Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of 1-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 615 μmol) in CH2Cl2 (2.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (85.8 μL, 739 μmol). The reaction was stirred 3 h and then directly purified by reverse phase HPLC to give the title compound as a white solid. MS (ESI pos. ion) m/z: 381 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=S)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:2].CNC(=N)S.[OH:21]S(O)(=O)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CC(=S)c1ccc(C)cc1
Agent: CNC(=N)S
Product: CCOC(=O)CC(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl(4-methylthiobenzoyl)acetate (16.447 g, 69 mmol) (obtained in preparation 3) and methylthiopseudourea.H2SO4 (10.56 g, 38 mmol) according to the procedure described in preparation 4, (1.82 g, 11.5%, mp 266–267° C.). 1H-NMR (DMSO-d6): δ 2.53 (s, 3H), 6.48 (s, 1H), 7.37–7.39 (d, 2H), 7.79–7.81 (d, 2H), 7.92 (bs, 2H). MS m/z: 235 (M+). Preparation 7 Synthesis of 6-(4-methylphenyl)-2H-3,4-dihydro-1,3-oxazin-2,4-dione
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C3CCCCC3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO.O>[CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(OC2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclohexyl 6-(cyclohexyloxy)pyrimidine-4-carboxylate (2.00 g; 6.57 mmol) in THF/EtOH/H2O (3/2/1, total volume 200 mL) was treated with a 5N solution of sodium hydroxide (3.94 ml; 19.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and then water was added. The aqueous layer was washed with DCM then acidified to pH 5 by addition of 1N HCl solution. The aqueous layer was washed with EtOAc (150 mL), then lyophilized and the obtained solid was washed with DCM. The suspension was filtered off and the filtrate was concentrated under vacuum to afford the title compound as a beige solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:35]N(C=O)C.CI>>[CH3:35][O:12][CH2:11][CH2:10][CH:9]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0° C. The reaction was stirred for 20 min and methyl iodide (22 μL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 88%) as a semisolid. ni/z=464 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([OH:12])[C:6]1=[S:13])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.CN([CH:29]=[O:30])C>>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[O:12][C:7]1[C:6](=[S:13])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[O:30][CH3:29]
Reactant: CCCCn1ccc(C)c(O)c1=S
Reactant: CN(C)C=O
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Product: CCCCn1ccc(OC)c(Oc2nc3ccccc3o2)c1=S
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 1-butyl-3-hydroxy-4-methylpyridine-2-thione (2-034-06) (50 mg) in DMF (1.0 mL) was added sodium hydride (60% wt, 15 mg) at room temperature. After the reaction mixture was stirred for 20 min, to the reaction mixture was added 2-chlorobenzoxazole (85 mg), and the reaction mixture was stirred at 75° C. for 17 h. After the reaction was quenched with water, the solvent was evaporated. To the residue were added aqueous saturated ammonium chloride solution and ethyl acetate, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography (toluene/acetone=4/1) to give 3-(benzoxazol-2-yloxy)-1-butyl-4-methoxypyridine-2-thione (2-034) (73 mg, 92%) as a yellow crystal. The obtained crystal was purified by recrystallization from methylene chloride and diethyl ether.
Reaction SMILES: [OH:1][CH:2]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([CH3:35])[CH:19]=2)=[CH:16][N:17]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].C1COCC1.Cl>CO.C(Cl)(Cl)Cl>[OH:1][CH:2]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([CH3:35])[CH:19]=2)=[CH:16][N:17]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCC(C(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C3CCC(C(=O)O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-{hydroxyl[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2 yl]methyl}cyclohexanecarboxylate in methanol (1.96 mL) was added 1N NaOH (0.79 mL, 0.79 mmol) and the mixture was stirred at room temperature for 16 h. THF (1.96 mL) was added and the mixture was stirred at 60° C. for 6 h, then cooled to room temperature and added HCl (1M in H2O) until the pH=3. The mixture was diluted with 3:1 CHCl3:isopropanol and the organic layers were separated, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford 4-{hydroxy[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic acid as a white solid. The cis and trans isomers were separated by supercritical fluid chromatography (chiral OJ column, 1:3 methanol/CO2 with an 11 minute run time). Characterization data for the cis isomer (Rt=5.15 min): MS ESI calc'd. for C23H24F3N4O3S [M+H]+ 493. found 493. 1H NMR (500 MHz, CD3OD) δ 8.69 (d, J=4.8, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H), 7.10 (s, 1H), 4.68 (d, J=5.1, 1H), 3.34 (s, 1H), 2.36 (s, 3H), 2.20 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.70 (m, 1H), 1.50-1.18 (m, 3H). Second eluting enantiomer Rt=8.26 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(O)(=O)C.[N+:19]([O-])([O-:21])=[O:20].[K+].OS(O)(=O)=O>O>[OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14]
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(ccc(O)c2[N+](=O)[O-])O1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 250 mL round bottom flask equipped with a magnetic stir bar was added 3 (810 mg, 4.2 mmol) and 15 mL of glacial acetic acid. The mixture was stirred at room temperature until all of the solid dissolved. To a 25 mL vial was added KNO3 (469 mg, 4.6 mmol) and just enough distilled water to dissolve all the KNO3. The aqueous KNO3 solution was transferred to the reaction flask with a pipet. The reaction flask was lowered into an ice water bath (˜10° C.). Concentrated H2SO4 (1 mL) was added drop-wise. The mixture was stirred until all starting material was consumed, as monitored by TLC analysis. Ethyl acetate (20 mL) was added, and the biphasic mixture was transferred into a 500 mL separatory funnel. Saturated aqueous Na2CO3 was added cautiously until the aqueous layer was pH˜7. The aqueous phase was extracted in ethyl acetate (3×20 mL), the combined organic phases were washed with brine (1×50 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 25:1 CH2Cl/EtOAc as eluent (Rf=0.3). The product gives off a red color on an analytical silica gel plate illuminated with a shortwave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 715 mg (72%) of 4 as a yellow solid. 1H NMR (300 MHZ, CDCl3): δ 7.70 (bs, 1H), 7.21 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 2.76 (s, 2H), 1.46 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 188.9, 154.4, 145.0, 126.4, 124.7(2), 113.1, 80.6, 49.0, 26.4; HRMS (EI+): calculated for C11H11NO5[M+] m/z 237.0637, found 237.0633.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([O:31][CH3:32])[CH:23]=1.[CH3:33][PH:34](=[O:36])[CH3:35]>CCCCCC.C(O)(C)C>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:34]([CH3:35])([CH3:33])=[O:36])=[CH:23][C:24]=2[O:31][CH3:32])[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: COc1cc(Br)ccc1B(O)O
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1cc(P(C)(C)=O)ccc1-c1cnc(N)c(O[C@H](C)c2c(Cl)ccc(F)c2Cl)c1

Procedure:
The title compound was prepared from 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo2-methoxy-phenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 483 (M+H)+; chiral purity 99.82% (column AD-H 4.6*250 mm 5 um; solvent:hexane/isopropanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.N1C=CC=CC=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>CO>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: CO
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.2 %

Procedure:
To a mixture of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.00 g) and pyridine (30 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction methanol (98:2-95:5, volume ratio) to give the title compound (250 mg, yield 27%) as orange crystals.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCCl>[ClH:1].[CH2:26]([O:25][CH:23]1[CH2:24][NH:21][CH2:22]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: CCCCOC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
1-Chloroethyl chloroformate (180 μL, 1.6 mmol) was added to a solution of 1-benzhydryl-3-butoxyazetidine (370 mg, 1.2 mmol) in 1,2-dichloroethane (6 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 1.5 hours. After cooling down to room temperature, methanol (7 mL) was added. The reaction mixture was again heated up to 70° C. and stirred for an additional 1.5 hours. After concentration to dryness, the crude mixture was triturated in pentane (2×5 mL) to give a yellow oil (179 mg, 86%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29](B5OC(C)(C)C(C)(C)O5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:8]5[CH2:13][CH2:12][O:11][CH2:10][CH2:9]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)[N:3]=[CH:4]1
Reactant: Cn1cnc(Br)c1
Reactant: CC1(C)OB(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)OC1(C)C
Product: Cn1cnc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1

Procedure:
[7-(1-Methyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 4-bromo-1-methyl-1H-imidazole and (4-morpholin-4-yl-phenyl)-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow foam (7 mg, 7%). LCMS (m/e) 376 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 7.92 (d, 1H, J=1.2 Hz), 7.55 (d, 2H, J=8.9 Hz), 5.52 (s, 1H), 7.27 (d, 1H, J=4.8 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.82 (d, 1H, J=4.8 Hz), 6.59 (bs, 1H), 3.93-3.87 (m, 4H), 3.76 (s, 3H), 3.18-3.13 (m, 4H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.O>CS(C)=O.O1CCCC1>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.63 g, 60% in mineral oil) was added to trimethylsulfoxonium iodide (36.5 g) in dimethyl sulfoxide (150 mL) and tetrahydrofuran (150 mL), was and stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (25.4 g) was added and the reaction was stirred for 3 hours. The reaction was poured into water (800 mL) and extracted three times with ether. The combined extracts were washed three times with water, and brine, dried over Na2SO4, filtered, and concentrated to yield the crude product which was used without further purification.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C1C=CC=CC=1>[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:9]([N:3]1[CH2:2][CH:1]2[O:8][CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:19])([OH:14])=[O:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C1CC2CNCC1O2
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)N1CC2CCC(C1)O2
Reaction time: 1 h

Procedure:
A solution of 11.3 grams (0.1 mole) 8-oxa-3-azabicyclo (3.2.1)octane in 20 ml of benzene was added to a suspension of 14.8 grams (0.1 mole) of phthalic anhydride in 50 ml of benzene at 8° C. The reaction mixture was stirred for 1 hour and then left overnight at room temperature. The product, 20.0 grams which separated, was filtered off and recrystallized from benzene ethanol. The product represented by formula (X) had a melting point of 149°-150.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([CH:11]=O)[N:10]=[C:4]2[N:3]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[C:21]([CH2:11][C:9]3[N:10]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]4[N:8]=3)=[C:20]([OH:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1ccn2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)ccn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30–1.80 (brm, 8H), 2.00–2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.68 (s, 1H), 2.70(s, 2H); 2.92 (m, 2H), 3.69 (m, 3H), 6.64 (d, J=3.56 Hz, 1H), 6.66 (d, J=3.56 Hz, 1H), 7.00 (m, 2H), 8.55 (d, J=6.97 Hz, 1H). Anal. Calcd. For C27H32O4N4: C, 68.05; H, 6.77; N, 11.76. Found: C, 68.24; H, 6.80; N, 11.77.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1)=[O:8]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 36.6 %

Procedure:
3-Dimethylaminobenzoic acid (50 mg, 0.3 mmol) was treated oxalyl chloride with in the same manner as that of Example 40, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (17 mg, yield 37%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH:7]1[C:15]2[C:10](=[CH:11][C:12](B(O)O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.CCO.[Cl:22][C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:22][C:23]1[N:24]=[N:25][C:26]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][CH:8]=[CH:9]3)=[CH:27][CH:28]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2ccc3[nH]ccc3c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of Na2CO3 (0.70 g, 6.6 mmol) in H2O (5 mL) was added indole-5-boronic acid (1.0 g, 6.2 mmol) and EtOH (25 mL). After stirring at rt for 30 min, 3,6-dichloropyridazine (935 mg, 6.30 mmol), toluene (50 mL) and Pd(PPh3)4 (0.30 g) were added. The mixture was stirred at 90° C. for 30 h and then evaporated in vacuo. The residue was treated with CH2Cl2 (100 mL), washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography, eluting with (CH2Cl2-MeOH=100:5) to give 0.35 g (37% yield) of the product as a yellow solid. 1H NMR (DMSO-d6) δ 6.52 (1H, s), 7.40 (1H, s), 7.50 (1H, d, 6.3 Hz), 7.86-7.90 (2H, m), 8.27 (1H, d, 6.9 Hz), 8.32 (1H, s), 11.32 (1H, s). MS m/e 230 (M+H+); Calculated MW: 229 for C12H8ClN5.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].[ClH:21]>CO>[ClH:21].[C:16]([C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCC(C(C)=O)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1 gram of 1,4 diacetyl-4-phenyl piperidine obtained in Example 2 was dissolved in 25 ml of methanol and sodium hydroxide solution (500 mg dissolved in 2.5 ml water) was added at room temperature. The solution was stirred at ambient temperature for 10 hrs. Thin layer chromatography showed the complete hydrolysis. The pH of the reaction mixture was adjusted to 2 using dilute hydrochloric acid and filtered to remove the salts. The filtrate was concentrated to remove methanol completely. 25 ml of isopropyl alcohol was added to precipitate the target molecule 4-acetyl 4-phenyl piperidine hydrochloride as white crystalline product. The product was dried under vacuum at 60° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[N:12]([O-])=O.[Na+].C1(S([NH:25][N:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=O)=O)C=CC=CC=1>O.N1C=CC=CC=1.C(O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[N:25]=[N:26][C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:12]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(C=NNS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(-c2nnn(-c3ccc(C(C)C)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
4-Isopropylaniline (1.35 g) was added to a mixed solution of 50% ethanol (16 ml) and concentrated hydrochloric acid (2.6 ml). To the mixture was added a solution of sodium nitrite (0.69 g) in water (4 ml) over 10 min below 5° C. and stirring was continued for 10 min. To a solution of 4-methoxybenzaldehyde phenylsulfonylhydrazone (2.9 g) in pyridine (60 ml) was added dropwise the above solution of diazonium salt during 20 min at -10° C.~-15° C., and stirring was continued for 30 min at -10° C. and for 30 min at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The extract was washed succesively with 4 N hydrochloric acid, water, aqueous sodium carbonate,and water, dried, and evaporated to dryness. The residue was purified by column chromatography on silica gel with benzene-hexane (1/2-2/1) as an eluate to give 2-(4-isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.6 g,54%). To a solution of 2-(4- isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.3 g) in dichloromethane (10 ml) was added dropwise boron tribromide (10 ml,2.6M solution in dichloromethane) at -10° C. Stirring was continued for 1 h at -10° C. and for 1 h at room temperature. To the mixture was added water (20 ml), and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated to dryness. The residue was recrystallized from benzene to give 1.1 g (72%) of the title compound.