Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:24])[O:21]2)=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](=[N:9]\[H])/[NH2:8].[BrH:31].CCOCC>C(O)(=O)C>[BrH:31].[BrH:31].[NH2:1][C@H:2]([C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:20](=[O:24])[O:21]2)=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: [H]/N=C(/N)NCCC[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1

Procedure:
The hydrochloride salt from Example VIII, above (0.247 g, 0.438 mmol), was treated with 3 ml of 32% hydrogen bromide in acetic acid for 75 min at room temperature. Addition of 70 ml ether gave crude 7-(L-arginamido)-3-phenylcoumarin dihydrobromide that was precipitated twice from methanol/ether yielding 0.221 g (91%) of an off white powder: mp 168°; TLC (SiO2 : ethyl acetate/2-butanone/formic acid/water-5:3:1:1) Rf=0.30. This material, without further purification, was dissolved in 4 ml of dry pyridine containing 0.11 ml (0.80 ml) of triethylamine and 0.436 g (1.99 mmol) of N-benzoyloxy-succinimide. The reaction proceeded overnight at room temperature. The pyridine was removed in vacuo and the crude product was purified by preparative layer chromatography on silica gel with several developments in ethyl acetate/formic acid/water (32:1:1). The purified material was taken up in 1000 ml ethyl acetate/1-butanol (1:1) and washed with 200 ml volumes of N HCI, brine (3x), and water (2x). The organic layer was evaporated in vacuo yielding 0.139 g (65.4%) of II as the hydrochloride salt: mp 251°; TLC (SiO2 : ethyl acetate/2-butanone/formic acid/water-5:3:1:1) Rf=0.67.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].[C:14]([CH2:16][CH2:17][N:18]([CH:23]=O)[CH2:19]C(O)=O)#[N:15]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][N:18]([CH2:17][CH2:16][C:14]#[N:15])[CH:23]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: N#CCCN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CCC#N)cc1-c1ccccc1

Procedure:
17.4 g of phenylacetylenecarboxylic acid ethyl ester and 15.6 g of N-(2-cyanoethyl)-N-formylglycine are dissolved in 100 ml of acetic anhydride, and the solution is refluxed for 24 h. The mixture is concentrated by evaporation under reduced pressure; the residue is then taken up in toluene, and purified by chromatography through silica gel. The solvent is evaporated off, and from the eluate is obtained 4-ethoxycarbonyl-1-(2-cyanoethyl)-3-phenylpyrrole in the form of a yellow oil (compound No. 3.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[C:8]([Cl:13])=[CH:9][CH:10]=[C:11]([Cl:12])[C:3]=1[O:2][CH3:1]
Reactant: CN
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Solvent: CCOCC
Product: CNC(=O)c1c(Cl)ccc(Cl)c1OC
Temperature: 4 °C

Procedure:
Methylamine (146.1 grams; 4.70 moles) contained in 40% aqueous methyl amine solution (365.4 grams) was placed in a 3-liter, 3-necked glass reaction flask equipped with addition funnel, stirrer, thermometer and reflux condenser and containing ether (1200 ml) cooled to 4° C. 2-methoxy-3,6-dichlorobenzoic acid chloride (375 grams; 1.56 moles) in ether (50 ml) was added dropwise with stirring maintaining the temperature below 8° C. After the completion of the addition the reaction mixture was stirred for an additional two hours at a temperature of between 2° and 5° C. The insoluble white solid was filtered with suction, washed with water, transferred to a 3-liter beaker and stirred fifteen (15) minutes with 10% sodium carbonate (2 liters). The insoluble white solid was filtered with suction, washed with water and dried. The product weighed 352 grams and had a melting point of 172.5°-175° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:31])=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2-fluorobenzoic acid: MS (APCI) m/z 420 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])[CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (689 mg, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:30][OH:31]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:30][OH:31])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Yield: 87.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-methyl-phthalimido)propanoic acid (2.40 g, 6.26 mmol), N,N′-carbonyldiimidazole (1.12 g, 6.91 mmol) and hydroxylamine hydrochloride (530 mg, 7.62 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)-propionamide as a white solid (2.19 g, 88% yield): mp, 180.0-181.5° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.49 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCR), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.61-7.74 (m, 3H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.67, 21.33, 34.31, 50.14, 55.45, 63.72, 111.75, 112.33, 119.61, 123.03, 123.52, 128.63, 131.32, 131.61, 134.88, 145.54, 147.67, 148.52, 166.02, 167.62, 167.73; Anal Calcd for C21H22N2O6: C, 63.31; H, 5.57; N, 7.03. Found: C, 63.29; H, 5.69; N, 6.86.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1C
Product: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Cl
Yield: 86 %

Procedure:
Compound 29 was prepared as described for 24 except that 28 was used in place of 23; 86% yield; m.p. 152°-3° C. (CHCl3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[O:23]([C:21]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCSc1cccc2nccn12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCSc1cccc2nccn12)Oc1ccccc1
Yield: 91.3 %

Procedure:
To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1,2-a]pyridine (5.83 g, 30 mmoles) and pyridine (4.36 ml, 60 mmoles) in methylene chloride (120 ml) was added phenyl chloroformate (7.53 ml, 60 mmoles) with stirring under ice-cooling and the mixture was stirred under ice-cooling for 30 minutes. The reaction solution was washed in turn with an aqueous 5% sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 8.61 g of the desired product (91.3%, oily product).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[S:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[S:6][C:7]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr

Procedure:
A mixture of ethyl 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylate (9.0 g, 0.035 mol), N-bromosuccinimide (6.53 g, 0.037 mol) and benzoyl peroxide (130 mg) in carbon tetrachloride (150 ml) was refluxed and illuminated with a sunlamp for 2 hours. The resulting suspension was cooled, filtered and the filter cake was triturated with methanol to give 9.9 g (85%) of the methanol-insoluble ethyl 3-bromomethyl-5-chlorobenzo-[b]thiophene-2-carboxylate: mp 148°-150° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(F)c2)cc1
Yield: 29.6 %

Procedure:
The title compound (85 mg, 30%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (275 mg, 0.818 mmol, prepared in example 1), 3-fluorobenzeneboronic acid (140 mg, 1.001 mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.033 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water), and 1,2-dimethoxyethane (5.5 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 270 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:17][C:18]2[O:22][C:21]([C:23]([O:25]CC)=O)=[N:20][CH:19]=2)[CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:32][CH2:31]1.C[Al](C)C.C1(C)C=CC=CC=1>ClCCCl>[CH:14]1([N:13]([CH2:17][C:18]2[O:22][C:21]([C:23]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:42][CH2:41]3)=[O:25])=[N:20][CH:19]=2)[S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:28])(=[O:11])=[O:12])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ncc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)C2CC2)c(C)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](cyclopropyl)amino}methyl)-1,3-oxazole-2-carboxylate (25 mg, 0.07 mmol) and 1-(N-methylpiperidin-4-yl-methyl)piperazine (26 mg, 0.13 mmol) in DCE (1 mL) was added trimethylaluminium 2M in toluene (65 μL, 0.13 mmol) and the mixture stirred at 60° C. for 1.5 h. The reaction mixture was washed with saturated aqueous NaHCO3 and extracted with DCM. The organic extract was dried over MgSO4, and concentrated in vacuo. The residue was purified by FCC eluting with 95:4.5:0.5 NH3/MeOH/DCM. This afforded the title compound as a colourless oil.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1COCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1COCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 67 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(diethylamino)methyl]-morpholin-4-yl]ethanamine in a yield of 67% of theory. Colourless crystals, m.p. 150°-151° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:12][C:13]([C:15]1[S:37][C:18]2[N:19]=[C:20]([S:35][CH3:36])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31])[CH:24]=3)[C:17]=2[C:16]=1[NH2:38])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([NH:12][C:13]([C:15]1[S:37][C:18]2[N:19]=[C:20]([S:35][CH3:36])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH2:33][CH2:34][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:31])=[O:32])[CH:24]=3)[C:17]=2[C:16]=1[NH2:38])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reactant: CN1CCNCC1
Product: CSc1nc(-c2cccc(NS(=O)(=O)CCN3CCN(C)CC3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
Reaction of N-methyl piperazine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and 0.1% aq TFA.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxybenzoate (1.84 g, 10 mmol) in N,N-dimethylformamide (100 mL) were added phenol (0.94 g, 10 mmol) and potassium carbonate (2.67 g, 20 mmol). The mixture was heated to 80° C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1) to give methyl 2-methoxy-4-phenoxybenzoate (2.1 g, 81%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12]I>CN(C)C=O>[CH3:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccc2cc[nH]c2c1
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
NaH(8.2mm) in N,N-dimethylformamide ("DMF") (20 mL) was cooled to 0° C., then treated with a solution of the known 1H-indole-6-methanol (1 g,6.8 mm) in DMF(8 mL). After stirring for 1 hour at 0° C., methyl iodide ("MeI") (0.51 mL, 8.2 mm) dissolved in DMF (2 mL) was added, and the mixture was stirred at 0° C. overnight, then poured into ice/H2O (250 ml) and extracted with EtOAc(50 mL×3). The organic fraction was dried over MgSO4, filtered, evaporated and purified by flash column chromatography to afford 1-methyl-1H-indole-6-methanol (0.82 g. 75%). This product (1-methyl-1H-indole-6-methanol, 1 g, 6.2 mm) was dissolved in a mixture of pyridine (5 mL) and acetic anhydride (Ac2O) (5 mL) and stirred at room temperature overnight. The solvent was evaporated, and the residue purified by flash column chromatography to afford 1.09 g of Acetic acid 1-methyl-1H-indol-6-yl methyl ester.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[CH2:25][OH:26])[CH:7]=[CH:8][C:9]=1[Cl:10].[CH3:27]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][CH:12]2[CH2:25][O:26][CH3:27])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of sodium hydride (10.5 mg) in THF (1 mL) was added a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (65.7 mg) in THF (1 ml), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added methyl iodide (49.7 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (58.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)ccc1CBr
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A mixture of 5-fluoro-2-methylbenzonitrile (10.0 g, 74.0 mmol), N-bromosuccinimide (NBS, 13.2 g, 74.0 mmol), benzoyl peroxide (0.2 g, 0.82 mmol), and carbon tetrachloride (100 mL) was refluxed for 18 h. The reaction mixture was then cooled to room temperature and filtered through fritted glass. The solid in the funnel was washed with carbon tetrachloride (3×50 mL) and evaporated to dryness under vacuum to provide 16.1 g, 102% yield of product.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[N:19]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:18]4[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>CC1C=CC=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH2:9][CH2:10]2)[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4n3Cc3cccnc3)CC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2nc3ccccc3n2Cc2cccnc2)CC1
Reaction time: 2 h
Yield: 50 %

Procedure:
To a stirred mixture of 76 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1-(3-pyridinylmethyl)-1H-benzimidazole and 360 parts of methylbenzene were added dropwise 41 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 2 hours at reflux. Another portion of 5 parts of ethyl carbonochloridate was added dropwise. Upon completion, stirring was continued for 2 hours at reflux. After cooling, the organic layer was washed with a sodium carbonate solution, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 35.6 parts (50%) of ethyl 4-[[1-(3-pyridinylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate (57).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:27]([F:34])[CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 4-chloro-2-fluorophenyl boronic acid (175 mg, 1.0 mmol) to afford after chromatographic purification the title compound (128 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 7.28-7.29 (m,1H), 7.05-7.15 (m, 4H), 3.6-4.2 (m, 3H), 2.80-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 429 [M+H+].