Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]([O:12]CC)=[O:11])=[O:9])=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]([OH:12])=[O:11])=[O:9])=[N:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Nc1ncc(C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cnc(NC(=O)C(=O)O)s1

Procedure:
Ethyl 5-methylthiazol-2-ylcarbamoylcarboxylate (3 g., 14 mmole) was combined with 120 ml. of water and 14 ml. of 1N potassium carbonate and heated on a steam bath for 10 minutes. The mixture was clarified by filtration, cooled in an ice-water bath, acidified with acetic acid, filtered to yield a first crop of product (400 mg.) and evaporated to yield a second crop of product (1.45 g.). The two crops were recrystallized from acetic acid affording purified 5-methylthiazol-2-ylcarbamoylcarboxylic acid [1.12 g., m.p. 212°-213° C. (dec.)].
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[CH:8]=[C:7]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:6]=1)(=O)=O.[C:24]([NH:27][C:28]1[CH:33]=[CH:32]C(S)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>C(O)(C)(C)C>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:1]([S:2][C:5]2[N:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[CH:8]=[C:7]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:6]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: Cc1cc(Nc2cc(N3CCOCC3)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: CC(=O)Nc1ccc(S)cc1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CCOCC3)n2)cc1
Temperature: 25 °C

Procedure:
The above-prepared [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL) over 20 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography to give the desired product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@H:7]([C:12]([O:14]C)=O)[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:5])=[O:4])[CH3:2].[NH:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19]>>[CH2:1]([S:3]([NH:6][C@H:7]([C:12]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)OC
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
EtSO2-Leu-OMe (3.3 g) was saponified (procedure example 1), coupled with H-Pro-OBzl (procedure example 23) and the resulting dipetide was hydrogenated (procedure example 23) using the indicated procedures to give 3.4 g of the title compound.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24](=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:35]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24](=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)=C1CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=C1CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)O)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
The potassium hydroxide (54.6 mg, 0.97 mmol) was added to a station (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)acetate (60 mg, 0.097 mmol) in ethanol (2 mL) and stirred for 6 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)acetic acid 39.3 mg (70%). 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.35 (m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.4 Hz, 2H), 6.97 (t, J=8.1 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 5.84 (s, 1H), 4.21 (t, J=6.2 Hz, 2H), 3.53 (br. s, 4H), 3.04 (t, J=6.2 Hz, 2H), 2.44 (s, 3H), 2.31-2.28 (m, 1H), 2.05 (br. s, 1H), 2.00 (s, 3H), 1.83 (br. s, 1H), 1.65 (br. s, 1H), 1.56 (s, 3H), 1.49 (s, 3H), 1.12 (s, 9H). UPLC (M+H)=575.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)=[O:8])[CH3:2]>C1COCC1>[CH3:15][C:13]1[CH:14]=[C:9]([C@@H:7]([OH:8])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:10]=[C:11]([CH3:16])[CH:12]=1
Reactant: CCOC(=O)CCC(=O)c1cc(C)cc(C)c1
Solvent: C1CCOC1
Product: CCOC(=O)CC[C@H](O)c1cc(C)cc(C)c1

Procedure:
To a stirred solution of ethyl-4-(3,5-dimethylphenyl)-4-oxobutyrate (0.5 g; 2.14 mmol) in THF (5 mL) was added a solution of (−)-chlorodiisopinocampheylborane (1.71 g; 5.34 mmol) in THF (1 mL). The resultant solution stirred at room temperature for 4 days. The reaction was concentrated in vacuo and dried under high vacuo for 1 h. The residue was dissolved in ethyl acetate (10 mL) and diethanolamine (470 mL) was added. A white precipitate formed and the resultant mixture was stirred for 2 h, after which the solid was filtered off and washed with pentane. The filtrate was concentrated in vacuo and purified by flash silica gel chromatography (0-20% EtOAc/hexanes gradient) to afford ethyl (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanoate as a clear oil. LCMS=219.3 (M+1−18)+. 1H NMR (CDCl3, 500 MHz): δ 6.99 (s, 2H), 6.95 (s, 1H), 4.72-4.69 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.45 (t, J=7.3 Hz, 2H), 2.34 (s, 6H), 2.11-2.06 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13]O)[CH:4]=1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>ClCCl>[Cl:26][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COc1cc(CO)cc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CCl)cc2ccccc12
Temperature: -5 °C
Reaction time: 23 h

Procedure:
15.0 g (79.7 mmol) of (4-methoxy-naphthalen-2-yl)-methanol [Chem. Pharm. Bull. 19(6), 1245-1256 (1971)] were dissolved in 100 ml of dichloromethane, the solution treated with 20 ml of triethylamine, cooled to −5° C. and treated slowly with 9.3 ml (119.5 mmol) methanesulfonyl chloride. Then, the reaction mixture was stirred at room temperature for 23 hours, concentrated in a water-jet vacuum, redissolved in 80 ml of tetrahydrofuran, treated with 11.25 g of sodium hydrogen carbonate and stirred for another 2 hours. The suspension was then diluted with 500 ml of water and extracted three times with 300 ml of ethyl acetate, the organic phases were washed once with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with pentane/dichloromethane (4/1). There were thus obtained 11.9 g (57.5 mmol), 72.5% 3-chloromethyl-1-methoxy-naphthalene as a colorless solid; MS: 206 (M)+.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:42])P(N(C)C)(N(C)C)=O>O1CCCC1>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:33]([CH3:42])[CH3:32])=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)N(Cc1ccccc1C(=O)N(C)C)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 0.1 ml of hexamethylphosphoramide was dissolved 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, and 0.2 ml of thionyl chloride was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 50% aqueous dimethylamine solution was added dropwise with stirring. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 0.49 g of N-acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)=[C:8]=[O:9]>C1(C)C=CC=CC=1>[N:1]1([C:8]([NH:7][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a solution of morpholine (0.684 g, 7.85 mmol, 0.687 mL) in toluene (8 mL) was added dropwise ethyl 4-isocyanatobenzoate (1.50 g, 7.85 mmol) in toluene (8 mL). After stirring for 18 h at room temperature, the precipitate was filtered, washed with cold toluene, and dried under vacuum to give 2.00 g (91%) of the title compound as a white solid. 1H NMR: δ7.96 (d, J=8.8 Hz, 2H, aryl), 7.45 (d, J=8.8 Hz, 2H, aryl), 6.80 (br s, 1H, NH), 4.35 (q, J=7.1 Hz, 2H, CO2CH2), 3.75-3.70 (m, 4H, CH2OCH2), 3.53-3.47 (m, 4H, CH2NCH2), 1.38 (t, J=7.1 Hz, 3H, CH3). 13C NMR: δ166.3, 154.4, 143.2, 130.7, 124.7, 118.5, 66.4, 60.8, 44.3, 14.3. IR (KBr): 3328, 1716, 1645, 1592, 1526, 1423, 1308, 1279, 1247 cm−1. MS (DCI/CH4): m/z (rel intensity) 307 (M+C2H5+, 39), 279 (MH+, 100). Anal. (C14H18N2O4): C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C:23]4=[O:27])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.[Zn].[Fe]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]5[CH2:26][CH2:25][CH2:24][C:23]5=[O:27])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:31]=1
Reactant: O=C1CCCN1CCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CCN5CCCC5=O)cn4)sc23)c(F)c1
Yield: 46 %

Procedure:
To impure 293 (0.76 g, 1.6 mmol) in EtOH (75 mL) was added zinc dust (1.04 g, 15.9 mmol), iron filings (0.89 g, 16 mmol) and saturated aqueous ammonium chloride solution (2 mL). The resultant mixture was heated to reflux for 18 h, then cooled, filtered through celite, concentrated and re-dissolved in dichloromethane. The solution was washed with water, 1 M NaOH, and brine, dried (anhydrous MgSO4), filtered, concentrated and the residue was purified by silica gel chromatography (15% MeOH/chloroform) to afford title compound 294 (0.33 g, 46% yield). MS (M+H): 449.2
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH:62]1([CH2:65][N:66]2[CH2:71][CH2:70][N:69]([C@H:72]3[CH2:77][CH2:76][C@H:75]([NH2:78])[CH2:74][CH2:73]3)[CH2:68][CH2:67]2)[CH2:64][CH2:63]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:62]1([CH2:65][N:66]2[CH2:71][CH2:70][N:69]([C@H:72]3[CH2:77][CH2:76][C@H:75]([NH:78][C:26]([C:20]4[CH:19]=[CH:18][C:17]([NH:16][C:9]5[N:8]=[CH:7][C:6]6[N:5]([CH3:29])[C:4](=[O:30])[C@@H:3]([CH2:1][CH3:2])[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]=6[N:10]=5)=[C:25]5[O:24][CH2:23][CH2:22][C:21]=45)=[O:28])[CH2:74][CH2:73]3)[CH2:68][CH2:67]2)[CH2:63][CH2:64]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (70 mg, 0.17 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (55 mg, 0.17 mmol) were dissolved in 15 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.37 mmol) and (trans) 4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (40 mg, 0.17 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[(trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 37 (25 mg, yield: 23.0%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH:24]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2n1)c1ccc2ccccc2c1

Procedure:
Synthesised according to example 1.59.1 using quinoline-2-carbaldehyde (3.0 g, 19.09 mmol) and 1-(naphthalen-2-yl)ethanone (3.25 g, 19.09 mmol); yellow solid; yield: 4.95 g (84%);
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][CH:6]=1.[SH:7][CH2:8][C:9]([OH:11])=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][C:2]1([S:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][O:3]1
Reactant: CC1=CCCO1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC1(SCC(=O)O)CCCO1

Procedure:
A mixture of 2-methyl-4,5-dihydrofuran and 2-mercaptoacetic acid in THF are treated with a catalytic amount of para-toluene sulfonic acid according to the procedure in Example I.A.2. After removal of the solvent, S-(2-methyl-tetrahydrofuran-2-yl)mercaptoacetic acid is obtained. Alternatively, mercaptosuccinic acid is reacted with 2-methyl-4,5-dihydrofuran and then converted to a mercaptosuccinic anhydride derivative by a dehydrating agent such as dicyclohexyl carbodiimide.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[CH:18]1([N:21]2[C:30]3[C:25](=[C:26](F)[CH:27]=[C:28]([F:31])[CH:29]=3)[C:24](=[O:33])[C:23]([OH:34])=[C:22]2[CH3:35])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([N:21]2[C:30]3[C:25](=[C:26]([NH:12][C:11]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=4[F:9])[CH:27]=[C:28]([F:31])[CH:29]=3)[C:24](=[O:33])[C:23]([OH:34])=[C:22]2[CH3:35])[CH2:20][CH2:19]1
Reactant: Cc1c(O)c(=O)c2c(F)cc(F)cc2n1C1CC1
Reactant: Nc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(O)c(=O)c2c(Nc3ccc(I)cc3F)cc(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.3 %

Procedure:
LDA (2N solution in heptane/tetrahydrofuran/ethylbenzene, 6 mL, and 12 mmol) was added dropwise to a stirred solution of 2-fluoro-4-iodoaniline (2.085 g, 8.8 mmol) in THF (14 mL) at −78° C. After 10 minutes, a solution of example 6c (0.9 g, 3.57 mmol) in THF (30 mL) was then added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 13 h. The solution was cooled to 0° C., quenched with 1N HCl (100 mL), extracted with EtOAc and dried (MgSO4). Purification by silica gel chromatography (10% MeOH/DCM) gave 340 mg (20%) of the title compound as light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.72 (s, 1H), 8.41 (s, 1H), 7.73 (dd, 1H, J=10.4, 1.6 Hz), 7.55 (dd, 1H. J=8.4, 1.6 Hz), 7.49 (t, 1H, J=8.4 Hz), 7.03 (dd, 1H, J=10.4, 1.6 Hz), 6.62 (dd, 1H, J=10.4, 1.6 Hz), 3.32-3.42 (m, 1H), 2.54-2.53 (m, 3H), 1.35-1.42 (m, 2H), 0.84-0.89 (m, 2H). MS (ES) [m+H] calc'd for C19H15F2IN2O2, 469; found 469.
Reaction SMILES: [OH:1][NH:2][C:3]([C@H:5]1[CH2:12][C:9]2([NH:11][CH2:10]2)[CH2:8][CH2:7][C@@H:6]1[C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=[O:4].[O-]S([O-])(=O)=O.[Ba+2]>CO>[OH:1][NH:2][C:3]([C@H:5]1[CH2:12][C:9]2([CH2:7][CH2:8]2)[CH2:10][NH:11][C@@H:6]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=[O:4]
Reactant: CC(C)c1cccc(C2=CCN(C(=O)[C@H]3CCC4(CN4)C[C@@H]3C(=O)NO)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)c1cccc(C2CCN(C(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)NO)CC2)c1

Procedure:
(6S,7S)-N-hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}- -azaspiro[2.5]octane-7-carboxamide (10 mg) was hydrogenated at 1.0 atm over BaSO4 in MeOH for one hour to give the desired product, Ms(ESI): (M+H)+=400.4.
Reaction SMILES: BrC12CC3CC(CC(CC(O)=O)(C3)C1)C2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Br:33][C:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][C:36]([CH2:44][N:45]=[C:46]=[O:47])([CH2:37]3)[CH2:35]1)[CH2:41]2.[F:48][C:49]1[C:50](=[O:56])[NH:51][C:52](=[O:55])[NH:53][CH:54]=1>N1C=CC=CC=1>[Br:33][C:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][C:36]([CH2:44][NH:45][C:46]([N:53]4[CH:54]=[C:49]([F:48])[C:50](=[O:56])[NH:51][C:52]4=[O:55])=[O:47])([CH2:37]3)[CH2:35]1)[CH2:41]2
Reactant: O=C=NCC12CC3CC(CC(Br)(C3)C1)C2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C(O)CC12CC3CC(CC(Br)(C3)C1)C2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCC12CC3CC(CC(Br)(C3)C1)C2)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 3-bromoadamantan-1-ylacetic acid and diphenyl phosphoryl azide in dry pyridine provided a solution comprising 3-bromoadamantan-1-ylmethyl isocyanate [I.R.: 2270 cm-1 ], which was reacted with 5-fluorouracil to provide 1-[N-(3-bromoadamantan-1-ylmethyl)carbamoyl]-5-fluorouracil substantially by the similar method to that of Example 45.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[F:39][C:40]1([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[F:39][C:40]1([F:46])[CH2:45][CH2:44][N:43]([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=4)/[N:13]([C@H:14]4[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]4)[C:12]=3[CH:26]=2)[CH2:42][CH2:41]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(F)(F)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed, and the residue was resuspended in 2 mL DMSO, cooled to 0° C., and 4,4-difluoropiperidine hydrochloride (348 mg, 2.210 mmol) and TEA (0.308 mL, 2.210 mmol) were added. The reaction was stirred for 30 minutes at 0° C. and then at RT for 16 hours. The reaction was concentrated, and the residue was purified by reverse-phase preparative HPLC, using 0.1% TFA in AC/water (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((4,4-difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (71 mg, 57.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H), 1.54-1.83 (m, 5H), 1.94-2.18 (m, 7H), 2.53 (br. s., 3H), 2.67-2.86 (m, 2H), 3.64 (s, 2H), 3.94-4.09 (m, 1H), 4.91 (br. s., 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.60-7.82 (m, 2H), 8.20-8.43 (m, 2H), 12.75 (br. s., 1H). MS, m/z (C30H36F3N5O2): calcd, 555.3. found, 555.9 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH:13][CH2:12][C:11]([F:17])([F:16])[F:10])=[S:15])[CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cccc(CO)c1
Solvent: CC(C)=O
Product: OCc1cccc(NC(=S)NCC(F)(F)F)c1

Procedure:
m-Aminobenzyl alcohol (0.123 g.) and 2,2,2-trifluoroethylisothiocyanate (0.141 g.) were heated under reflux in acetone (5 ml.) for 2 hours. Volatile material was evaporated in vacuo and the crude residue was fractionated on a silica gel column (20 cm.×1 cm. diameter) eluted with ethyl acetate to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)thiourea. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard (δ=0) had the following resonances (δ): 7.2 (4H, multiplet); 4.6 (2H, singlet); 4.3 (2H, multiplet).