Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[C:15]([CH3:19])[C:16]([CH3:18])=[CH:17][C:8]=3[NH:7][C:6]=2[N:20]=1.[H-].[Na+].[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29]Cl)[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][N:7]1[C:8]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:21])=[CH:3][C:2]([CH3:1])=[N:20][C:6]1=2)[CH3:25]
Reactant: CCN(CC)CCCCl
Reactant: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCN1c2cc(C)c(C)cc2N(C)C(=O)c2c(C)cc(C)nc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 1.8 mg of 6,11-dihydro-2,4,6,8,9-pentamethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 30 ml of dimethyl formamide and 0.34 gm of 50% sodium hydride in mineral oil was stirred in a nitrogen atmosphere at 50° C. for 30 minutes. Then, a solution of 1.5 gm of 3-diethylaminopropyl chloride in 15 ml of dimethyl formamide was added dropwise at room temperature, and the mixture was heated on an oil bath at 120° C. for 2 hours and then evaporated in vacuo. The residue was admixed with dilute ammonia, and the mixture was repeatedly extracted with ether. The combined ether extracts were dried with sodium sulfate, the ether was distilled off, and the residue was recrystallized from petroleum ether (m.p. 100°-140° C.), yielding 53% of theory of the compound named in the heading, which had a melting point of 104°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH:19](O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:21])([CH3:22])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Yield: 52.1 %

Procedure:
To a solution of methyl 2-(3-chloro-5-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (250 mg, 0.64 mmol) in dichloromethane (5 mL) was added a solution of trifluoroacetic acid (300 mg, 0.8 mmol) in dichloromethane (5 mL) under a nitrogen atmosphere with an ice bath slowly (1.5-2 h). The resultant mixture was stirred at room temperature for 3 h. The mixture was treated with 1 g of Sodium bicarbonate and filtered. The filtrate was concentrated, and purified on preparative Thin layer chromatography to afford 125 mg of methyl 2-(3-chloro-5-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield=52%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]([O:28][C:26](=[O:27])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)=[CH:24][CH:23]=1)([CH3:31])[CH3:30]
Reactant: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)n(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2-(4-Isopropoxycarbonylamino-phenyl)-6-methoxy-indole-1-carboxylic acid tert-butyl ester (17.4 g, 41 mmol), CH2Cl2 (50 mL), and TFA (50 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted in CH2Cl2, and washed with sat. aq. NaHCO3. The organic layer was dried, concentrated, and triturated with ether to provide [4-(6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.4 g, 86%) as a grayish solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Br:22])[CH:15]=2)[C:7]=1[F:23])[CH3:2].C(ON=O)(C)(C)C.[ClH:32]>CC#N>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:32])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Br:22])[CH:15]=2)[C:7]=1[F:23])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)c(Oc2cc(Br)cc(C#N)c2)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 60 °C
Yield: 64 %

Procedure:
The aniline 117b (3.98 g, 10.10 mmol) was dissolved in anhydrous CH3CN (35 mL) under nitrogen. This solution was then added dropwise to a mixture of tert-butylnitrite (2.40 mL, 20.20 mmol) and CuCl2 (2.72 g, 20.20 mmol) that had been prepared under nitrogen and warmed to 60° C. The reaction temperature was maintained at 60° C. for 2 h, then cooled to 0° C. A 5% aqueous HCl solution (80 mL) was added, and the mixture was extracted with 1:1 EtOAc/hexanes (3×75 mL). The combined organics were washed with brine (75 mL), dried over anhydrous MgSO4, and evaporated. The remaining oil was purified by flash chromatography on silica gel (0% to 30% EtOAc/Hexanes) to provide 2.67 g (64%) of the [4-chloro-3-(3-bromo-5-cyano-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (117c).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=3)[N:8]=[C:2]12.C(O)C.[OH-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:8]=[C:2]12
Reactant: CCOC(=O)Cc1ccc(-c2cn3ccsc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2cn3ccsc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
A mixture of 5.7 g of ethyl 4-(imidazo[2,1-b]thiazol-6-yl)phenyl-acetate, 25 ml of ethanol, 0.96 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 2.9 g of 4-(imidazo[2,1-b]thiazol-6-yl)phenylacetic acid as colorless crystals melting at 248°-249°C with decomposition.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][CH2:20][NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[C:24]1([CH2:23][C:22]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11]3)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added, at ambient temperature, to a solution of 6.88 mmol of the product obtained in Step B in 30 ml of acetone. The solution is stirred for 2 hours at ambient temperature and is then filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica gel to yield the title product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4](=O)[NH:5][N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.P(Br)(Br)([Br:24])=O.CN(C=O)C>>[Br:24][C:4]1[N:5]=[N:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:8][C:3]=1[C:2]([F:21])([F:20])[F:1]
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-2H-pyridazin-3-one (example C.26 step 6) (9.61 g, 31 mmol), POBr3 (26.8 g, 94 mmol) and DMF (0.72 mL, 9 mmol) was stirred for 3 h at 105° C. under nitrogen atmosphere. The reaction mixture was poured (the mixture was nearly solid) onto water (300 mL) and stirred for 2 h at 23° C., the precipitated solid was filtered off and applied onto silica gel for silica gel column chromatography with heptane/EtOAc 4:1→2:1 to give the title compound as a light brown solid (11.22 g, 97%). MS (ISP) 371 [(M+H)+], 373 [(M+2+H)+]; mp 123-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[NH:20][C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[N:20]([CH2:41][C:42](=[O:43])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)[nH]c(=O)n(C)c12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)n(CC(=O)c3ccccc3)c(=O)n(C)c12
Yield: 84.3 %

Procedure:
A solution of methyl 6-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (50 mg), α-bromoacetophenone (27 mg) and potassium carbonate (25 mg) in N,N-dimethylformamide was stirred at 25° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (51 mg) as a white solid.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.C[O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:23]>>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH2:12][C:13]([NH:23][C@H:22]([C:21]([OH:31])=[O:20])[CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:15])[CH3:11])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N[C@@H](Cc2cccnc2)C(=O)O)cc1
Yield: 17 %

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(3-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-β-(3-pyridyl)alanine (166 mg, 17%). The title compound was prepared via hydrolysis of the methyl ester using 1N aqueous NaOH in dioxane/water (129 mg, 100%).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:7]=1[CH:8](OC)[O:9]2.[Br-].[Br:27][C:28]1[S:32][C:31]([Zn+])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:27][C:28]1[S:32][C:31]([CH:8]2[C:7]3[CH:16]=[C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:19][C:6]=3[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[O:3][CH:2]([F:25])[F:1])[O:9]2)=[CH:30][CH:29]=1
Reactant: [Zn+]c1ccc(Br)s1
Reactant: COC1Oc2cccc(OC(F)F)c2-c2ccc(NS(C)(=O)=O)cc21
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(c1ccc(Br)s1)Oc1cccc(OC(F)F)c1-2
Reaction time: 0.08 h

Procedure:
A solution of Example 96C (50 mg, 0.13 mmol) in dichloromethane (20 ml) at −20° C. was treated with borontrifluoridediethyletherate (184 mg, 1.3 mmol) dropwise, stirred for 5 minutes, treated with 5-bromo-2-thienylzincbromide (7.8 ml of 0.5M solution in THF, 3.9 mmol) dropwise over 2 minutes, stirred for 15 minutes, treated with saturated NaHCO3 solution (15ml), extracted with dichloromethane. The extract was concentrated and the concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product. MS (ESI(−)Q1MS) m/z 500 and 502 (M−H)−; 1H NMR (400 MHz, CD3OD) δ 8.29 (d, J=9 Hz, 1H), 7.32 (dd, J=9 Hz, 2 Hz, 1H), 7.21(t, J=9 Hz, 1H), 7.16 (d, J=2 Hz, 1H), 6.88 (t, J=74 Hz, 1H), 6.84-6.89 (m, 3H), 6.59 (dd, J=4 Hz, 1Hz, 1H), 6.39 (s, 1H), 3.01 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].C[O:13]B(OC)OC.C([Li])(C)(C)C>>[F:11][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][S:9][C:10]=2[C:2]=1[OH:13]
Reactant: Fc1ccc2ccsc2c1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Product: Oc1c(F)ccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
(Ref: Briner, K; Burkholder, T. P; Conway, R. G; Cunningham, B. E; Finley, D. R; Heinz, L. J; Jesudason, C. D; Kohlman, D. T; Liang, S. X; Xu, Y. C. Preparation and use of serotonergic benzothiophenes. WO 0109126 A1. Chem. Abs. 134:162912). To a solution of 7-bromo-6-fluoro-1-benzothiophene (0.2 g, 0.9 mmol) and trimethylborate (0.2 mL, 1.8 mmol) at −78° C. was added tert-butyllithium dropwise. After 10 mins at −78° C. the reaction was quenched by pouring onto saturated ammonium chloride. This was extracted with ethyl acetate (3×10 mL) and the solvent removed in vacuo from the combined organic extracts. The residue was taken up in ethyl acetate (4 mL) and 10% aqueous hydrochloric acid (4 mL) was added, the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The residue was taken up in TBF (10 mL), water (2 mL) and cooled to 0° C. then 10% aqueous sodium hydroxide (2 mL) and 28% hydrogen peroxide (1 mL) were added to this and stirred for 0.5 h at 0° C. The mixture was warmed to room temperature and stirred for 2 hours, before a acetic acid (3 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL), dried (MgSO4) and the solvent removed in vacuo, to give a purple solid. This was purified by flash chromatography with a gradient of 0-20% ethyl acetate in iso-hexane to give the title compound (56 mg, 38%); δH (300 MHz, CDCl3) 7.41 (4H, m, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccc2c1N
Yield: 93.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3,5-bis(trifluromethyl)phenylboronic acid (258 mg, 1.000 mmol) were reacted to afford the title compound 200 mg, 94% yield as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.50 (br, 1H), 8.13 (s, 2H), 7.99-7.93 (m, 2H), 7.84-7.73 (m, 2H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=443 (M+H). HPLC 2.85 min.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CC(C)=O.O>[CH2:49]([O:48][C:46]([CH2:45][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][C@H:16]1[C@@H:20]([NH:22][C:23]1[N:28]=[C:27]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[CH:30]2)[CH:26]=[CH:25][N:24]=1)[CH3:21])=[O:47])[CH3:50]
Reactant: CCOC(=O)CBr
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)Nc2cccc3ccccc23)C[C@H]1[C@H](C)Nc1nccc(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.5 %

Procedure:
To a solution of 2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 26 mg) in 0.5 mL of acetone was added potassium carbonate (11 mg) and ethyl bromoacetate (13.2 mg). The solution was stirred for 48 hours at room temperature, then diluted with 0.5 mL of water and extracted with 3×0.5 mL of CH2Cl2. The combined organics were washed with 1 mL of brine, dried with Na2SO4, and concentrated. The residue was purified by preparative HPLC (60:40 95% H2O-5% TFA:95% CH3CN-5% TFA) followed by preparative thin-layer chromatography, eluting with 95:5 25 CHCl3-isopropanol to provide 8.7 mg of the title compound. Mass spectrum (ESI) 579.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:22]([O-])([OH:24])=[O:23].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C(=O)Cc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A heterogeneous mixture of 2-(3,4-dichloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ethanone (8.33 g, 25.6 mmol) in acetic anhydride (65 ml) was added dropwise to a cooled (0° C.) solution of 65% nitric acid (140 ml) and acetic anhydride (21.3 ml). The resulting mixture was stirred at 0° C. for 2 h. Water was added dropwise and the resulting heterogeneous mixture was allowed to stir and warm-up slowly. The crude was then filtered and the beige solid was washed several times with distilled water and dried under HV (6.98 g, 74%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][B:44]1[O:48]C(C)(C)C(C)(C)[O:45]1>CC#N>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:43][B:44]([OH:48])[OH:45])=[CH:33][CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(CBr)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCB(O)O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 65 °C
Yield: 81 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (85.0 mg, 0.172 mmol), potassium carbonate (0.119 g, 0.859 mmol), and 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.152 g, 0.688 mmol) in MeCN (3 mL) in a sealed tube was heated to 65° C. with stirring. After 2 hours the mixture was cooled to RT, filtered to remove solids, and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/water to give the title compound (77 mg, 81%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.15 (s, 1H) 8.03 (s, 2H) 7.97 (dd, J=8.8, 5.4 Hz, 2H) 7.53 (d, J=9.0 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.90 (d, J=9.1 Hz, 2H) 3.58 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.24-2.38 (m, 1H) 0.76-1.10 (m, 3H) 0.47 (br. s., 1H). LCMS (m/z, ES+)=553 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5]([CH3:8])([CH3:7])[CH2:4][O:3]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>ClCCl>[CH3:1][C:2]1([CH3:9])[N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:8])([CH3:7])[CH2:4][O:3]1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)COC(C)(C)N1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1C(C)(C)COC1(C)C
Reaction time: 16 h
Yield: 80 %

Procedure:
12.11 g (100.0 mmol) of 2,2,4,4-tetramethyl-1,3-oxazolidine (can also be employed in the form of the mixed fraction) were added gradually at room temperature to a solution of 5.43 g (50.0 mmol) of ethyl chloroformate in 50 ml of dry dichloromethane. After stirring for 16 hours, the reaction mixture was poured into 40 ml of 2N HCl. The phases were separated, the aqueous phase was extracted three times with 20 ml of ether each time and the combined organic phases were deacidified and dried over solid sodium hydrogen sulphate and sodium sulphate in the amount ratio 1:2. After the removal of the solvent in vacuo at a maximum of 100 mbar/40° C. bath temperature, the crude product was distilled under reduced pressure. 8.05 g (80%) of the title compound were obtained as a colorless liquid of b.p.: 87° C./10 mbar and RF =0.61 (silica gel, ether/pentane 1:1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:23])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[C:31]([C:30]1[CH:35]=[CH:36][C:27]([CH2:26][NH:25][C:13](=[O:23])[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (3.71 g) is added to an ice-cold stirred solution of cinnamic acid (3.13 g) in 30 mL tetrahydrofuran. After stirring for an additional 1 hr, methyl 4-(aminomethyl)benzoate hydrochloride (4.7 g) and triethylamine (3.23 mL) are added and the final mixture stirred while immersed in an ice water bath for an additional 30 min, followed by stirring overnight at room temperature. After removal of the solvent by rotary evaporation, the residue is taken up in chloroform (250 mL) and extracted with water (200 mL), 1N HCl (3×50 mL), water (100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) and the final chloroform layer dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo, the crude product (2.74 g) is suspended in 100 mL tetrahydrofuran and 20 mL 2N NaOH and the mixture stirred at room temperature overnight. The mixture is then made acidic by addition of excess 1N HCl, and the precipitate recovered by filtration. After washing the filter cake with water and pressing to remove as much water as possible, the white solid is crystallized from methanol/2N HCl as N-(4-carboxybenzyl)cinnamamide, m.p. 238°-239° C.