Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH2:5][OH:6].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: OCc1cc(O)cc(O)c1
Product: CCOC(=O)COc1cc(O)cc(CO)c1

Procedure:
the subtitle compound was prepared from 3,5-dihydroxybenzyl alcohol (5 g) and ethyl bromoacetate (5.96 g) by the method of example 21 step (ii). Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 1.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Cl>C(O)C.C(O)(=O)C.O.[Fe]>[CH3:1][O:2][C:3]1[C:4]([NH2:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C=O)c1N
Yield: 112.6 %

Procedure:
5 g of 3-methoxy-2-nitrobenzaldehyde are dissolved in a solution of 100 ml of ethanol, 100 ml of acetic acid and 50 ml of water. After addition of 11.4 g of iron and of 1.4 ml of concentrated hydrochloric acid, the reaction medium is heated at reflux for 10-15 minutes. After having cooled the reaction medium, 150 ml of water are added and the reaction mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with 500 ml of a saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and evaporated under vacuum to provide 4.7 g of 3-methoxy-2-aminobenzaldehyde in the form of a colorless oil, used without purification in the following stage. (Yield: quantitative)
Reaction SMILES: N[C:2]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].S(=O)(=O)(O)[O-].[Na+].C([O-])(O)=O.[Na+].[BrH:56]>C(#N)C.O.CCOC(C)=O.[Cu]Br>[Br:56][C:2]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu]Br
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
A solution of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (601 mg, 1.055 mmol) in acetonitrile (6 mL) and conc. HBr (6 mL, 48% aq) was cooled in an ice-water bath and then treated with a solution of sodium nitrite (95 mg, 1.372 mmol) in water (1 mL). After 15 min, copper(I) bromide (182 mg, 1.266 mmol) was added to the mixture. The mixture was then heated to 50° C. After 30 min, the solution was cooled to room temperature and diluted with EtOAc. Sodium bisulfate (15 mL, 5% aq) and saturated aqueous NaHCO3 solution (20 mL) were added to the solution. The organic phase was separated and washed by brine (40 mL), dried over Na2SO4, concentrated and then purified by silica gel chromatography(0-35% EtOAc in hexanes) to give methyl 2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (430 mg, 64% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (br. s., 1H), 0.75-0.93 (m, 2H), 0.97 (d, J=6.6 Hz, 1H), 1.88-2.04 (m, 1H), 3.01 (d, J=4.9 Hz, 3H), 3.28 (s, 3H), 3.91 (s, 3H), 5.72-5.85 (m, 1H), 7.21 (t, J=8.6 Hz, 2H), 7.33 (dd, J=10.0, 2.8 Hz, 1H), 7.49 (dd, J=2.8, 1.3 Hz, 1H), 7.52 (s, 1H), 7.58 (s, 1H), 7.85-7.92 (m, 2H). LCMS (m/z, ES+)=633, 635 (M+H+).
Reaction SMILES: ClCCl.[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][C:14]2=[O:25])[CH:7]([C:26]([NH:28][CH3:29])=[O:27])[CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([N:16]=[CH:15][C:14](=[O:25])[N:13]2[CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]2[C:26]([NH:28][CH3:29])=[O:27])=[CH:18][CH:19]=1
Reactant: CNC(=O)C1CC(O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
To 2 mL of a dichloromethane solution containing 11 mg of 4-hydroxy-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-N-methylpiperidine-2-carboxamide, 13 mg of Dess-Martin periodinane was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and chloroform. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 12 mg of a yellow oily substance, 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-N-methyl-4-oxopiperidine-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:10])=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][O:1][C:2]1[C:3]([F:10])=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)ccc(Br)c1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)ccc(Br)c1F
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A quantity of 3.7 g of 3-hydroxy-2,4-difluoro-bromobenzene is dissolved in 25 ml of acetone and 2.5 g of potassium carbonate is added followed by 2.2 ml of methyl iodide. The mixture is stirred at 20° C. for 6 hours and the solvent evaporated. After addition of dichloromethane, the suspension is filtered. Evaporation of the solvent affords the desired product.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:35]([NH2:37])=[O:36])[CH:13]=[C:14]([C:17]4[S:18][C:19]([CH2:22][CH2:23][C:24]([CH3:34])([O:26][Si](CC)(CC)CC)[CH3:25])=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:38]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:35]([NH2:37])=[O:36])[CH:13]=[C:14]([C:17]4[S:18][C:19]([CH2:22][CH2:23][C:24]([OH:26])([CH3:34])[CH3:25])=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-{3-methyl-3-[(triethylsilyl)oxy]butyl}-2-thienyl)-1H-indole-7-carboxamide (55 mg, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1 M in THF, 0.3 mL, 0.3 mmol) was added and the mixture was stirred at rt for 2 h. Additional TBAF (1 M in THF, 0.7 mL, 0.7 mmol) was added, and the mixture was stirred at 45° C. overnight. The reaction mixture was concentrated, re-diluted in dichloromethane (20 mL), and washed with water (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography, eluting with 0-15% methanol in dichloromethane. The residue was then repurified by Gilson HPLC (NH4OH buffer). The product fractions were combined and concentrated in an EZ2 Genevac evaporator, giving 17 mg (40%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1>>[NH2:26][C:24]1[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=[C:16]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:8])[CH2:14][CH2:13]2)[N:25]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCCC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(Cyclohexylcarbonyl)piperazine (5.9 g., 0.03 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (7.2 g., 0.03 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(cyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 223°-225° C., resolidifying and remelting at 248.0°-250.0° C. (corr.)
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[CH2:11][C:12]2[CH:17]=[C:16]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])=[CH:5][CH:4]=1.O1CCCC1>[Pd].C(O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[CH2:11][C:12]2[CH:17]=[C:16]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CC2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 57.1 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-[5-((2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetamide (300 mg, 0.687 mmol), 10% palladium on carbon (300 mg) and a mixed solvent of tetrahydrofuran and ethanol (2:1 v/v, 40 mL) were mixed, and hydrogenation was performed at room temperature and at an initial pressure of 392 kPa. After completion of the reaction, catalyst was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=2:1 v/v) to obtain 172 mg (57%) of the title compound as colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:25][C:4]1[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:26]2[CH2:28][CH2:27]2)[CH:3]=1
Reactant: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ccccc1C(F)(F)F
Reactant: F[B-](F)(F)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCC1(c2ncc(C3CC3)cc2Cl)CC1)c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
150 mg of N-[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide (step 4), 61 mg potassium cyclopropyltrifluoroborate and 340 mg cesium carbonate were dissolved in 3 ml of a mixture of toluene and water (3:1) in a microwave vial. The reaction mixture was degassed with argon for 1 min and 14 mg of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added. The vial was sealed and the reaction mixture was then stirred at 100° C. in a microwave reactor for 30 min, then at 130° C. for 30 min. Then the mixture was cooled to ambient temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a brown sticky solid, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 61 mg of N-[[1-(3-chloro-5-cyclopropyl-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide was obtained as a pale yellow sticky solid. 1H-NMR (CDCl3): 8.19 ppm (d, 1H), 7.65 ppm (d, 1H), 7.52 ppm (m, 2H), 7.40 ppm (d, 1H), 7.30 ppm (d, 1H), 6.20 ppm (s, 1H, broad), 3.68 ppm (d, 2H), 1.85 ppm (m, 1H), 1.05 ppm (m, 5H), 0.88 ppm (m, 1H), 0.70 ppm (m, 2H).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(Cl)(=O)C(Cl)=O.[C:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([NH2:33])[CH:31]=2)[CH:26]=[N:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>CN(C=O)C.ClCCl>[C:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([NH:33][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[OH:4])[CH:31]=2)[CH:26]=[N:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: O=C(O)c1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirring solution of salicylic acid (1.06 g, 7.7 mmol) and DMF (1 drop) in dichloromethane (100 mL) at 0° C. was added oxalyl chloride (1.13 mL, mmol). After 1 h, the ice bath was removed and stirring was continued for 3.5 h. Solvent was removed under vacuum with minimum heat, and after evacuating further to remove residual oxalyl chloride, the residue was redissolved in dichloromethane (80 mL) and cooled to 0° C. To this solution was then added a solution of 1-Boc-6-aminoindazole (1.86 g, 8 mmol) in dichloromethane (10 mL). After stirring for 10 min, triethylamine (1.24 mL, 8 mmol) was added. After 1 h, the solution was transferred to a separatory funnel and washed with cold water (200 mL). The organic layer was then washed with cold satd aq NaHCO3 (200 mL), dried over MgSO4, filtered and concentrated under vacuum. The product was chromatographed over silica gel (0 to 60% EtOAc in hexane) and recrystallized from dichloromethane/hexanes to give 0.482 g (17%) of crystals.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C=O)C>[CH3:12][CH:2]1[CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:19][C:17](=[CH2:16])[CH2:18][O:1]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C1COC(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a mixture of tert-butyl N-(2-hydroxypropyl)carbamate (5.00 g, 28.54 mmol, 1.00 eq) in DMF (100.00 mL), was added NaH (2.51 g, 62.79 mmol, 2.20 eq) in one portion at 0° C. under N2. The mixture was stirred at 0° C. for 1 hr, then 3-chloro-2-(chloromethyl)prop-1-ene (3.57 g, 28.54 mmol, 1.00 eq) was added to the mixture, the mixture was stirred at 0° C. for 4 hr. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with saturated brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1) to afford tert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.20 g, 9.68 mmol, 33.91% yield) as yellow oil.
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[C:9]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[C:13]([CH2:28]Br)[C:12]=2[CH:30]=1.CO.O>C1COCC1>[Cl:7][C:8]1[C:9]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[C:13]([CH2:28][O:2][CH3:1])[C:12]=2[CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc([N+](=O)[O-])c3)c(CBr)c2cc1Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
Potassium carbonate (279 mg, 2.01 mmol) was added to a solution of dimethylcarbamic acid 6-chloro-4-bromomethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 6b-1-3) (500 mg, 1.01 mmol) in THF (7.5 mL)/methanol (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (40 mg, 10%) as a white solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].NC[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:10][CH2:9][CH2:8][NH:7][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:3][C:1]#[N:2]
Reactant: NCCc1ccccn1
Reactant: CSC(=NCCSCc1ccccn1)NC#N
Product: N#CN=C(NCCSCc1ccccn1)NCCSCc1ccccn1

Procedure:
The reaction of N-cyano-N'-[2-(2-pyridylmethylthio) ethyl]-S-methylisothiourea with 2-((2-aminoethyl)pyridine by the method described in Example 7 afforded the title compound m.p. 78°-80°. (Found: C, 56.2; H, 5.7; N, 21.9; S, 16.5%. C18H22N6S2 requires: C, 55.9; H, 5.7; N, 21.7; S, 16.6%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:11].ClC1C=CC(C(C2C=CC(F)=CC=2)O)=CC=1F>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([OH:11])[CH3:9])=[C:13]([F:19])[CH:14]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Cl)cc1F
Agent: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1
Product: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 4.22 g (24.14 mmol) of 4-bromofluorobenzene and 5.00 g (28.97 mmol) of 4-chloro-2-fluoroacetophenone in analogy to the synthesis of the compound from Example 176A. A difference was that the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1). 5.23 g (73% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19]>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([CH2:17][CH2:18][OH:19])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: Nc1c(CCO)cccc1C(O)c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Nc1c(CCO)cccc1C(=O)c1ccc(Cl)cc1
Yield: 47.8 %

Procedure:
A mixture of 6.0 g (0.022 mole) of 2-amino-3-[(4-chlorophenyl)hydroxymethyl]benzene ethanol, 8.7 g (0.10 mole) of activated manganese dioxide and 250 ml of benzene was heated at reflux utilizing a Dean-Stark trap for 5 hours. The hot mixture obtained was filtered through Celite and the filtrate was concentrated to give a solid residue. This residue was recrystallized successively from carbon tetrachloride, cyclohexane and benzene, and 2-propanol to yield 2.9 g (48%) of the titled compound as a yellow solid,
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][OH:38].CC(C)([O-])C.[K+]>>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=1)[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:38][CH2:37][C:33]2[O:32][CH:36]=[CH:35][CH:34]=2)[N:7]=1)=[O:30]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: OCc1ccco1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(OCc2ccco2)n1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
A mixture of 2-chloro-4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]pyrimidine (0.18 g), approximately one equivalent of 2-furylmethanol (0.043 g) and potassium tert-butoxide (1M in tert-butanol, 0.88 ml) was stirred and heated to 100° C. for 2 hours. The mixture was partitioned between methylene chloride and water and the organic phase was washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound as a solid (0.17 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 3.2 (m, 4H), 3.73 (m, 4H), 5.01 (s, 2H), 6.29 (d, 1H), 6.42 (m, 2H), 6.97 (m, 1H), 7.1 (m, 1H), 7.24 (m, 2H), 7.49 (d, 1H), 7.63 (s, 1H), 7.87 (s, 1H), 8.03 (d, 1H), 9.03 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5](OC)=[O:6].[H-].[Al+3].[H-].[H-].Cl>O1CCCC1.O>[Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(OC)c(Br)c1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CO)c(O)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
28 g (0.12 mole) of methyl 3-bromo-2-hydroxy-4-methoxybenzoate (prepared according to the method of T. M. CRESP et al., J. Chem. Soc. Perkin Trans., Part 1, (1973), 340-345) dissolved in 250 ml of tetrahydrofuran, are added dropwise, in the course of 75 minutes, at 0° C. to a suspension of 6.06 g (0.159 mole) oflithium aluminum hydride in 100 ml of tetrahydrofuran. The reaction mixture is stirred for 3 hours at ambient temperature. Subsequently, there is added a mixture of 11.5 ml of water and 12 ml of tetrahydrofuran, followed by acifification with 28.6 ml of concentrated hydrochloric acid dissolved in 300 ml of water. The mixture is extracted with dichloromethane. The organic phases are washed with water, dried over anhydrous sodium sulfate and then evaporated pressure. The residue (22.9 g) is used as such in the following step. Yield: 91% of theory.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)=[CH:3]1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.1 %

Procedure:
A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carboxylic acid 35 (0.5 g, 1.5 mmol), 3-aminopyridine 36 (0.28 g, 3 mmol), HATU (1.14 g, 3 mmol) and DIPEA (0.78 g, 6 mmol) in DMF (4 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered and the solid was washed with H2O and dried under vacuum to give Compound 224 as a yellow solid (0.13 g, 23% yield). MS (ESI) calcd for C22H13F3N2O3: 410.09. found: 411 [M+H].