Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13](=[O:48])[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=2)[C:17]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:16]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]C(OC(C)(C)C)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[CH:28]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:23]=3[N:15]3[C:16]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:13](=[O:48])[CH2:14]3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1ccccc1-3
Temperature: 100 °C
Yield: 75000 %

Procedure:
TFA (5 mL) was added to a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-2-(2-(tert-butoxycarbonylamino)phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (5.6 g, 10 mmol) in toluene (90 mL) and heated at 100° C. for 1 h. The reaction mixture was allowed to cool and then was carefully poured into a solution of NaHCO3 (10 g) in H2O (200 mL) while stirring. The resulting white precipitate was collected by filtration, flushed with water and EtOAc and dried under N2 to yield methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-one-10-carboxylate (2.9 g, 7.5 mol, 75%) as white solid. LCMS: m/e 389 (M+H)+, ret time 2.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1C=[CH:41][CH:40]=[CH:39][C:38]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][C:29]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1ccccc1O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Oc4ccccc4OC)cc3)c2cc1OC
Yield: 21.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methoxyphenol (32 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (16 mg, yield 18%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C@H:5]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:10][C:2]([C:2]4[CH:10]=[CH:9][C:5]5[N:6]=[CH:7][S:8][C:4]=5[CH:3]=4)=[CH:3][C:18]=3[CH2:19][CH2:4]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2ncsc2c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ncsc5c4)cc3CC[C@@H]12
Yield: 47 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid(178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 6-bromobenzothiazole (139 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (20% ethyl acetate/hexanes eluent) to give 106 mg (47%) of the title compound as an amorphous solid. mp 183°-187°. FDMS: m/e=362. α[D]589 =+87.80 (c=0.55, chloroform).
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:15]=2[CH:16]=[C:17]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C(O)(=O)C>CCOC(C)=O.CO.Br[Zn]Br.[Pd]>[N:10]1[NH:9][N:8]=[C:12]([NH:13][C:14]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:15]=2[CH2:16][CH:17]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)[CH:11]=1
Reactant: O=C(O)C1CC(=Cc2cc(Cl)ccc2Nc2cnnn2Cc2ccccc2)C1
Agent: [Pd]
Agent: Br[Zn]Br
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CC(Cc2cc(Cl)ccc2Nc2cn[nH]n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
To a solution of 3-(2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzylidene)cyclobutanecarboxylic acid 7 g (75 mg, 0.19 mmol) and dibromozinc (17.1 mg, 0.076 mmol) in EtOAc (2 mL) and MeOH (2 mL) was added 10% Pd on C [wet Degussa type] (40 mg, 0.038 mmol). The reaction was then flushed with hydrogen via vacuum/hydrogen cycles (3×) and the mixture stirred under a hydrogen atmosphere for 2 h at room temperature. Additional 10% Pd on C [wet Degussa type] (40 mg, 0.038 mmol) was added and stirred under hydrogen for a further 1 h. Acetic acid (23 mg, 21.60 μL, 0.38 mmol) was then added and mixture stirred under hydrogen overnight. Additional acetic acid (22 mg, 21.60 μL, 0.38 mmol) was added and stirred under hydrogen atmosphere again overnight. The reaction mixture was then filtered through celite washing through with methanol. The filtrate was concentrated and the material purified by FractionLynx to afford the title compound I-28 as a white solid (1.5 TFA salt) (4.0 mg, 3.9% yield). 1H NMR (500 MHz, d6-DMSO) δ 7.78 (1H, brs), 7.59 (1H, brs), 7.46 (1H, brs), 7.10-7.12 (1H, m), 7.06 (1H, d), 2.87-2.94 (1H, m), 2.72 (2H, d), 2.50-2.55 (1H, masked signal), 2.18-2.25 (2H, m), 1.84-1.90 (2H, m). MS m/z: 307.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1>>[CH:1]1([N:4]([CH:23]2[CH2:28][CH2:27][N:26]([C:30]3[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=3)[CH2:25][CH2:24]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.80 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:37]1[CH:36]=[CH:35][N:27]2[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:8])=[CH:39][CH:38]=3)=[O:23])[CH2:25][C:26]=12
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 113.5 %

Procedure:
To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 800 mg of solid. The solid is dissolved in methylene chloride washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is filtered through hydrous magnesium silicate, dried with Na2SO4 and concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 400 mg of the desired product as a white solid, m.p. 232°-235° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1[C:21]([O:35][CH3:36])=[C:22]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1.C(C1C=CC(OC)=C(N[C:48](NC2C3C(=CC=CC=3)C(OC3C=CN=C(C#N)N=3)=CC=2)=[O:49])C=1)(C)(C)C>>[C:26]([C:24]1[CH:25]=[C:20]([NH:19][C:48]([NH:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:9][CH:10]=2)=[O:49])[C:21]([O:35][CH3:36])=[C:22]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=1)([CH3:28])([CH3:29])[CH3:27]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Nc1ccc(OC2CCOCC2)c2ccccc12
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(C#N)n2)c2ccccc12
Product: COc1c(NC(=O)Nc2ccc(OC3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared from the above amine and N-(3-amino-5-tert-butyl-2-methoxyphenyl)methanesulfonamide by the procedure described for 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-cyano-pyrimidin-4-yloxy)-naphthalen-1-yl] -urea (Example 1).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].CN(C1C=CC=CN=1)C.[C:16]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17].C(N(CC)CC)C>ClCCl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]#[N:17])[CH:19]=1)(=[O:26])=[O:25]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of bromopropylamine hydrogen bromide (0.219 g, 1 mmol) in dichloromethane (2 ml) is treated with a solution of dimethylaminopyridine (0.004 g) in dichloromethane (0.5 ml) followed by a solution of 3-cyano-benzenesulfonyl chloride (0.2 g, 1.0 mmol) in dichloromethane (0.5 ml). Triethylamine (0.3 ml, 2.16 mmol) is added and the reaction mixture stirred at ambient temperature for 2 hours, then quenched with water and saturated aqueous NaHCO3, and extracted into dichloromethane. The organic phase is washed with aqueous 1M HCl solution and brine, dried over MgSO4 and evaporated to afford crude N-(3-bromopropyl)-3-cyano-benzenesulfonamide. (13C NMR, 100 MHz, CDCl3, 30.2, 32.6, 41.9, 114.3, 117.5, 130.7, 130.9, 131.1, 136.3, 142.1).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1>C(O)(=O)C>[Br:1][C:12]1[S:11][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: BrBr
Reactant: Brc1cccc(-c2cccs2)c1
Solvent: CC(=O)O
Product: Brc1cccc(-c2ccc(Br)s2)c1
Yield: 68 %

Procedure:
A solution of bromine (8 g; 50 mM) in 20 mL of glacial acetic acid was added dropwise to a vigorously stirred solution of 2-(3'-bromophenyl)thiophene (12 g; 50 mM) in 80 mL of glacial acetic acid. The resulting mixture was heated to reflux 5 hrs, cooled and poured onto ice. A solid separated which was filtered and washed with ice water, and purified on silica gel using hexane as solvent to give 68% of 2-bromo-5-[3'-bromophenyl]thiophene as an amorphous solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NC1CCC([OH:30])C1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH:4]([OH:30])[CH2:5]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCC(O)C1
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3-aminocyclopentanol hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.50-1.58 (m, 1H), 1.70-1.78 (m, 3H), 1.96 (bs, 4H), 2.34 (s, 3H), 3.32 (s, 3H), 4.20-4.32 (m, 2H), 7.69-7.75 (m, 1H), 7.79-7.85 (m, 1H), 8.20-8.29 (m, 1H), 8.69 (bs, 1H); MS (ESI) m/z 314.8 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH2:10][C:9](C(C)(C)C)(C)[CH:8]=[CH:7][C:6]=1O)(C)(C)[CH3:2]>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:2]=[CH:1][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:2]=[CH:1][CH:5]=[CH2:6].[CH2:2]=[CH:1][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)C1=C(O)C=CC(C)(C(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
Following the completion of Step III, 2,4-di-t-butyl-4-methylphenol (one part by weight per hundred parts of total monomers) was added as a 10 weight percent solution in 50/50 (by volume) toluene/isopropyl alcohol, and the polymer recovered by adding the polymerization mixture to isopropyl alcohol. The coagulated polymer was collected by filtration and dried under reduced pressure. Physical properties of the butadiene/styrene teleblock polymer prepared by this procedure are shown in Table I.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([CH:20]=O)[NH:16][C:15]=1[CH3:22])=[O:13])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1>C(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:28]2\[C:29](=[O:34])[NH:30][C:31]3[C:27]\2=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)[NH:16][C:15]=1[CH3:22])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of {3-[(5-Formyl-2,4-dimethyl-1H-pyrrole-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.200 g, 0.62 mmol) and 5-Fluoro-1,3-dihydro-indol-2-one (0.011 g, 0.62 mmol), pyrrolidine (0.003 ml) in ethanol (2 ml) was heated at 78° C. for 3 hours. The reaction was cooled to 0° C. and the resulting precipitate filtered, washed with cold ethanol. The product was suspended in ethanol (4 ml) and stirred at 72° C. for 30 minutes. The reaction was filtered, the precipitate dried in a vacuum oven at 40° C. to yield the desired compound as a solid (0.265 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 13.8 (s, 1H); 11.00 (s, 1H); 7.80 (m, 2H); 7.70 (m, 1H); 7.0 (m, 1H); 6.9 (m, 2H); 3.30 (q, 2H); 3.10 (q, 2H); 2.50 (dd, 6H) 1.60 (m, 2H)); 1.40 (s, 9H). LCMS: method D, RT=2.86 min, [M+Na+=479], and [M−Boc+Na+=379].
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:17])[C:11]3[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=3[N:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:8]2=[O:40])[C:3]2[CH:41]=[CH:42][CH:43]=[CH:44][C:2]1=2.[CH3:45][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[S:1]1[CH:5]=[C:4]([CH2:6][C:7]2([CH3:45])[C:13](=[O:14])[N:12]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:17])[C:11]3[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=3[N:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:8]2=[O:40])[C:3]2[CH:41]=[CH:42][CH:43]=[CH:44][C:2]1=2
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 130 mg (0.22 mmol) of 2-(3-Benzo[b]thiophen-3-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Example 37, in 5 mL of DMF at 0° C. is added 0.43 mL (0.43 mmol, 2.0 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 27 μL (0.43 mmol, 2.0 equiv) of methyl iodide is added. The resulting solution is stirred 4 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 3/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 106 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.92 (m, 1H), 7.66-7.05 (m, 16H), 6.81 (d, 1H, J=8.1), 4.85 (m, 1H), 4.31 (s, br, 2H), 3.80 (s, 3H), 2.97 (d, 1H, J=15.2), 2.77 (d, 1H, J=15.2), 1.20 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 618 (MH+), 617 (M+), 453; Anal. (C37H35N3O4S) Calcd. C, 71.71; H, 5.74; N, 6.76; S, 5.26 Found C, 71.94; H, 5.71; N, 6.80; S, 5.19.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>O1CCOCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[N:11][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethoxycarbonylisothiocyanate (16.7 g) was added to a stirred solution of 2-amino-5-brompyridine (20 g) in dioxane (200 mL). The mixture was stirred for 2 h at r.t. A white solid precipitated. Hexane (20 mL) was added and the white solid was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12].CC(C)=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:19](=[O:20])[NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)nc(N)[nH]1
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 74.1 %

Procedure:
A suspension of 6-methylisocytosine (0.98 g, 7.8 mmol), and 2-isocyanatoethyl methacrylate (2.20 g, 14.1 mmol) in dry pyridine (35 mL) was heated under reflux for 2 h, giving a clear solution. Cooling induced the formation of crystals. Acetone was added (20 mL), and the resulting microcrystalline powder was filtered. Recrystallization from ethanol/CHCl3 (1:1, v/v) gave analytically pure product (1.62 g, yield is 74%) 1H NMR (400 MHz, CDCl3) 13.00 (s, 1H, intramol H-bonding), 11.97 (s, 1H, CH2—NH—CO), 10.53 (s, 1H, CH2—NH—CO—NH), 6.20 (s, 1H, CHH.═.C), 5.80 (s, CCH3CH—CO), 5.56 (s, 1H, CHH═C), 4.31-4.28 (t, J=5.6, 2H, OCH2CH2N), 3.62-3.58 (q, J=5.6 Hz, 2H, OCH2CH2N), 2.26 (s, 3H, CH3—C—NH), 1.96 (s, 3H, CH3—C═CH2), IR (neat) 3250-2800, 1726, 1699, 1664, 1641, 1583, 1521, 1253, 1172, 939 cm-1; Melting point Tm=206.7° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.O>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 2.5 g (7.7 mmol) N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 51 ml THF at 4° C. was added dropwise over 30 min 10.2 ml (10.2 mmol) potassium bis(trimethylsilyl) amide (1M in THF). The reaction mixture was stirred for 30 min and subsequently treated at 4° C. dropwise over 30 min with 1.46 ml (7.7 mmol) 3,5-bis-trifluoromethyl-benzylbromide. The reaction mixture was stirred for 1.5 h at 4° C., treated with 31 ml water and extracted. The aqueous phase was separated and adjusted to pH 12 with 2N NaOH and subsequently extracted with 30 ml ethyl acetate. The aqueous phase was separated, the combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2: MeOH=99:1) to yield 3.6 g (84.1%) product as beige foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[OH:39].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[O:39][C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 38 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (1.14 g, 8.25 mmol) is added to a solution of methyl 3-(5-fluoro-2-nitrophenyl)-tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.93 g, 2.74 mmol) and 2,4-dichlorophenol (0.66 g, 4.07 mmol) in N,N-dimethylformamide at 38° C. The reaction mixture is stirred at 38° C. for 3 days, cooled to room temperature and poured into 1M hydrochloric acid. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and 30% to 40% ethyl acetate in hexanes solutions gives the title product as a yellow foam which is identified by NMR spectral analysis.