Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)N>>[F:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)=[CH:20][C:19]=1[O:18][CH3:17]
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: COc1cc(N)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1cccc(F)c1
Yield: 54 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (2.0 g, 8.96 mmol) and 3-methoxy-4-[(3-fluorobenzyl)oxy]aniline (2.67 g, 10.8 mmol) to give the title compound as a white solid (2.06 g, 54%); NMR Spectrum: 3.79 (t, 2H), 3.80 (s, 3H), 4.31 (t, 2H), 5.12 (s, 2H), 7.03 (d, 1H), 7.18 (m, 2H), 7.29 (m, 2H), 7.35 (d, 1H), 7.45 (q, 1H), 8.22 (s, 1H); Mass Spectrum: 426 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]4[C:20]([CH2:19][CH2:18][CH2:17][N:16]([O:21]C5CCCCO5)[C:15]4=[O:28])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C1COCC1.O>C(O)(=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]4[C:20]([CH2:19][CH2:18][CH2:17][N:16]([OH:21])[C:15]4=[O:28])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ncc3c(ccn3Cc3ccc(F)cc3)c2CCCN1OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1c2ncc3c(ccn3Cc3ccc(F)cc3)c2CCCN1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3-(4-fluorobenzyl)-7-(tetrahydro-2H-pyran-2-yloxy)-7,8,9,10 tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one (18.53 mg, 0.045 mmol) was dissolved in acetic acid, THF and Water (3.5 ml, 5:1:1). The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by preparative HPLC to provide the title compound as a white powder (9.0 mg, 61% yield). 1H NMR (300 MHz, MeOH) □ ppm 8.57 (s, 1 H) 7.60 (d, J=3.20 Hz, 1 H) 7.11-7.20 (m, 2 H) 6.90-6.99 (m, 2 H) 6.72 (d, J=3.01 Hz, 1 H) 5.44 (s, 2 H) 3.51 (t, J=6.50 Hz, 2 H) 3.03 (t, J=7.16 Hz, 2 H) 2.14-2.25 (m, 2 H). LC-MS (APCl, M+H+): 329.1. HPLC: 98% purity.
Reaction SMILES: [C:1]([O:8]CC)(=O)/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[NH2:12].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:4]([CH:3]1[CH2:2][C:1](=[O:8])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[NH:12]1)([OH:6])=[O:5]
Reactant: NNc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCOC(=O)/C=C\C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)N1
Temperature: 100 °C
Yield: 76 %

Procedure:
2 parts of monoethyl maleate are added with stirring to 25 parts of water containing 2 parts of p-hydrazinobenzene sulphonate and 1 part of sodium carbonate. The mixture is heated at 100° C for 5 hours. The resulting solution is warmed with sodium carbonate and the pH finally adjusted to 3-4 with hydrochloric acid. The 3carboxy-1-(4'-sulphophenyl)-5-pyrazolidone thus formed is filtered off and dried between 50°-100° C. The actual weight yield is 4 parts of strength 74% (determined by N.M.R.) which represents a yield of 76%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([O:29][CH3:30])=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][NH:14][C:22]2[NH:27][C:26](=[O:28])[C:25]([O:29][CH3:30])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: COc1cnc(NCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
2-[3-(Piperidinomethyl)phenoxy]ethylamine * (1.38 g) and 2-nitroamino-5-methoxypyrimidin-4-one(1.00 g) were stirred under reflux, for 19 hours, in pyridine (15 ml). The reaction mixture was worked-up in a manner analogous to that of Example 5 to give the title compound which was converted to 2-[2-[3-(piperidinomethyl)phenoxy]-ethylamino]-5-methoxypyrimidin-4-one maleate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[CH2:33]([Zn]CC)[CH3:34]>C1COCC1>[CH2:33]([C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:11]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1)[CH3:34]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[Zn]CC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
To a solution of N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)-benzamide (0.1 g, 212 μmol, example 12) in THF (1 mL) were added tetrakis(triphenyl-phosphine)palladium(0) (12.2 mg, 10.6 μmol) and diethylzinc (1M solution in n-hexane, 137 μL, 137 μmol) and the brown solution was stirred at reflux for 16 hours. The solvent was evaporated and the brown gum was diluted with 1M aqueous HCl and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light yellow solid (0.051 g; 51%). MS (ESI): m/z=467.16 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[CH2:34][S:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][S:35][CH2:34][C@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:44]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:12]([OH:14])=[O:13])=[O:45])=[CH:42][CH:41]=1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-S-(4-methylbenzyl)-L-cysteine (67 mg, 0.3 mmol). The final product was triturated with ether to yield 130 mg (65%) of the desired material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([N:17]([CH3:19])[CH3:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C1([O:26][C:27](=O)[NH:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)C=CC=CC=1>O1CCOCC1>[CH3:18][N:17]([CH3:19])[C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[O:26])[CH2:10][CH2:9]1
Reactant: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CCCN)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CCCNC(=O)NCCc2c[nH]c3ccccc23)CC1
Yield: 17.8 %

Procedure:
The mixture of [4-(3-aminopropyl)-1-phenyl-cyclohexyl]-dimethylamine (380 mg, 1.46 mmole) was added to a solution of [2-(1H-indol-3-yl)ethyl]carbamic acid phenyl ester (409 mg, 1.46 mmole) in dioxane (10 ml). The batch was then refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (5 ml) and dried with Na2SO4. The solvent was removed by distillation under a vacuum. The residue was the diastereoisomeric mixture of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea, which was separated and purified by flash chromatography on silica gel (70 g). Methanol/EE (3:1, 1500 ml; 1:1, 500 ml; and 1:2, 1000 ml) was used as eluent. The more nonpolar diastereoisomer of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea (Example 35, 95 mg, m.p. 126° C., 15%) and the more polar diastereoisomer of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea (Example 36, 116 mg, m.p. 57° C., 18%) were isolated in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:21])[C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[C:12]([C:22]#[N:23])=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.[H-].[Na+]>>[NH2:23][C:22]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH:11]=2)[N:15]([CH3:21])[C:16](=[O:20])[C:17]=1[CH2:18][CH3:19]
Reactant: CCCC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Product: CCc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
Using the procedure described in EXAMPLE 40, the product of Step A was reacted with NaH to afford the title compound. HPLC/MS: 457.9 (M+I), 459.9 (M+3); Rt=4.29 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[OH-].[NH4+:14]>CO>[NH2:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1
Reactant: [NH4+]
Reactant: Nc1cccc(OCCCCl)c1
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cccc(N)c1
Temperature: 100 °C

Procedure:
The 3-(3-chloropropoxy)phenylamine (1.98 g, 11.6 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.37 g of an oil.
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1

Procedure:
Methyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoate (Preparation 33, 1.25 g, 4.746 mmol) was stirred in methanol (15 mL) and a 1M aqueous solution of sodium hydroxide (15 mL) for 3 hours at room temperature. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to pH3 with potassium hydrogen sulphate and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound that was used without purification in the next step.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23]C2CCCCO2)[CH:17]=[CH:16][C:15]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>CO>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[N:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)[O:20][CH2:21][CH2:22][OH:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCOC3CCCCO3)cc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: OCCOc1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
p-Toluenesulfonic acid monohydrate (45.2 mmol) is added to 4-{2-fluoro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperazine-1-carboxylic acid, tert.-butyl ester (22.6 mmol) in MeOH (50 ml) at room temperature. The reaction mixture is stirred at room temperature for 1.5 h. After the mixture is extracted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtered. The solvent is evaporated. To the residue in CH2Cl2 (9 ml), TFA (17.5 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. The solvent is removed by evaporation and dried to give brown crude oily product, 2-(3-fluoro-4-piperazin-1-yl-phenoxy)-ethanol. To the crude product in DMF (100 ml), potassium carbonate (113 mmol) is successively added at 0° C. The mixture is stirred at 0° C. for 15 min. 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7.H.-pyrrolo[2,3-.d.]pyrimidine-2-carbonitrile (22.6 mmol) is added to the mixture at 0° C. The reaction mixture is stirred at room temperature for 3 h and quenched with saturated ammonium chloride. The mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=3:2 (v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 525.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[OH:8])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[O:8][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: OCc1ccc(F)cc1
Reactant: CCc1cnn(-c2cc(C#N)ccn2)c1O
Product: CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(4-ethyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile and 4-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: [C:1]([O:7]C(C)(C=C)C)(=[O:6])[CH:2]=[C:3]([CH3:5])[CH3:4].CO>O>[C:3]([CH:2]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[C:1]([OH:7])=[O:6])([CH3:4])=[CH2:5]
Reactant: C=CC(C)(C)OC(=O)C=C(C)C
Solvent: O
Solvent: CO
Product: C=C(C)C(CC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 200 %

Procedure:
In a nitrogen atmosphere, a mixture of the 125 mmol of sodium hydride, obtained from 5.00 g of a 60% suspension in mineral oil by removal of mineral oil with n-hexane washing, and 30 ml of toluene was heated to reflux with stirring, and subjected to dropwise addition of 20.0 g of 2-methyl-3-buten-2-yl senecioate having a purity of 96.9% over one hour. After reflux was continued for 22 hours, the reaction mixture was cooled to room temperature, and 10 ml of methanol and 40 ml of water were added dropwise thereto. The organic phase was extracted with water and then discarded. The aqueous phases were combined and then made acidic with 20% hydrochloric acid, followed by extraction with diethyl ether. The diethyl ether solution was subjected to typical work-up including washing, drying and concentration to obtain 20.0 g of the crude product having a purity of 3.6% on basis of stoichiometric amount. The content of each isomer in the crude product was analyzed using capillary GC analysis and GC-MS under the similar conditions as in Example 1. The results are shown in Table 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)([O-:3])=[O:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>O>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:13][N:12]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridin-2-amine (2.70 g, 11.7 mmol), p-toluenesulfonyl chloride (2.67 g, 14.0 mmol) and pyridine (20 mL) was stirred at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 92%) as a white solid. A mixture of 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 10.7 mmol) thus-obtained, N,N-diisopropylethylamine (2.44 mL, 14.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr, iodoacetamide (2.59 g, 14.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.28 g, 99%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]3[N:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:14]=[C:15]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[C:11]=3[CH2:10]S[C:8]=12.O[O:31][S:32]([O-:34])=O.[K+].CCOC(C)=O>C1COCC1.O>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]3[N:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:14]=[C:15]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[C:11]=3[CH2:10][S:32](=[O:34])(=[O:31])[C:8]=12
Reactant: CNc1cccc2c1SCc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1cccc2c1S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazol-6-amine (90 mg, 0.22 mmol) in THF: H2O (1:1, 10 mL) is added oxone (545 mg, 0.88 mmol) and the reaction mixture is stirred at RT for 3 h. After this time, EtOAc is added to the reaction mixture that is washed with water. The organic layer is separated, dried over Na2SO4, concentrated under reduced pressure. The solid residue is purified by silica gel flash chromatography (40% EtOAc in pet.ether) the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.56 (m, 3H), 7.47-7.44 (m, 2H), 7.26-7.22 (t, J=8.1 Hz,1H), 6.80-6.74 (m, 2H), 5.98-5.96 (d, J=7.6 Hz,1H), 4.87 (s, 2H), 3.95-3.94 (m, 2H), 3.65 (m, 4H), 3.61-3.59 (m, 2H), 2.83-2.82 (d, J=4.7 Hz, 3H). MS (ESI+): 439.0. HPLC (max plot) 95.63%; Rt 4.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 70-72% yield.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]([CH2:18][C:19]4[N:28]=[C:27]([CH3:29])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[C:13]4=[N:30][CH2:31][CH2:32][N:12]4[C:11]=3[N:10]=[CH:9]2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:29][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH2:18][N:14]2[C:15](=[O:17])[C:16]3[NH:8][CH:9]=[N:10][C:11]=3[N:12]3[CH2:32][CH2:31][N:30]=[C:13]23)[N:28]=1
Reactant: COc1ccc(Cn2cnc3c2C(=O)N(Cc2nc(C)c4ccccc4n2)C2=NCCN23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2C(=O)c3[nH]cnc3N3CCN=C23)nc2ccccc12
Temperature: 70 °C

Procedure:
To 3-(4-methoxybenzyl)-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]pinin-4(5H)-one 13 (858 mg, 1.89 mmol) was added TFA (20 ml), and stirred at 70° C. over night. The mixture was concentrated and purified by flash chromatography (MeOH/DCM, MeOH contains 10% ammonia) to afford the product 5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 14.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc2c(c1C)OC(C)(C)C2=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)cc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Bromine (10.0 mL, 195 mmol) was added to a solution of acetic acid (150 mL) containing 2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (26.4 g, 139 mmol) synthesized in Reference Example 17, and the mixture was stirred at room temperature for 3 hours. After that, the reaction solution was poured into 5% aqueous solution of sodium sulfite. The generated crystals were collected by filtration, and recrystallized from methanol to give 32.8 g of the title compound (yield: 88%).