Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 12 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (18 mg, yield 12%). 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.09-8.05 (m, 3H), 7.78 (s, 1H), 7.71-7.68 (t, J=7.8 Hz, 1H), 7.24-7.19 (m, 2H), 3.66 (s, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C23H16F4N4O3: 474.13. found: 475.1 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:1].[NH:37]([C:38]([NH:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reaction time: 18 h

Procedure:
A solution of 44 mg (0.12 mmol) of 7-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 32.8 μl (0.24 mmol) of triethylamine and 28 mg (0.24 mmol) of phenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 20 mg (36.1% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N#N.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1F>CN(C=O)C.O>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: -6 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled slurry of NaH (475 mg, 11.8 mmol, 60%) in dry DMF (10 mL) was added CH2(COOEt)2 dropwise under an N2 atmosphere. After 20 minutes, 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.6 mmol) was added dropwise over 10 minutes and the mixture was stirred at −6° C. overnight. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified chromatography to give diethyl (2,5-difluoro-4-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.87˜7.84 (m, 1H), 7.54˜7.58 (m, 1H), 4.98 (s, 1H), 4.23˜4.27 (m, 4H), 1.28 (t, J=7.0 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].BrC[CH2:11][C:12]([O:14][CH3:15])=[O:13].O>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8]
Reactant: COC(=O)CCBr
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Sodium hydride (4.44 g, 60% dispersion in oil, 111 mmol) was added to a solution of 1,4-butanediol (10.0 g, 111 mmol) in THF (200 mL). After stirring 1 h at rt, the mixture was cooled to 0° C. and methyl bromomethylacetate (10.82 mL, 114 mmol) was added and the reaction was allowed to warm to room temperature. After 16 h, water (100 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (20%→30% EtOAc/Hexane) to afford 2.88 g (16%) of (4-hydroxy-butoxy)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:12][N:11]([C:21]([C:23]2[C:24]([Cl:39])=[C:25]([NH:31]C(=O)OC(C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[CH:28]=2)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C:25]1[CH:26]=[C:27]([CH:28]=[C:23]([C:21]([N:11]2[CH2:12][CH:13]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)=[O:22])[C:24]=1[Cl:39])[C:29]#[N:30]
Reactant: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(N)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Yield: 86.5 %

Procedure:
(+/−)-tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg, 0.208 mmol) was treated with TFA (25% in 1,2-dichloroethane, 2 mL, 6.49 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-7.5% methanol/dichloromethane). (+/−)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)-4-chlorobenzonitrile (86 mg) was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
In a dry round-bottomed flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 25.2 mmol) was dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 1.22 g, 30.6 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min then cooled back to 0° C. and SEM-Cl (5.4 mL, 30.4 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with 50 mL water and extracted with 150 mL diethyl ether (2×). The combined organic layers were washed twice with 30 mL water and once with 30 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on ˜20 g SiO2 and chromatographed over 200 g SiO2 with EtOAc/Hexanes (gradient: 0-15% EtOAc). All fractions containing product were combined and concentrated to afford 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (6.61 g, 80%) as a pale yellow oil which gradually solidified. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.38 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H), 5.68 (s, 2H), 3.50-3.65 (m, 2H), 0.88-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:25])[C:23]#[CH:24]>>[CH2:22]([NH:25][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[C:23]#[CH:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: C#CCN
Product: C#CCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-propynylamine to obtain 4-(2-propynylamino)-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 352.2.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[C:38]([OH:45])[CH:37]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:46](OCC)(=O)C>C1COCC1.[Pd]>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:16]([O:31][CH2:32][CH:33]([CH3:46])[CH2:35][CH3:34])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([OH:45])[CH:37]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(C)=O
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc([N+](=O)[O-])c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)COc1cccc(OCc2ccc(OC)cc2)c1-c1cc(-c2ccc(N)c(O)c2)c(C(=O)OC(C)(C)C)c(N)n1

Procedure:
A solution of tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(3-hydroxy-4-nitrophenyl)nicotinate (2.32 g, 3.78 mmol) in ethyl acetate (15.0 mL) and THF (15.0 mL) was hydrogenated at 1 atm in the presence of palladium on charcoal (10%, 0.10 g) overnight. The resulting mixture was filtered on Celite and washed with ethyl acetate and THF. The combined filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-4-(4-amino-3-hydroxyphenyl)-6-[2-[(4-methoxybenzyl)oxy]-6-(2-methylbutoxy)phenyl]nicotinate. (2.21 g, 100%); LC-MS (m/z=584, M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:22])=[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:32][C:33]([NH2:35])=[O:34].O>CN(C=O)C>[NH2:35][C:33](=[O:34])[CH2:32][N:14]1[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)=[O:9])[C:11](=[O:22])[C:12]2[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]1=2
Reactant: NC(=O)CI
Reactant: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.276 mmol), potassium carbonate (57 mg, 0.41 mmol) and iodoacetamide (255 mg, 1.38 mmol) in DMF (1.5 mL) was stirred at 50° C. for 18 hrs. Additional iodoacetamide (255 mg) and potassium carbonate (57 mg) were added, and the reaction was stirred at the same temperature for another 12 hrs. After cooling, cold water was added, and the resulting ppt was collected by filtration after chilling in an ice bath. The collected crude solid was recrystallized from aq. ethanol to give the title compound (65 mg) as a lt. brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:25]O>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:25]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)on1
Reaction time: 24 h

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:9][CH:10]=[C:11]([C:17](=[O:28])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[C:19]=2F)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].O>C1COCC1>[F:26][C:20]1[CH:19]=[C:18]2[C:23](=[C:22]([F:24])[C:21]=1[F:25])[N:9]([C:4]1([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8]1)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:28]
Reactant: CCOC(=O)C(=CNC1(CCO)CCCC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C2(CCO)CCCC2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To an iced solution of ethyl 3-[1-(2-hydroxyethyl)-cyclopentylamino]-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (22.7 g, 56.3 mmol) in THF (200 mL) was added NaH (3.60 g, 90.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture portionwise at 0° C. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were concentrated in vacuo. Flash chromatography (AcOEt:Hexane=2:1) of the residue give the title compound as a colorless solid (14.1 g, 65%). 1H-NMR (400 MHz, DMSO-d6) δ 1.27 (3H, t, J=7.3 Hz), 1.53-1.75 (4H, m), 2.10-2.26 (4H, m), 2.31-2.44 (2H, m), 4.23 (2H, q, J=7.3 Hz), 4.55-4.60 (1H, m), 7.99-8.07 (1H, m), 8.80 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH2:12]([N:11]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:24][N+:21]([O-:23])=[O:22])=[C:3]([O:2][CH3:1])[CH:10]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: C[N+](=O)[O-]
Reactant: CCN(CC)c1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 44 %

Procedure:
A solution was prepared by dissolving 30 grams (0.14 mol) of 2-methoxy-4-(N,N-diethylamino)benzaldehyde in 150 ml of nitromethane, and added with 4 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystals was obtained. The yield was 44%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)=[C:18]([O:33]C)[CH:17]=1)=[N:5][CH:6]=[N:7]2.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][N:24]=3)=[C:18]([OH:33])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: COc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of (5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine (2.71 g, 5.69 mmol) in CH2Cl2 (25 mL) cooled to −50° C., was added 1 M BBr3 in CH2Cl2 (17 mL, 17 mmol). The solution was allowed to warm to room temperature and stirred overnight, and then quenched slowly with methanol. The solvent was removed by rotary evaporation and the residue was suspended in chloroform. The product was collected by suction filtration to give 2.70 g (quantitative) of 5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol. The product was used in the following reaction without further purification. 1H NMR (CD3OD): δ 8.78 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 7.93 (m, 1H), 7.54 (m, 1H), 7.45 (d, J=5.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H) 6.87 (dd, J=7.8, 2.1 Hz, 1H), 4.12 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H). LC/MS: 460.97 (M+−1).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[N:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:24][CH2:23][CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])=[CH:12][CH:13]=1
Reactant: NCCCN1CCCCC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCCN2CCCCC2)cc1

Procedure:
For example, terephtalic acid monomethyl ester chloride is treated with an alkylamine, in this case 3-piperidinopropylamine, and triethylamine, in a suitable solvent such as dichloromethane at ambient temperature for 1-12 hours to provide the desired amide, N-(3-piperidin-1-yl-propyl)-terephthalamic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:11](=[O:12])[CH:9]([CH3:10])[NH:8]2
Reactant: C[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1Nc2cc(Br)ccc2NC1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl )-alanine (22 g, 76 mmol) in acetic acid (300 ml) was added iron powder (10 g, 180 mmol), and the mixture was stirred for 2 hours at 90° C. The reaction mixture was cooled and filtered, and the acetic acid was evaporated. The remaining slurry was extracted with methylene chloride (3×200 ml). The combined extracts were combined, dried over magnesium sulfate, filtered, and evaporated to afford 6-bromo-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (9.4 g, 51%). A sample was recrystallized from ethanol: m.p. 133-135° C. 1H-NMR (DMSO-d6) δ1.23 (d, J=6.81 Hz, 3H), 3.80 (q, J=6.81 Hz, 1H), 6.27 (bs, 1H), 6.63 (d, J=8.35 Hz, 1H), 6.72 (dd, J=8.35, 1.76 Hz, 1H), 6.80 (d, J=1.76 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a colorless foam (42%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[Br:13]Br.O>CC(O)=O>[Br:13][C:7]1[C:8]([OH:11])=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:12])[CH:1]=2
Reactant: BrBr
Reactant: Oc1ccc2ccc(O)cc2c1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2cc(Br)c(O)cc2c1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of naphthalene-2,7-diol (5.00 g, 31.3 mmol) in AcOH (25 mL) was added Br2 (3.3 mL, 62.6 mmol) in AcOH (25 mL) dropwise over 15 minutes at 10-15° C., then mixture was stirred at 10-15° C. for 1 hour. Sn powder (7.75 g, 64.6 mmol) and H2O (20 mL) was added and the mixture was heated to 80° C. for 1 hour. The mixture was diluted with ice-water (50 mL), the extracted with EtOAc (30 mL×3), organic was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (PE/EtOAc=15/1) and further prep-HPLC (0.1% TFA as additive) gave the product (2.0 g, yield 27%) as a solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)=[N:17]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Triethylamine (0.18 g, 1.8 mmol) and ethyl isocyanate (0.13 g, 1.8 mmol) were added to a solution of 5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole (0.35 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole-1-carboxamide (0.27 g, yield: 59.2%). mp: 67-69° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.63 (s, 6H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 5.79 (q, J=0.8 Hz, 1H), 6.85-7.00 (m, 1H), 7.00-7.15 (m, 2H), 8.07 (d, J=8.6 Hz, 1H).