Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[C:22]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[S:11][C:12]=2[CH:18]=1)(=[O:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccc(O)cc3s2)cc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Under N2, 24 (4.0 mmol) was dissolved in THF (100 ml) and, at 0° C., NaH (8.2 mmol) was slowly added. The mixture was stirred for 30 min at 0° C. and acetyl chloride (6.0 mmol) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The reaction was hydrolyzed and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 7:3 hexane/ethyl acetate as the eluent to yield 1.24 g (74%) of 25 as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][C:17]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[OH:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:17]1([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC1(CC(NC(=O)OCc2ccccc2)C(=O)O)CCCCC1
Agent: B
Solvent: C1CCOC1
Product: CC1(CC(CO)NC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A mixture of 0.510 g (1.60 mmol) of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoic acid, 5 mL of THF, and 10 mL of 1.0 M BH3.THF in THF was stirred at 0° C. for 2 h. The mixture was allowed to warm to rt for 16 h. The reaction mixture was then cooled with an ice bath and quenched with 20 mL of MeOH and 2 mL of HOAc. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC to afford 0.3655 g (75%) of benzyl 1-hydroxy-3-(1-methylcyclohexyl)propan-2-ylcarbamate. MS ESI +ve m/z 328 (M+Na).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)[CH2:13][C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.[NH2:47][C:48]1[CH:49]=[CH:50][C:51]2[O:55][C:54](=[O:56])[NH:53][C:52]=2[CH:57]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:11]=[C:12]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]1)[CH2:13][C:14]([NH:47][C:48]1[CH:49]=[CH:50][C:51]2[O:55][C:54](=[O:56])[NH:53][C:52]=2[CH:57]=1)=[O:15]
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc2oc(=O)[nH]c2c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
HOBt (72 mg, 0.53 mmol) and DMAP (81 mg, 0.66 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (150 mg, 0.44 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (102 mg, 0.53 mmol) followed by 5-amino-3H-benzooxazol-2-one (66 mg, 0.44 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (90% ethyl acetate in hexane) to afford 65 mg (32%) of 3-oxo-N-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 477.12 (M+1)+, 96.35%, 1H NMR: (DMSO-d6): δ 11.6 (s, 1H), 10.2 (d, 1H), 7.8 (q, 2H), 7.6 (m, 3H), 7.22 (m, 1H), 7.08 (t, 1H), 3.74 (m, 1H), 3.6 (s, 2H), 3.52 (s, 1H), 3.32 (s, 1H), 3.16 (m. 1H), 3.8 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11]([N:13]([CH3:25])[C@@H:14]([C:22](O)=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OC(=O)N(C)[C@@H](C(=O)N(C)[C@@H](C(=O)NCC1CCCO1)CC1C=CC=CC=1)CC1C2C(=CC=CC=2)C=CC=1)(C)(C)C.S([O-])(O)(=O)=O.[Na+]>[C:6]([O:10][C:11](=[O:12])[N:13]([C@@H:14]([C:22](=[O:23])[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25])([CH3:7])([CH3:9])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.6 %

Procedure:
3-Aminopropan-1-ol (0.39 mL, 5.12 mmol) was added at room temperature to a solution of N-tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.30 g, 4.65 mmol) in N,N-dimethylformamide (40 mL). 1-Hydroxybenzotriazole monohydrate (0.63 g, 4.65 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g, 4.65 mmol) were added successively. The reaction mixture was stirred for 22 h at room temperature. It was diluted with 1 0% sodium hydrogensulfate solution (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica (45 g) with dichloromethane/methanol (10:1) to give 1.01 g of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2phenylethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[NH2:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([C:49](=O)[CH2:50][CH2:51][CH:52]=O)[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=[CH:33][CH:32]=1.[BH3-]C#N.[Na+].[OH-].[K+]>C(O)(=O)C.CO>[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:38]=[C:39]([CH:49]3[CH2:50][CH2:51][CH2:52][N:29]3[CH:24]3[C:25]4[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:22][CH2:23]3)[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2nc(C(=O)CCC=O)oc2-c2ccc(C)cc2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2N)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2nc(C3CCCN3C3CCCc4c(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cccc43)oc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxy-1-naphthaleneamine (0.21 g), 1-[4,5-bis(4-methylphenyl)oxazol-2-yl)butan-1,4-dione (0.12 g), NaBH3CN (84 mg) and KOH (30 mg) in acetic acid (0.5 ml) and methanol (4 ml). After being stirred for 3 days at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-[4,5-bis(4-methylphenyl)oxazol-2-yl]pyrrolidin-1-yl]-1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxynaphthalene (0.24 g).
Reaction SMILES: Cl.[CH:2]1([CH:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[N:17]3)=[C:11]([CH3:25])[CH:10]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1>CN(C)C=O.O>[CH:2]1([CH:7]([NH:8][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=2)[C:9]2[CH:10]=[C:11]([CH3:25])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[N:17]3)=[C:13]([CH3:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: Cc1cc(C(N)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a mixture of (+/−)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride (1.002 g, 2.680 mmol) and potassium carbonate (1.51 g, 10.7 mmol) in N,N-dimethylformamide (5.36 mL) was added methyl 6-fluoronicotinate (472 mg, 2.95 mmol). The reaction was heated to 85° C. After 15 h, the reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) gave methyl (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 8.67 (d, J=1.6 Hz, 1H), 7.99 (dd, J=9.0, 2.0 Hz, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.12 (s, 2H), 6.28 (d, J=9.0 Hz, 1H), 4.43-4.33 (m, 1H), 3.87 (s, 3H), 2.36-2.23 (m, 1H), 2.04-1.97 (m, 7H), 1.77-1.41 (m, 6H), 1.37-1.28 (m, 1H). MS (M+1): 473.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH2:13]([CH:15]1[O:20][CH2:19][CH2:18][NH:17][CH2:16]1)[CH3:14]>>[CH2:13]([CH:15]1[CH2:16][N:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:18][CH2:19][O:20]1)[CH3:14]
Reactant: CCC1CNCCO1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: CCC1CN(c2n[nH]c(=O)c3ccccc23)CCO1

Procedure:
4-chlorophthalazin-1(2H)-one and 2-ethylmorpholine were processed using a method similar to that described in Example 1A to afford the title compound. MS (APCI+) M/Z 260 (M+H)+.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[NH2:12].OS(O)(=O)=O.[CH3:18]O>>[NH2:12][C:3]1[C:4]([CH3:11])=[C:5]([CH:9]=[CH:10][CH:2]=1)[C:6]([O:8][CH3:18])=[O:7]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(C)c1N
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1C
Temperature: 70 °C
Yield: 91 %

Procedure:
To stirred solution of methyl 3-amino-2-methylbenzoic acid (5 g, 33.1 mmol) in methanol (50 mL), was added conc. H2SO4 (5 mL) at 0° C. and the mixture was heated at 70° C. for 22 h. On completion, methanol was removed under reduced pressure, and then sat. sodium bicarbonate solution was added and the product extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to yield methyl 3-amino-2-methylbenzoate (5 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH:12]=[CH:13]Cl)=[O:11].Cl.[NH2:16]O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][N:16]=[CH:13][CH:12]=1
Reactant: NO
Reactant: O=C(C=CCl)c1cc(F)c(Cl)cc1Cl
Agent: Cl
Solvent: CO
Product: Fc1cc(-c2ccno2)c(Cl)cc1Cl

Procedure:
A mixture of 57.6 g of 2-chlorovinyl 2,4-dichloro-5-fluoro-phenyl ketone, 16.4 g of hydroxylamine hydrochloride and 150 ml of methanol is heated at the boiling point under reflux for 6 hours, a precipitate separating out after about one hour. This is filtered off cold with suction, washed with a little methanol and dried at 50° C. in vacuo. 33.3 g (63.2%) of 5-(2,4-dichloro-5-fluoro-phenyl)-isoxazole of melting point 112°-113° C., which according to investigations by NMR spectroscopy, contains about 6 mole % of an isomer, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)NCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 17.9 %

Procedure:
Ethyl 4-chlorobenzylcarbamate (865.9 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (996.7 mg) were dissolved in tetrahydrofuran (15 ml), and to the solution was added sodium hydride (162.1 mg). The reaction mixture was heated at reflux for 3 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer-was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=10:1) to give the title compound (294.7 mg, 18%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][N:34]([CH3:36])[CH3:35])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][N:34]([CH3:36])[CH3:35])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CN(C)Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Solvent: O
Product: CN(C)Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 65.9 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 70 mg (0.14 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-dimethylaminomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 30-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture to precipitate a solid, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 36 mg of the title compound as a gray solid. (Yield: 68%)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=O)[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:23].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(Cc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 195.2 %

Procedure:
A mixture of 1-benzyl-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.3 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml) and ethanol (20 ml) was refluxed for 18 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 1-benzyl-6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 149) (0.37 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+:12].[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14].[C:20](=O)(O)[O-].[K+]>O>[CH:5](=[O:6])[C:7]1[CH:20]=[CH:9][C:8]([OH:11])=[C:13]([OH:15])[CH:14]=1.[NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+:12].[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]
Reactant: O=C([O-])O
Agent: CC(=O)[O-]
Agent: O=C1CNC(=O)N1
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1ccc(O)c(O)c1

Procedure:
Similarly, the other acylated-5-(substituted benzal) hydantoins can be prepared by heating the appropriately substituted benzaldehyde and an anhydrous alkali metal alkanoate together with hydantoin and the corresponding acid anhydride. The reaction is generally conducted at an elevated temperature until the reaction is substantially complete. For example, in the reaction of benzaldehydes with hydantoin in the presence of anhydrous sodium acetate and acetic anhydride, the reaction is generally carried out at about 125°-140° C. it has also been found that potassium bicarbonate can be used in place of the anhydrous alkali metal alkanoate with similar results being obtained. After the condensation is complete, the reaction mixture is cooled, usually overnight, treated with water and then refrigerated for several hours. The crystalline product is then filtered, washed with water and dried. The major portion of the product appears to be the mono-acylated compound, together with small amounts of di-acylated compound. Where the aromatic aldehyde starting material contains phenolic hydroxylic groups, it has been found that these are acylated under the conditions of the reaction. Thus protocatechualdehyde, hydantoin, anhydrous sodium acetate, and acetic anhydride gave acetylated 5-(3',4'-diacetoxybenzal) hydantoin.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH:9]=[O:10])=[CH:3][CH:2]=1.[CH2:12]([Mg]Br)[CH:13]=[CH2:14]>C1COCC1>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([C:7]#[C:8][CH:9]([OH:10])[CH2:14][CH:13]=[CH2:12])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C#CC=O)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc(C)cc1
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 3-p-tolylprop-2-yn-1-al (4.69 g; 32.5 mmol; 1 eq) in THF (40 mL) was added to a solution of allylmagnesium bromide (49 mL; 1M in Et20, 1.5 eq) at 0° C. over 25 minutes. Stirring was continued for an additional 2 h, and the reaction was carefully quenched with water (50 mL) at 0° C. MTBE (100 mL) was added, the layers were stirred, and then allowed to separate. The aqueous phase was re-extracted with MTBE (50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated using a rotary evaporator, and purification of the residue by flash chromatography (4:1→2:1 heptane/EtOAc) afforded the desired homoallylic alcohol (4.9 g; 26.3 mmol; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 ((s, 3 H)) 2.56 (t, 2 H) 4.64 (t, 1H) 5.19-5.26 (m, 2H) 5.88-5.99 (m, 1H) 7.10 (d, 2H) 7.31 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH2:14])[CH:6]=[CH:7][CH:8]=1.CN1[CH:23]=[CH:22][C:21](=[O:24])N(C)C1=O.[O-]CC.[Na+]>C(O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][N:12]3[CH:23]=[CH:22][C:21](=[O:24])[NH:14][C:13]=23)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1[nH]ncc1-c1cccc(C(F)(F)F)c1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccn2ncc(-c3cccc(C(F)(F)F)c3)c2[nH]1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a mixture of 4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (2.7 g, 11.88 mmol) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.999 g, 14.26 mmol) in ethanol (35 ml) was added sodium ethoxide (1.132 g, 16.64 mmol). After heating to reflux 16 hours under Agonr, the reaction was cooled to RT and the volatiles removed in vacuo. The mixture was diluted with 30 mL H2O and acidified to pH=4 with AcOH. The resulting solid was collected by vacuum filtration. The solid was taken up in a 4:1 DCM/2-propanol solution, washed with water, dried over Na2SO4, and rotovaced to give pure 3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (2.07 g, 7.41 mmol, 62.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:14]#[CH:13]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2ccc(=O)oc2c1
Yield: 60 %

Procedure:
In 100 ml DMF at 70° C. for 12 hours, 0.1 mole 7-hydroxy-coumarin is reacted with 0.1 mole propargyl bromide in the presence of 0.1 mole potassium carbonate. The compound of the title is obtained at a 60% yield. This compound melts at 118° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[N:19](COC)[C:18]=3[CH:27]=2)[CH2:9]1)(C)(C)C.[Cl-].[Li+].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CO>[NH2:7][C@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:27]=2)[C:11](=[O:13])[CH2:12]1
Reactant: COCN1C(=O)COc2ccc(N3C[C@H](NC(=O)OC(C)(C)C)CC3=O)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CO
Product: N[C@@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A solution of {(3R)-1-[4-(methoxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-5-oxopyrrolidin-3-yl}carbamic acid tert-butyl ester (120 mg, 0.31 mmol) in methanol (2 ml) was cooled in an ice bath. Lithium chloride (80 mg, 0.92 mmol) and concentrated sulfuric acid (0.5 ml) were added thereto, and the mixture was then stirred at 80° C. for 2 hours. After cooling, the reaction solution was neutralized with a saturated sodium hydrogen carbonate aqueous solution and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol) to yield 58 mg (75%) of the title compound in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(C)c4)c3)c2cc1OC
Yield: 85 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate from the previous step (115 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (145 mg, 0.26 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.48-7.16 (m, 9H), 6.36 (s, 1H), 3.99 (s, 6H), 2.38 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][C:12](=[O:14])[CH3:13])[CH:3]=1.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([O:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)O
Product: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Reaction time: 8 h

Procedure:
4-Methyl-2-acetoxy-benzoic acid (18 g.) was dissolved in thionyl chloride (200 ml.), and the solution was left to stand overnight at room temperature. Removal of excess thionyl chloride by suction gave a paste of crude 4-methyl-2-acetoxy-benzoyl chloride which was dissolved in acetone (200 ml.).