filtered off. The solution was cooled at room temperature and treated with 1.5 N etheric solution of HCl. The solid product was filtered and dried yielding 1.2 g (yield 38%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]-benzohydroxamic acid hydrochloride as white solid; m.p.=167-168° C. (dec.)
Reaction SMILES: [C:1](O)(=[O:4])CC.[Cl:6][C:7]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:8]=1[CH2:9][NH:10][C:11](=[O:21])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Cl)[CH3:13]>>[Cl:6][C:7]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:8]=1[CH2:9][NH:10][C:11](=[O:21])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:4][CH3:1])[CH3:13]
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reactant: CCC(=O)O
Product: COc1ccccc1C(C)C(=O)NCc1cccc(C(F)(F)F)c1Cl
Yield: 42 %

Procedure:
The titled compound was prepared from 22-methoxyphenyl)propionic acid in 42% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in Example 184b. MS (ESI) 372 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>N1CCCCC1.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2,6-di-tert-butyl-4-mercapto-phenol (1.2 g, 5.2 mmol) and 4-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.4 mmol) in 5 mL of piperidine was degassed and then heated to 90° C. for 15 h. The reaction was cooled to room temperature, toluene (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (40 mL), washed with 1 N HCl (2×30 mL) and water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Chromatography (2-20% ethyl acetate/hexanes) afforded 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-ethoxycarbonylmethyl-piperidine-1-carboxylic acid tert-butyl ester as a foamy solid (2.1 g, 94%). ESI/CI-MS m/z 506 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#[N:2].C(N)(=[S:32])C.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([C:1](=[S:32])[NH2:2])[CH:4]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Reactant: CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1

Procedure:
Heat N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 51) (1.00 g, 2.57 mmol) with thioacetamide (0.386 g, 5.14 mmol) at reflux temperature in 4N HCl in dioxane (30 mL) for 4 h. Allow to cool, pour onto water and neutralize with NaHCO3. Collect 0.98 g (90%) of a precipitate. Purify a portion of the material by silica gel chromatography (25-80% EtOAc/hexanes gradient) to give a yellow solid. MS (ES): m/z 424 (M+1); HPLC: Rt=1.90 min, (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
55 mg (0.16 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 68 mg (82% of theory)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[Br:19][C:20]1[CH:28]=[C:24]([C:25]([N:4]=[S:2]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:9][CH:10]=2)([CH3:1])=[O:3])=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=N)=O)cc1
Reactant: O=C(O)c1cncc(Br)c1
Product: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)cc1
Yield: 74.6 %

Procedure:
In a manner similar to that described in Example 480 (step 6), tert-Butyl [4-(S-methylsulfonimidoyl)phenyl]carbamate (0.141 g, 0.522 mmol) and 5-bromonicotinic acid (0.104 g, 0.522 mmol), were converted to the title compound (0.177 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:18])[C:11]2=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(p-nitrophenyl)-2-imidazolidinone (25 g) in 450 ml of dimethylformamide is stirred under nitrogen and sodium hydride (50%, 6.4 g) added in small portions. The mixture is stirred at 50° for 11/2 hours, cooled to room temperature, and then methyl iodide (25 g) is added. After stirring 2 hours, the pH of the reaction mixture is 9. Another batch of methyl iodide (4 g) is added over 6 hours until the pH of the mixture is about 8. Water (150 ml) is added, the precipitated solid is filtered off, washed with dimethylformamide/water (1:1), then with water (2×150 ml). The solid is dried to give 1-(p-nitrophenyl)-3-methyl-2-imidazolidinone, m.p. 207°-208°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH2:11][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
In a 500 ml round bottomed flask was suspended 55 g of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole in 250 ml of diethyl ether. The suspension was warmed to reflux and 33 g of 4-chlorophenyl isocyanate was added at a rate to maintain reflux. After cooling and standing overnight the precipitated product was filtered yielding 78 g of white solid. mp 173°-175° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:8]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cccs2)cc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 26.7 parts of p-ethylbenzoyl chloride, 13.3 parts of thiophene in 80 parts of methylene chloride are added 41.1 parts of stannic chloride in 40 parts of methylene chloride at 30° C. Upon completion, stirring is continued for 3h. 30 at reflux temperature. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic layers are washed with water, dried, filtered and evaporated. The residue is evaporated once more from benzene. The latter residue is distilled, yielding p-ethylphenyl 2-thienyl ketone; bp. 200°-205° C at 12 mm. pressure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[CH2:2]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:15]=[CH:16][CH:17]=1)[CH2:2]2
Reactant: COc1ccccc1B(O)O
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Product: COc1ccccc1-c1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 58 %

Procedure:
Using general procedure E, quinuclidin-3-yl3-bromophenylcarbamate, 2-methoxy-phenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (75 mg, 58%). 1H NMR (500 MHz, CDCl3) δ 7.49 (br s, 1H), 7.41 (br s, 1H), 7.37-7.28 (m, 3H), 7.23 (d, J=7.5 Hz, 1H), 7.04-6.94 (m, 3H), 4.83 (m, 1H), 3.80 (s, 3H), 3.29 (m, 1H), 2.97-2.70 (m, 5H), 2.10 (m, 1H), 1.91-1.82 (m, 1H), 1.74-1.65 (m, 1H), 1.62-1.53 (m, 1H), 1.46-1.37 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 156.4, 153.4, 139.4, 137.6, 130.9, 130.2, 128.8, 128.6, 124.8, 120.8, 119.9, 117.3, 111.2, 72.0, 55.6, 55.4, 47.4, 46.5, 25.4, 24.5, 19.5 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.52 min; (M+1) 353.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:18][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)([CH2:16][OH:17])[O:14][C:13](=[O:29])[C:12]=1[OH:30].Cl.[CH3:32][N:33]([CH2:35][C:36](Cl)=[O:37])[CH3:34].C(N(CC)CC)C>CN(C=O)C.Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:16][O:17][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32])([CH2:18][S:19][C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[O:14][C:13](=[O:29])[C:12]=1[OH:30]
Reactant: CN(C)CC(=O)Cl
Reactant: O=C1OC(CO)(CSc2nc3ccccc3[nH]2)C(Sc2nc3ccccc3[nH]2)=C1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)OCC1(CSc2nc3ccccc3[nH]2)OC(=O)C(O)=C1Sc1nc2ccccc2[nH]1

Procedure:
A solution of 4-(1H-benzoimidazol-2-ylsulfanyl)-5-(1H-benzoimidazol-2-ylsulfanylmethyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one (220 mg, 0.50 mmol), dimethylaminoacetyl chloride hydrochloride (174 mg, 1.10 mmol) and triethylamine (0.280 mL, 2.00 mmol) in DMF (15 mL) was stirred for 22 h. The reaction mixture was then passed through a plug of SiO2, which was then washed with hexane to remove excess DMF, and subsequently with a 1:1 mixture of EtOAc and MeOH to collect dimethylamino-acetic acid 3-(1H-benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-ylmethyl ester. Upon evaporation of solvent, the residue was subjected to column chromatography (SiO2: CH2Cl2:MeOH:Acetic Acid, 87:10:3 v/v/v) which yielded an off-white solid which was dissolved in 0.5 M HCl and lyophilized (73 mg, 26%, GLI-1007817b). 1H NMR (D2O, 300.16 MHz) δ: 7.20-7.38 (m, 8H), 4.67 (q, J=12.0 Hz, 2H), 3.9104.18 (m, 4H), 2.86-2.96 (m, 6H).). 13C NMR (D2O, 75.04 MHz) δ: 167.4, 165.4, 155.7, 147.2, 145.3, 131.5, 130.9, 126.2, 126.1, 113.1, 112.7, 102.0, 85.2, 65.8, 56.6, 43.7, 36.4. MS (ESI-Pos) m/z: 526.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reaction time: 16 h

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 79) in 60 ml of methanol. Under normal-pressure hydrogen gas, the solution was vigorously stirred. After 16 hours, the reaction was ceased, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 0.94 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:17][CH:16]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution of 4,4'-dichlorobutyrophenone (21.7 g, 0.1 mol) in 350 mL of methanol plus 27 mL of 1N HCl plus 25 mL of water and the reaction stirred at room temperature for 21 hours (overnight). The solid was collected by filtration and dried to give 20.23 g of a white solid. Recrystallization of the solid from isopropyl alcohol gave 8.37 g (29%) of the title compound as a light yellow solid, mp 125-126° C.