Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH2:15]([O:22]CC1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: COc1ccc2cc(Cl)nc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 84.6 %

Procedure:
1,3-dichloro-7-methoxyisoquinoline (2.00 g, 8.8 mmol, 1.0 eq.) was dissolved in 30 mL anhydrous toluene and sodium benzyloxide (2.30 g, 17.6 mmol, 2.0 eq.) was added. The mixture was heated to 80° C. for 18 h. TLC indicated the reaction was complete. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel (eluted with petroleum ether) to give 2.20 g of xxxvii-a as a white solid (84.6%). LCMS m/z=300.1, 302.0 (M+1) (Method B) (retention time=2.23 min).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of methyl (4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenoxy)acetate obtained in Example 22 (1.11 g), 1 M sodium hydroxide solution (12 mL), methanol (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 3 h. 1 M hydrochloric acid solution was added to the reaction solution, and the solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with water, diethyl ether and dried under reduced pressure to provide the title compound (1.05 g, 98%) as crystals.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)=[CH:7][CH:6]=1.[NH2:28][C:29]([NH2:31])=[S:30].C(N(CC)CC)C>C(O)(=O)C>[NH2:31][C:29]1[S:30][C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[N:28]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Bromine (0.68 mL, 13 mmol) was added to a solution of 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone (4.5 g, 13 mmol) in acetic acid (100 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (40 mL) and to the solution was added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol) were added and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. A saturated aqueous sodium hydrogencarbonate (200 mL) was added to the residue and the resulting solid was collected by filtration and washed with water. 2N hydrochloric acid (35 mL) was added to the solids and the mixture was stirred at 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and, thereafter, 8N aqueous sodium hydroxide (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (100 mL) were added. The resulting crude crystals were collected by filtration, and were washed with water. The crude crystals were recrystallized from ethanol to obtain 2.7 g of the title compound (9.1 mmol, yield 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(F)ccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-fluoro-N1-phenylbenzene-1,2-diamine (866 mg, 4.3 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (890 mg, 4.7 mmol), HOAt (640 mg, 4.7 mmol), 4-methylmorpholine (1.0 mL, 9.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (900 mg, 4.7 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow-orange solid (quantitative). The crude product was used in the following step without further purification. LCMS (Method B): RT 3.83 min [M+H]+ 374.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH2:14])=[C:12]([Cl:15])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>>[NH2:14][C:13]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]=1[Cl:15]
Reactant: COC(=O)c1cc2nc[nH]c2c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc2nc[nH]c2c1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
See step d) of example H2 starting from 6-amino-7-chloro-1H-benzoimidazole-5-carboxylic acid methyl ester and 2 equivalents of a solution of NaOH 1 N. The reaction is stirred for 18 hours at 70° C. After evaporation, the residue is suspended in EtOAc and H2O, then the aqueous phase is acidified to pH 2-3 with concentrated HCl. The aqueous phase is coevaporated with toluene and the crude reddish solid is used directly in the next step without further purification. LC/MS: 212/214 (M+1)+
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:7][C@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:16][CH:17]([C:19]#[N:20])[CH2:18]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (180 mg, 0.49 mmol) in dichloromethane (3 ml) at 0° C. was added trifluoroacetic acid (1.2 ml, 15.6 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to afford 1-((R)-2-amino-3,3-dimethyl-butyryl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:15][CH2:16][N:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[OH-].[Na+]>Cl>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][N:3]([CH2:15][CH2:16][N:17]2[N:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH3:2])=[CH:11][CH:10]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)CCn1ncc2ccccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCc1ccc(N)cc1)CCn1ncc2ccccc2c1=O
Temperature: 55 °C
Yield: 96.5 %

Procedure:
Stannous chloride dihydrate (13.05 g) was dissolved in concentrated hydrochloric acid and stirred at 55° C. N-Methyl-N-(4-nitrophenethyl)-2-(2H-phthalazin-1-on-2-yl)ethylamine hydrochloride (7.5 g) was added portionwise over 1 hour and the solution was then heated a further 4 hours at 100° C. The partly cooled solution was poured onto crushed ice containing 500 ml of a 20% aqueous solution of sodium hydroxide and then extracted three times with methylene chloride. The resultant organic extracts were combined, dried (MgSO4), filtered and evaporated to give a pale yellow oil (6.0 g). Chromatography of the oil on silica [Merck "Kieselgel 60" (Trade Mark)] eluting with methylene chloride gave, after collection and evaporation of appropriate fractions, the title compound as a pale yellow oil (3.5 g) which was used in part (C) without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]cnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1[nH]cnc1Br
Yield: 23.3 %

Procedure:
A solution of methyl 4-bromo-1H-imidazole-5-carboxylate (0.708 g, 3.5 mmol) was stirred in a solution of MeOH (20 mL) and 2N NaOH (20 mL, 40 mmol) at 40° C. for 4 h, then additional 2N NaOH (20 mL, 40 mmol) was added and the reaction mixture kept at 40° C. for another hour. The reaction mixture was then acidified by addition of 1M HCl (100 mL) and extracted with EtOAc. The organic extracts were dried (Na2SO4), and the solvent was evaporated to provide crude 4-bromo-1H-imidazole-5-carboxylic acid (0.156 g, 24%) as a white solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C(N)C[NH2:12]>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Cl)n1
Reactant: NCCN
Product: COc1cccc(N)n1

Procedure:
2-Chloro-6-methoxypyridine (5.0 g) was heated with ethylenediamine (30 ml) at 120° C. overnight. The excess ethylenediamine was removed by rotary evaporation. The residue was dissolved in a small volume of 2.5 M aqueous sodium hydroxide and extracted thoroughly with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give (2-aminoethyl)(6-methoxy(2-pyridyl)amine as an orange syrup. The amine (2.58 g) was treated with benzotriazole carboxamidinium 4-methylbenzenesulfonate (0.86 g) and 4DIEA (0.45 mmol) in acetonitrile (6 ml) and stirred overnight at room temperature. Trituration with ether gave the guanidine, amino-{2-[(6-methoxy(2-pyridyl))amino]ethyl} carboxamidinium 4-methylbenzenesulfonate as an oil. The oily guanidine (200 mg) was reacted with 100 mg of resin according to Resin Method C (90° C., overnight) to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][C:6]2[C:7](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:29]=[CH:28][C:6]2[C:7](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2=Cc1cccc(NS(C)(=O)=O)c1
Agent: BrB(Br)Br
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(O)ccc32)c1
Yield: 69 %

Procedure:
Demethylate the corresponding methoxy mixture of Example 161 using BBr3 to give the title compound in 69% yield. MS (ES) 392 (M+1), 390 (M−1). HPLC shows 48% of the faster eluting isomer and 45% of the slower isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH2:22])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1N
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To crude 4-(4-methyl-3-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (3.5 g) in EtOH/water (60 ml, 1:1) was added iron powder (4 g) and solid NH4Cl (4 g) and the mixture heated to reflux temperature for 1.5 hr. After cooling to room temperature the reaction was filtered through Celite and the filter cake washed with further EtOH. The majority of the solvent was removed in vacuo before addition of ethyl acetate and aqueous K2CO3. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated, to leave an oil that was triturated with isohexanes to afford a pale brown solid (3 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(C)C)=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[OH-].[K+].Cl>C(O)(C)C>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([OH:15])=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)OC(=O)C(C(=O)O)=C1SC=CS1
Reaction time: 1 h
Yield: 69 %

Procedure:
A 14.4 g portion of diisopropyl 1,3-dithiol-2-ylidenemalonate (0.05 mol) was dissolved in 50 ml of isopropanol, 2.95 g of potassium hydroxide (0.05 mol) was added to the solution at 30° C., and the resulting mixture was stirred for 1 hour. The solution was acidified with 6N hydrochloric acid and extracted with 200 ml of methylene chloride and washed with water and saturated brine in that order. After drying on magnesium sulfate, the solvent was removed by distillation under a reduced pressure and the resulting residue was crystallized from ether to obtain 8.5 g of isopropyl hydrogen 1,3-dithiol-2-ylidenemalonate in the form of white crystals (yield, 75%). Then, 2.7 g (0.011 mol) of the obtained crystals and 3.6 g (0.012 mol) of 2-chloro-1methylpyridinium p-toluene sulfonate were dissolved in 20 ml of dichloromethane to which was then added dropwise a dichloromethane solution of 0.51 g (0.011 mol) of ethanol and 3.46 g (0.034 mol) of triethylamine at 10° C., subsequently stirring the resulting mixture for 2 hours at room temperature. The reaction solution was poured into ice water, extracted with dichloromethane and then washed with 2N hydrochloric acid, 10% sodium carbonate aqueous solution and water in that order. After drying on magnesium sulfate, the solvent was removed by distillation under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain 1.0 g of the title compound in the form of crystals having a melting point of 54° C. (yield, 35%).
Reaction SMILES: BrC1C=C(C=CC=1)/[CH:5]=[N:6]/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br-].[Al+3].[Br-].[Br-]>O>[Br:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[CH:5]=[N:6][N:7]=[CH:8]2
Reactant: Brc1cccc(/C=N/N=C/c2cccc(Br)c2)c1
Agent: [Al+3]
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: Brc1cccc2cnncc12
Temperature: 192.5 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a 250 mL 3-neck round-bottom flask was added (1E,2E)-1,2-bis(3-bromobenzylidene)hydrazine (13.0 g, 35.5 mmol), aluminum(III) chloride (71.0 g, 533 mmol), and aluminum(III) bromide (71.0 g, 266 mmol). The mixture was stirred at 185-200° C. for 1 hour. The dark gum was cooled in an ice bath and slowly treated with 1.5 L of water. The suspension was filtered, and the precipitate was washed with 5% HCl. The solution was made basic with 15% potassium hydroxide and extracted with EtOAc three times. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc and hexane to provide 5-bromophthalazine (3.12 g, 42%). LCMS (M+H) 209.2 calc. for C8H6BrN2 209.0. 1H NMR (400 MHz, CDCl3): δ ppm 7.78-7.83 (m, 1H) 7.95 (d, J=8.02 Hz, 1H) 8.14 (d, 1H) 9.49 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cccc(F)c21
Reaction time: 1 h

Procedure:
To a flask containing 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (1.5 g, 4.1 mmol) was added TFA (20 mL). The reaction was stirred under nitrogen for 1 hours and then concentrated in vacuo to afford an oil. Addition of water caused a white precipitate to form. The solid was collected by filtration, washed with water, washed with ether, and then dried in vacuo (0.68 g). MS (m/z)=308 (M+H)+. Calculated for C15H14FNO5 307.08.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][CH:32]1[CH2:35][NH:34][CH2:33]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH:32]([F:31])[CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: FC1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(F)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-fluoro-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-fluoro-azetidine following General Procedure B.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH:2]=[O:1])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: COc1cc(-c2cc(C=O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-Trimethoxyphenyl)pyridine (1.01 g) was dissolved in benzene (10 mL), and to the solution activated manganese dioxide (purity: 85%, 3.78 g) was added. The mixture was stirred at room temperature for 5 hours, and activated manganese dioxide (purity: 85%, 3.78 g) was additionally added. The mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:7]1[CH:8]=[C:4]([CH2:3][O:2][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:20])[N:5]=[CH:6]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1c[nH]cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
To an ice-cold solution of 4-(hydroxymethyl)imidazole hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 18 h, the resultant precipitate was collected by vacuum filtration. The solid was partitioned between EtOAc (75 ml) and saturated NaHCO3 (75 mL). The aqueous layer was separated and extracted again with EtOAc (75 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2Cl2 to 90:10 CH2Cl2/MeOH) gave 2-(1H-imidazol-4-ylmethoxy)-1,3-dihydro-2H-isoindole-1,3-dione (800 mg, 22%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ5.03 (2H, s), 7.30 (1H, s), 7.55 (1H, s), 7.81-7.86 (4H, m), 12.08 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[CH2:13](OC(C1NC2C(C=1)=CC=CC=2)=O)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][N:6]2[CH3:13]
Reactant: O=Cc1c[nH]c2cccc(F)c12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: Cn1cc(C=O)c2c(F)cccc21
Yield: 54 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 4-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for the ethyl-indole-2-carboxylate, the title compound (0.24 g, 54%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].CN(C=O)C>O>[O:10]1[C:9]2[CH:14]=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCO2
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNCC(=O)Nc1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 2-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (2 mmol), potassium carbonate (10 mmol), 2-methoxyethylamine (2 mmol) and anhydrous DMF (4 mL) was stirred for 2 hours at 100° C. (monitored by TLC). The mixture was cooled to room temperature, treated with cold water (30 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to afford N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-methoxy-ethylamino)-acetamide (Compound XIa, 96 mg, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ=9.29 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=8.7, 2.4 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.32-4.15 (m, 4H), 3.46 (t, 2H, 4.8 Hz), 3.36 (s, 3H), 3.34 (s, 2H), 2.82 (t, 2H, J=4.8 Hz), 2.17 (s, 1H). 13C NMR (75 MHz, CDCl3/CD3OD/TMS): δ=169.48, 143.16, 139.87, 131.43, 116.84, 112.74, 108.89, 71.41, 64.28, 64.12, 58.68, 52.57, 49.35.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)(O)=[O:2].S(Cl)([Cl:29])=O.CN(C)C=O>C(Cl)Cl>[CH3:19][S:16]([NH:15][C:13]1[C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:7]2[C:8](=[O:10])[CH:9]=[C:4]([C:1]([Cl:29])=[O:2])[O:5][C:6]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)O)cc(=O)c2cc1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Yield: 98.5 %

Procedure:
3.0 g of 2-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 30 ml of methylene chloride. Thereto were added 3.8 g of thionyl chloride and 0.1 ml of N,N-dimethylformamide. The mixture was refluxed for 1.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain 3.1 g (yield: 98.4%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride.