Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[C:44]([OH:46])=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)CC)C.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>C(#N)C>[C:57]([O:56][C:54]([N:61]1[CH2:66][CH2:65][N:64]([C:44]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][N:38]2[C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[O:46])[CH2:63][CH2:62]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: O=C(O)C1CCCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2C(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
26.6 g of BOP, 13.6 g of 1-(carbobenzyloxy)-2-piperidinecarboxylic acid and then 11.9 ml of triethylamine are added, at 0° C., to a solution of 8 g of 1-Boc-piperazine in 80 ml of acetonitrile. The medium is stirred at AT for 12 hours and then concentrated. The medium is taken up in EtOAc, and washed three times with a saturated Na2CO3 solution and then with a saturated NaCl solution. After drying over MgSO4 and evaporation, 35.45 g of reaction crude are recovered. It is taken up in DCM and then washed twice with 5M sodium hydroxide, and with a saturated NaCl solution, and then dried over MgSO4. After evaporation, the solid is triturated in TBME, filtered, rinsed with TBME, and then dried, to give 17.93 g of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[OH:39].[F-].[Cs+]>COCCOC.CO>[OH:39][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=4[NH:7][C:6]=3[CH:21]=2)=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccc(O)c(OC)c3)cc1N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A mixture of Example 1B (92 mg, 0.3 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (112 mg, 0.45 mmol), Pd(PCy3)2Cl2 (11 mg, 0.015 mmol), and CsF (144 mg, 0.9 mmol) in DME (20 mL) and methanol (10 mL) was heated to reflux for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 95 mg (81%) of the desired product. MS (DCI) m/e 391 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.26 (s, 1H), 8.36 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.1, 1.9 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.17-7.19 (m, 2H), 7.06-7.09 (m, 2H), 6.87 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Mg].[CH:2](Br)([CH3:4])[CH3:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#N.Cl.CC[O:18]CC>O1CCCC1>[CH:2]([C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH2:6])=[O:18])([CH3:4])[CH3:3]
Reactant: CCOCC
Reactant: N#Cc1ccccc1N
Reactant: CC(C)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1ccccc1N
Reaction time: 1 h

Procedure:
To a suspension of magnesium turnings (7.53 g) in dry ether (100 ml) was added dropwise a solution of isopropyl bromide (36.87 g) in dry ether (50 ml) at reflux temperature for 1 hour. The mixture was heated at the same temperature for 1 hour and then allowed to cool to 5˜10° C. in an ice bath. To the mixture was added dropwise a solution of 2-aminobenzonitrile (11.81 g) in dry tetrahydrofuran (100 ml) at the same temperature for 1 hour. The mixture was stirred additionally 1 hour and then heated under reflux for 3 hours. The reaction mixture was allowed to cool to 5˜10° C. in an ice bath. A 3N aqueous hydrochloric acid was added dropwise to the mixture for 1 hour and then heated under reflux for 3 hours. The resultant mixture was concentrated in vacuo to remove the organic solvent. The residue was extracted with chloroform (2×300 ml). The extracts were combined and washed with a brine (2×100 ml). Dryness over magnesium sulfate and evaporation gave a crude product. The product was purified by column chromatography on silica gel with chloroform. The fractions containing the desired product were combined and evaporated in vacuo to afford a pure 2-isopropylcarbonylaniline (15.35 g) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH:20]([CH3:22])[CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Cl[C:33]1[S:34][C:35]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:36]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=1>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:33]3[S:34][C:35]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:36]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=3)[CH2:15][C@H:14]2[O:19][CH:20]([CH3:21])[CH3:22])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC(C)C)nc1Cl
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)NCCOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC(C)C)C2)nc1C(=O)NCCOC
Yield: 73.8 %

Procedure:
The same operation as in Example (1h) was performed using cis(±)-4-chloro-N-(3-isopropoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (148a) (0.150 g, 0.427 mmol), diisopropylethylamine (0.186 mL, 1.07 mmol) and ethyl 2-chloro-4-[(2-methoxyethyl)carbamoyl]-1,3-thiazole-5-carboxylate obtained in Example (149a) (0.167 g, 0.572 mmol), to obtain 0.180 g of the title compound as a yellow solid (74%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4](Cl)[CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[K+]>CS(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:20]2[CH:21]=[CH:22][C:17](=[O:16])[CH:18]=[CH:19]2)[CH:3]=1
Reactant: Oc1ccncc1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 90.1 %

Procedure:
First, a mixture containing 2.40 g of 4-amino-2-chloro-5-nitrobenzotrifluoride, 2.0 g of 4-hydroxypyridine, 684 mg of 86% potassium hydroxide, 15 ml of dimethylsulfoxide was heated in an oil bath at 70° C. for 2 hours. The mixture was cooled and ice water was added to the mixture. Precipitated crude crystals were filtered and recrystallized with methanol/ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[C:14]([O:29][C@H:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:31][C:32](O)=[O:33])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(Cl)CCl.CI>C(Cl)Cl>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][C:32](=[O:33])[CH2:31][C@H:30]([O:29][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CI
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A solution of (R)-2-amino-3-benzyloxy-1-propanol (0.46 g, 2.33 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (1.29 g, 2.83 mmol) in CH2Cl2 (20 mL) was treated with EDC·MeI (0.78 g, 2.79 mmol) and stirred for 16 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and concentrated. Flash chromatography on silica gel with 45% EtOAc-hexanes afforded 1.1 g (69%) of 3-benzyloxy-(R)-2-[(R)-3-tetradecanoyloxytetradecanoylamino]propanol as a colorless solid: mp 42-44.5° C.; 1H NMR δ 0.88 (t, 6H, J=6.5 Hz), 1.0-1.7 (m, 42 H), 2.50 (t, 2H, J=7.5 Hz), 2.46 (m, 2H), 3.56 (br s, 1H), 3.5-3.75 (m, 3H), 3.78 (dd, 1H, J=11, 4 Hz), 4.08 (m, 1H), 4.51 (s, 2H), 5.17 (m, 1H), 6.36 (d, 1H, J=7.8 Hz), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:7][Si](C)(C)C)[CH2:6][CH2:5]1)[CH3:2]>CO.Cl>[CH2:1]([O:3][C:4]1([OH:7])[CH2:6][CH2:5]1)[CH3:2].[CH3:1][O:3][C:4]1([OH:7])[CH2:6][CH2:5]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCOC1(O)CC1
Product: COC1(O)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
A solution of (1-ethoxycyclopropyl)oxy-trimethylsilane (25 ml, 124.9 mmol) in methanol (60 ml) was treated with conc. HCl (3 drops), stirred at 20° C. for 16 h, concentrated at 20° C., and the residue distilled (55° C., 19-20 mbar) to give 1-ethoxycyclopropanol/1-methoxycyclopropanol (92:8, 10.36 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:19](C(O)=O)[C:20]([OH:22])=[O:21])[CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1
Reactant: COc1cccc(COc2ccc(C(C=C(C)C)C(C(=O)O)C(=O)O)cc2)c1
Solvent: Cc1ccccc1
Product: COc1cccc(COc2ccc(C(C=C(C)C)CC(=O)O)cc2)c1
Yield: 64.7 %

Procedure:
A suspension of compound 33.3 (0.136 mmol) in toluene was refluxed for 16 h. After removing the solvent, the residue was purified using silica gel column chromatography (TFA/Dichloromethane/ethyl acetate=Jan. 5, 1940) to give compound 33 as a white solid (0.088 mmol). MS ESI m/e: 339 (M−H) 1H NMR (500 MHz) (DMSO-d6) δ 11.97 (1H, s); 7.31 (1H, t, J=10 Hz); 7.14 (2H, d, J=11 Hz); 6.99 (2H, m); 6.87 (3H, m); 5.22 (1H, m); 5.03 (2H, s); 3.75 (1H, m); 3.75 (3H, s); 2.44-2.53 (2H, m); 1.63 (3H, s); 1.62 (3H, s).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[CH:4][N:3]=[N:2]1.[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:5]4[S:1][N:2]=[N:3][CH:4]=4)=[O:14])[CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cnns1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnns1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 68.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1,2,3-thiadiazol-5-ylcarbamate (190 mg, 0.686 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (153 mg, 0.624 mmol) and diisopropylethylamine (0.217 ml, 1.25 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 159 mg (68.4%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([O:22][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])[CH2:28][CH2:29]1)=[O:26]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(O)C1
Reactant: CN(C)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)OC1CN(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (38.9 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under a nitrogen atmosphere, and N,N-dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added at room temperature, followed by stirring overnight. N,N-Dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added again at room temperature, and the reaction mixture was stirred for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added tert-butyl methyl ether (1 ml)-heptane (2 ml) to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.1 mg, 47%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[C:12]1=[S:27].[OH-].[Na+]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[C:12]1=[S:27]
Reactant: COC(=O)c1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1

Procedure:
substituting methyl 4-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl]benzoate and sodium hydroxide gave 4-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl]benzoic acid, m.p. 211°-212° C.;
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.O>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CSCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of ethyl 2-mercaptoacetate (0.593 mL, 5.25 mmol) in THF (10 ml) was added to a suspension of NaH (60% dispersion in mineral oil, 204 mg, 5.10 mmol) in THF (20 ml) at room temperature, followed by the addition of a solution of 2-((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (intermediate 212, 1.71 g, 4.61 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature for approximately 20 h and diluted with ethyl acetate and water. Layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried using MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with a gradient of EtOAc (0-40%) in hexane. Fractions containing the product were combined and evaporated to yield the title compound as colorless oil. (UPLC-MS 3) ESI-MS 264.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.93 (br s, 1H), 4.25-4.14 (m, 2H), 3.39-3.30 (m, 2H), 3.23 (s, 2H), 2.77 (t, 2H), 1.44 (s, 9H), 1.35-1.21 (t, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[C:14]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1nn(-c2ccccc2)c2ccccc12
Temperature: 30 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a mixture of methyl 1H-indazole-3-carboxylate (3.44 g), phenylboronic acid (4.76 g), pyridine (2.84 mL) and N,N-dimethylformamide (70 mL) was added copper (II) acetate (5.32 g), and the mixture was stirred at 30° C. overnight. The insoluble material was filtered off, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.58 g, 32%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:16](=[O:17])[C:15]3[CH:18]=[C:19]([CH2:21][CH3:22])[S:20][C:14]=3[NH:13][C:12]2=[O:23])[N:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[N:42]=[C:41](C(Cl)(Cl)Cl)[O:40][N:39]=2)=[CH:28][CH:27]=1.C(=O)([O-])[O-:48].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:11]2[C:16](=[O:17])[C:15]3[CH:18]=[C:19]([CH2:21][CH3:22])[S:20][C:14]=3[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:42][C:41](=[O:48])[O:40][N:39]=4)=[CH:28][CH:27]=3)[C:12]2=[O:23])[N:6]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(-c3nc(OC)cc(OC)n3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(-c3nc(OC)cc(OC)n3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
A mixture of 3-(4,6-dimethoxypyrimidin-2-yl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.24 g), potassium carbonate (0.25 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 31%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH:27]([C:29]1[N:30]([CH3:42])[CH:31]=[C:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[N:33]=1)=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:27]([C:29]3[N:30]([CH3:42])[CH:31]=[C:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[N:33]=3)=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1csc2ccccc12
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(NC(=O)OC(C)(C)C)cn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by tert-butyl 2-formyl-1-methyl-1H-imidazol-4-ylcarbamate.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].N1C=CC=CC=1.[CH3:25][C:26]([CH3:34])([CH3:33])[C:27]([NH:29][C:30]([NH2:32])=[S:31])=[O:28]>O.C(O)C>[CH3:25][C:26]([CH3:34])([CH3:33])[C:27]([NH:29][C:30]1[S:31][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:32]=1)=[O:28]
Reactant: CC(C)(C)C(=O)NC(N)=S
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 88 %

Procedure:
A 500 ml reaction flask fitted with a magnetic stirrer, heating mantle, thermometer and water-cooled condenser was charged with 44.7 g (0.138 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide, 350 ml of absolute ethanol and 15 g (0.19 mole) of pyridine. A 26 g sample (0.162 mole) of N-trimethylacetylthiourea [m.p. 140°-42°; prepared as described by Moore and Crossley in The Journal of the American Chemical Society, vol. 62, p. 3273 (1940)] was added to the reaction solution. As the substituted thiourea dissolved, the reaction temperature increased from 24° to 31°. The solution was refluxed for four hours and poured into 1.5 liters of water. With stirring, the residual oil crystallized. The product was collected and washed with water. There was obtained 46.8 g (88%) of white solid, m.p. 147°-52°. One recrystallization from ethyl acetate-heptane yielded material which melted at 153°-55°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.3 (tert-butyl), 3.8 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C@@H:24]1[O:29][CH2:28][C@@H:27]([OH:30])[CH2:26][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]([CH:24]1[O:29][CH2:28][C:27](=[O:30])[CH2:26][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: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCC(C(c2ccccc2)c2ccccc2)OC1
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Into a solution of DMSO (0.13 g, 1.64 mmol) in methylene chloride (5 ml) at −78° C. was added a solution of oxalyl chloride (0.11 g, 0.82 mmol) in methylene chloride (1 ml) in a dropwise manner A solution of trans-2-diphenylmethyl-tetrahydropyran-5-ol 11 (0.2 g, 0.75 mmol) in methylene chloride (2 ml) was added next. The reaction was continued for 15 minutes, triethylamine (0.38 g, 3.73 mmol) was next added portion wise and the reaction mixture was allowed to come to room temperature for over a period of 30 minutes. Additional methylene chloride (10 ml) was added, and washed with sat. aqueous NaHCO3, brine, and then dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (SiO2, Hexane/Ethyl Acetate 8.5:1.5) gave 2-diphenylmethyl-dihydro-pyran-5-one 12 (0.18 g, 91%) as a liquid.