Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=1)=[O:4].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:20][N:21]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCl)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)CCl)cc2)=NN1
Yield: 83.9 %

Procedure:
4.0 g (14.8 millimoles) of β-(p-chloroacetylaminobenzoyl)-propionic acid are refluxed with 0.74 g (14.8 millimoles) of hydrazine hydrate and 70 ml of ethanol for 3 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 3.3 g (84% of theory) of 6-(p-chloroacetylaminophenyl)-4,5-dihydropyridaz-3-one are obtained as pale yellow crystals (identical with the compound from Example 1, according to its melting point and infrared and NMR spectra).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH2:19]O)[C:12]=1[OH:21].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH2:19][C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[C:12]=1[OH:21]
Reactant: Cc1cc(CO)c(O)c(CO)c1C
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: O
Product: Cc1cc(Cc2ccc(O)cc2O)c(O)c(Cc2ccc(O)cc2O)c1C
Temperature: -12 °C
Yield: 55.7 %

Procedure:
In a one liter reaction flask were dissolved 220.0 g of resorcinol in 300 ml of de-mineralized water. To this solution 18.22 g of 2,6-bis(hydroxymethyl)-3,4-dimethylphenol was added and stirred until it dissolved. 5 ml of concentrated hydrochloric acid was then added and the reaction mixture stirred at ambient temperature for about 15 hours. The mixture was then chilled to -12° C. and the crystalline precipitate isolated in a chilled Buchner funnel. The crude product was suspended in 300 ml of de-mineralized water and re-isolated by vacuum filtration. The wet solid was first partially air dried and then vacuum oven dried at 60° C. to yield 20.4 g product having a purity of about 95% as determined by HPLC.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CC(C)=O>[CH3:15][O:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Temperature: 25 °C
Yield: 24 %

Procedure:
To solution of 5-chlorosulphonyl-2-methoxy-benzoic acid (0.5 g, 1.99 mmol) in acetone (5 ml) was added N-methylpiperazine (0.219 g, 2.19 mmol) and triethylamine (0.33 ml, 2.3 mmol) and the mixture stirred at RT. After 2 hours the reaction mixture was filtered and the collected solid washed with acetone, water and then diethylether to yield 2-methoxy-5-(4-methyl-piperazine-1-sulphonyl)-benzoic acid (150 mg, 24%). (LC/MS (acidic method): Rt 0.34, [M+H]+ 315).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([OH:25])=[O:24]>COCCOC.CCCC>[C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([NH:19][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[CH:21]=1)([OH:25])=[O:24]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Solvent: CCCC
Product: COc1ccc(C(=O)O)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A solution of 5.06 g (0.02 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane was mixed with a solution of 6.69 g (0.04 mole) of 3-amino-4-methoxybenzoic acid in 125 ml of 1,2-dimethyethane, and the mixture was stirred at 25° C. for about 16 hours. The reaction mixture was heated gently for 30 minutes and then allowed to cool before being filtered to remove the hydrochloride salt of the excess starting amine. The filtrate was concentrated under vacuum and then diluted with water. The resulting precipitate was collected and was then recrystallized three times from a mixture of ethanol and water to give 1.9 g of white solid N-(5-carboxy-2-methoxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 259°-261° C. Analysis: Calculated for C23H29NO5 : %C, 69.2; %H, 7.3; %N, 3.5; Found: %C, 69.3; %H, 7.3; %H, 3.6.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:28])=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)O)c1F
Product: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)NC2CCN(C)CC2)c1F

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.66 (m, 7 H) 1.75 (m, 4 H) 1.82-2.04 (m, 4 H) 2.15 (m, 3 H) 2.66-2.81 (m, 2 H) 3.16 (s, 1 H) 3.70 (m, 1 H) 3.90 (s, 3 H) 4.05 (t, J=13.8 Hz, 2 H) 4.77 (m, 1 H) 7.24 (t, J=8.1 Hz, 1 H) 7.96-8.13 (m, 2 H) 8.26 (s, 1 H) 8.35 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:27]([O-])([O-:29])=[O:28].[K+].[OH-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:27]([O-:29])=[O:28])[C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1NCCOc2ccc(F)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1NCCOc2c1cc(F)cc2[N+](=O)[O-]

Procedure:
7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (346 mg, 1.91 mmol) in Acetonitrile (10 mL) and Trifluoroacetic anhydride (0.85 mL, 6.0 mmol) was treated with Potassium nitrate (0.203 g, 2.00 mmol) at room temperature for 24 h. Aq. NaOH (15% w/w, 10 mL) was added and the mixture extracted 3×15 mL DCM. The DCM extract was washed with water (20 mL) and brine (20 mL) then dried over sodium sulfate and conc. in vacuo. 1H-, 19F-NMR and HPLC showed a 2-3:1 mixture of 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one and 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, which was chromatographed (ISCO, 40 g, 0-75% EtOAc:Hex) to give 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, enriched in the mixture, but still containing 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one. This mixture was dissolved in Ethanol (10 mL) and added to Palladium on Carbon 10% (0.05 g) wetted with a small amount of water. The mixture was shaken under an atmosphere of Hydrogen (40 psi) for 1.5 h, then filtered through Celite, washing with ethanol. Conc. in vacuo gave a white solid, which was taken up in Et2O with minimal MeOH to solubilize, then extracted with 15 mL 1N HCl. The aq. extract was washed once with ether (10 mL) then basified with 15% NaOH, then extracted 8×10 mL DCM. The organic layers were dried over sodium sulfate and conc. in vacuo to give 9-Amino-7-fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one as a white solid (120 mg, 35% over two steps.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH3:14]>>[CH:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC[Mg]Cl
Reactant: OCCCC1CCCCC1
Product: CCCCC(O)CCC1CCCCC1

Procedure:
The alcohol was prepared using the method described in Example 1206A starting with 3-cyclohexylpropyl carboxaldehyde (prepared by Swern oxidation of 3-cyclohexyl-1-propanol) and butylmagnesium chloride.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.BrBr.C(OCC)(=O)C>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:14]3[C:13](=[O:16])[NH:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1nc2ccc3c(c2s1)C(=O)NCC3
Temperature: -10 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium thiocyanate (8.62 g, 0.088 mol) was added to a stirred solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one (I-66a: 1.8 g, 0.01 mol) in acetic acid (60 mL) at −10° C. and this was followed by the addition of bromine (5.33 g, 0.033 mol). The resulting reaction mass was stirred at −10° C. for 3 hours and further at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was diluted with ice water and filtered. The resulting mixture was basified at 0° C. using KOH solution to pH 10 and extracted using ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1.4 g of the product (58.33% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)NCCCl)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[Sn:28]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50].CCN=C=NCCCN(C)C>C(#N)C>[F:42][C:2]([F:1])([F:41])[C:3]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)ON2C(=O)CCC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Compound 15 (170 mg, 236 mmol) was dissolved in acetonitrile (5 mL), N-hydroxysuccinimide (54 mg, 472 mmol) and EDCI (90 mg, 472 μmol) were added and the mixture stirred 6 h at 20° C. The solvent was removed under vacuum and the residue was purified over silica gel using dichloromethane/acetone (1/1) as eluant to give 155 mg (190 μmol, 80% yield) of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:22])([P:14](=[O:21])([O:18]CC)[O:15]CC)[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].C[Si](Br)(C)C.CO>C(Cl)Cl>[F:22][C:2]([F:1])([P:14](=[O:15])([OH:21])[OH:18])[C:3]1[C:4]([F:13])=[C:5]([F:12])[C:6]([F:11])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CCOP(=O)(OCC)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Yield: 67.4 %

Procedure:
Diethyl perfluorobenzylphosphonate (1.90 g, 5.97 mmol) was dissolved in dry CH2Cl2 (4 ml), stirred and TMSBr (3.66 g, 23.88 mmol) was added. The mixture was stirred for 2 hours at room temperature after which volatiles were removed on a rotary evaporator to give a thick yellow oil. MeOH (5 ml) was added and the suspension stirred for 90 minutes, after which the product was collected by filtration yielding white crystals (1.20 g, 77%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Br[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][NH:4][CH2:1][CH2:2][CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCN
Reactant: BrCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCNCCOc1ccccc1

Procedure:
47.2 g. Propylamine was dissolved in 100 ml. absolute alcohol with cooling and 40.2 g. β-bromophenetole was added portionwise to the solution formed. After completion of the addition the reaction mixture was allowed to stand at room temperature for one week with occasional agitation. The excess of amine and solvent were then removed under vacuum from the steam bath and the residual colourless solid obtained on cooling was treated with an excess of 5N aqueous sodium hydroxide. An oil was liberated which was then extracted with ether, washed with water and dried over anhydrous sodium sulphate. After removal of the solvent the residual oil was distilled under vacuum to give N-2-phenoxylethyl-N-propylamine, boiling point 90°-92° C./0.2 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:27]OC(OC)N(C)C.CC(C)([O-])C.[K+].Cl>CC1CCCO1.C1COCC1>[N+:24]([C:8]1[CH:7]=[C:3]2[C:2]([CH:1]=[CH:27][NH:6][C:4]2=[O:5])=[CH:10][C:9]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:15][CH2:16]1)([O-:26])=[O:25]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: Cc1ccccc1N1CCN(c2cc3cc[nH]c(=O)c3cc2[N+](=O)[O-])CC1
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzamide (3.0 g, 8.46 mmol) and dimethylformamide dimethyl acetal (1.32 g, 11.08 mmol) in 2-methyl tetrahydrofuran (60 mL) were heated in a Dean stark apparatus at 105° C. for 30 min. The progress of the reaction was monitored by LCMS. The volume of the reaction was reduced to half and the reaction mass was cooled to 55° C. A solution of potassium tert-butoxide (1.44 g, 12.8 mL, 12.86 mmol) in THF (1 M) was added dropwise over a period of 30 min. The reaction mixture was allowed to heat at 65° C. overnight. After completion of the reaction, solvent was removed in vacuo, residue obtained was acidified with 1.5 N HCl. The aqueous layer was extracted in dichloromethane (5×75 mL). The combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) using 1.0-1.25% methanol in dichloromethane to afford the compound 7-nitro-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one. Yield (0.25 g, 8.3%; and reddish brown solid).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.C(OC(=O)C)(=O)C>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 95 °C
Yield: 73.6 %

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (20.3 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (88%, 9.3 g.) and acetic anhydride (74 ml.) was heated (to 95° C.) during one hour, then cooled, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y4 =(CH3)2N, Y2 =H, Z4 =Z5 =Z6 =Z7 =Cl) (20.3 g., m.p. 227°-229° C.).
Reaction SMILES: Br[C:2]([F:20])([F:19])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH:7]1[C:15]([O:17][CH3:18])=[O:16])([F:5])[F:4].C(=O)(O)[O-].[Na+:25].[S:26](S([O-])=O)([O-:28])=[O:27].[Na+].[Na+].C(#N)C>O>[CH3:18][O:17][C:15]([CH:7]1[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:6]1[C:3]([F:5])([F:4])[C:2]([F:20])([F:19])[S:26]([O-:28])=[O:27])=[O:16].[Na+:25]
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)Br)C1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged 2.00 g (5.49 mmol) of dimethyl 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylate, 0.920 g (11.0 mmol) of sodium bicarbonate, 1.62 g (9.30 mmol) of sodium dithionite, 15 mL of acetonitrile and 15 mL of water, and the mixture was stirred at 50° C. for 8 hrs. The disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. Thereafter, acetonitrile was distilled off in vacuo to obtain an aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate (precursor compound (a-4)) represented by the following formula (a-4) without carrying out further purification, which was used for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[OH:14])[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCC2O)c1
Agent: O=[Cr](=O)(O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C2CCCC2=O)c1
Reaction time: 1.5 h
Yield: 69131.8 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-cyclopentanol (6.4 g, 0.033 mmoles) in 140 ml of methylene chloride, add a mixture of pyridine chlorochromate (14.4 g, 0.066 mmoles), and silica gel (14.4 g). After 1.5 hours, an equivalent amount of oxidizing agent and silica gel is added and the reaction is stirred an additional 3.5 hours. Reduce the solvent in half in vacuo at 35° C. and chromatograph on silica with 3-1 hexanes-ethyl acetate to yield 4.34 g of the titled compound. 1H NMR (CDCl3): 7.25 (m, 1H), 6.81-6.74 (m, 3H), 3.8 (s, 3H), 3.31 (m, 1H), 2.5 (m, 2H), 2.3 (m, 1H), 2.1 (m, 2H), 1.9 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26](Cl)[N:25]=[CH:24][C:23]=2[N:22]=1.[CH3:34][NH2:35].C1COCC1>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26]([NH:35][CH3:34])[N:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CN
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1nc2cnc(Cl)nc2n(C)c1=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ncc2nc(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1

Procedure:
A Smith vial (2-5 mL) is charged with N-[4-methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-pheny]-3-trifluoromethyl-benzamide (15 mg, 0.032 mmol), 2M methylamine solution in THF (160 μL, 0.32 mmol), and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 45 minutes in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound; 1H NMR 400 MHz (DMSO-d6) δ 10.51 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (bs, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.80-7.76 (m, 3H), 7.27 (d, J=8.2 Hz, 1H), 3.56 (s, 3H), 2.94 (s, 3H), 2.19 (s, 3H); MS m/z 469.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4ccc(F)cc4)cc3c2C1
Yield: 7.1 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol 4-fluoroaniline, 0.001 gm (7%) of the title compound were recovered.