Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:43]=[CH:42][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1)[C:19]1C=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1([CH2:4][N:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[C:39](=[O:40])[CH2:38][N:35]2[CH2:34][CH2:33][CH:32]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Product: O=C(c1ccc(Oc2ccccc2)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Yield: 17.4 %

Procedure:
The title compound (30 mg) was prepared according to the general procedure of Example 1 from 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (73 mg, 0.31 mmol) and [4-(4-benzyloxy-benzoyl)-piperidin-1-yl]-acetic acid (110 mg, 0.31 mmol). 1H NMR (400 MHz, MeOD) δ: 8.01 (d, J=9.1 Hz, 2H), 7.44 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.1 Hz, 2H), 7.33 (d, J=7.1 Hz, 1H), 7.12 (d, J=9.1 Hz, 2H), 4.66 (s, 1H), 4.57 (s, 2H), 4.38 (s, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.78-3.66 (m, 4H), 3.36 (d, J=7.1 Hz, 2H), 3.33-3.29 (m, 5H), 2.68-2.58 (m, 2H), 2.18-2.02 (m 4H), 1.11-0.87 (m, 1H), 0.65-0.43 (m, 2H), 0.32-0.21 (m, 2H). HRMS calculated for C33H38N4O5=571.2920. found (ESI, [M+H]+), 571.2949. LRMS m/z: ES+=571.1 (M+H), retention time 1.49.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:22].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:22])=[CH:7]2
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: Brc1cccc2cnccc12
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: O
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
3.1 A suspension of 6.24 g (30.0 mmol) of 5-bromoisoquinoline and 17.5 g (30 mmol) of magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml of 2-propanol is stirred at room temperature for 50 hours. The reaction mixture is evaporated in vacuo, and saturated sodium chloride solution, saturated sodium hydrogencarbonate solution and dichloromethane are added. The organic phase is separated off and washed a number of times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with tert-butyl methyl ether, giving 5-bromoisoquinoline 2-oxide as colourless crystals; HPLC/MS: 1.51 min, [M+H] 224/226.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
To 7-azaindole 1 in dichloromethane was added 6-chloronicotinoyl chloride 8, followed by aluminum chloride, under an atmosphere of nitrogen at −10° C. The reaction was stirred and allowed to warm to room temperature overnight. The reaction was quenched with 3 N hydrochloric acid and concentrated hydrochloric acid was added until all solids dissolved. The mixture was extracted with dichloromethane and the combined organic portions were dried with magnesium sulfate, filtered, and the filtrate was concentrated. The resulting solid material was recrystallized from chloroform/hexane to provide (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:24])[CH:3]=1.C([Si](C)(C)[O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])(C)(C)C.C([Si](C)(C)OCCOC(O)C)(C)(C)C.C[Si](C)(C)[O-].[K+]>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:24])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Agent: CC(O)OCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
(4,5-Dichloro-2-fluoro-phenyl-(7-fluoro-6-nitro-quinazolin-4-yl)-amine (Compound 25, 0.723 grams, 1.94 mmol), 2-[2-(tert-butyl-dimethyl -silanyloxy)-ethoxy]-ethanol (Compound 28a (0.64 grams, 2.9 mmol) and potassium trimethylsilanolate (0.75 gram, 5.83 mmol) were dissolved in dry DMSO (42 ml) and the resulting mixture was stirred under nitrogen atmosphere for 5 hours at 25° C. The obtained deep crimson mixture was thereafter extracted with ethyl acetate (EtOAc) and water, and the organic phase was washed with NaHCO3 (4%) and brine, and dried over Na2SO4. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of 2% MeOH in CH2Cl2 as eluent, to obtain Compound 29a (0.217 gram, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.51 g (2.7 mmol) of 2,6-dichlorobenzamide and 0.41 g (3.2 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-dichlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.86 g (2.7 mmol) of 4,5-dibromo-2-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.28 g (Yield 43%) of the title compound as a solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#N)=[CH:30][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[OH:37]>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:37])=[CH:30][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminum hydride (54-ml., 25% solution in toluene) is added with stirring to a solution of p-hexadecylaminobenzonitrile (11.4 g.) under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The crude product is dissolved in dichloromethane and filtered through hydrated magnesium silicate (80 g.) to give a white crystalline material on removal of the solvent. The product is recrystallized from dichloromethane/hexanes giving colorless fine needles (6.0 g.), m.p. 84°-85° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl isonipecotate (27.6 g, 175 mmol) in dichloromethane (50 ml) was added dropwise over 10 minutes to a solution of 3-chlorobenzoyl chloride (20 ml, 160 mmol) and triethylamine (28 ml, 200 mmol) in dichloromethane (500 ml) cooled to between 10 and 15° C. The reaction was then stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with ether, the solution washed with 1N hydrochloric acid, sodium carbonate solution (×3) and brine. It was then dried over MgSO4 and evaporated under reduced pressure, to give the title compound as a solid, 44.4 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 2-hydroxy-4-methoxy-1-nitrobenzene (520 mg, 3.08 mmol), benzyl bromide (522 mg, 3.08 mmol) and potassium carbonate (637 mg, 4.61 mmol) in DMF (3 mL) is stirred at 65° C. for 18 h. The mixture is poured into water and the mixture extracted with EtOAc. The organic phase is washed with water (3×) and brine (1×) and is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11](Br)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]([C:6]2[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2cc3ccccc3s2)n1
Temperature: 140 °C
Yield: 16.9 %

Procedure:
A 5 mL Personal Chemistry microwave tube was charged with 1-(2-(4-(benzo[b]thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (103 mg, 0.22 mmol), phenyl boronic acid (55 mg, 0.44 mmol), a 2 M aqueous solution of sodium carbonate (0.22 mL, 0.44 mmol), dioxane (2 mL) and tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.044 mmol). The vessel was sealed and heated to 140° C. for 20 min with stirring. After cooling to r.t. the mixture was diluted with ethyl acetate (10 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (chloroform/methanol 99:1 to 96:4 followed by a second column: ethyl acetate/hexane/methanol 50:48:2) to afford the title compound (17 mg, 17%). 1H NMR: δ (CDCl3, 400 MHz) 1.47 (s, 6H), 3.60-3.68 (m, 2H), 3.81-3.92 (m, 2H), 6.32 (br. s., 1H), 6.92 (s, 1H), 7.26 (t, J=7 Hz, 1H), 7.32 (t, J=7 Hz, 1H), 7.36 (dd, J=3 Hz, 2H), 7.44-7.47 (m, 3H), 7.50 (d, J=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 8.22 (s, 1H): HRMS (M+H)+ Calcd. C25H23N5O2S 458.1650. found 458.1616.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]([CH:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH2:19][CH:18]2[CH:24]([CH3:26])[CH3:25])=[O:16])[C:5]1=[O:27].C(O)(C(F)(F)F)=[O:29].CS(C)=O>>[NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([S:13]([CH3:14])=[O:29])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]([CH:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH2:19][CH:18]2[CH:24]([CH3:26])[CH3:25])=[O:16])[C:5]1=[O:27]
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ccc2c(c1)n(CCN)c(=O)n2C(=O)C1CC(C)CCC1C(C)C
Solvent: CS(C)=O
Product: CC1CCC(C(C)C)C(C(=O)n2c(=O)n(CCN)c3cc(S(C)=O)ccc32)C1
Reaction time: 18 h

Procedure:
A 10 mL reaction flask was charged with 3-(2-Amino-ethyl)-1-(2-isopropyl-5-methyl-cyclohexanecarbonyl)-5-methylsulfanyl-1,3-dihydro-benzoimidazol-2-one (Compound #42, 300 mg) and 1% TFA/DMSO (1 mL). Oxygen was bubbled through the reaction mixture for 20 min and sealed. The reaction mixture was stirred for 18 h and crude product was purified by preparative HPLC (Ultro 120 (10 um) C18Q) using a 40-60% acetonitrile/H2O (with 0.1% TFA) gradient. The pure fractions were combined, concentrated and lyophilized to give a light fluffy colorless solid (296 mg 94%). MS (ESI) m/z 406 (M++1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](C4C=CC([N+]([O-])=O)=CC=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O>C(OCC)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:8][C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(Cc4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
Prepared from starting compound A1 and 4-picolylchloride hydrochloride as described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl ether is added and the resulting mixture stirred for 30 min. The precipitate is filtered off and dried. M.p. 196-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=O)[C:4]=12)=[O:7].C([NH2:16])=O>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([NH:16][C:9](=[O:8])[C:4]=12)=[O:7]
Reactant: COc1cccc2c1C(=O)OC2=O
Reactant: NC=O
Solvent: O
Product: COc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of 3-methoxyphthalic anhydride (24.0 g, 134.8 mmol) and formamide (120 ml) was stirred and held at 210° C. for 5 hours and was then allowed to cool to room temperature overnight. Water (100 ml) was added and the solid material filtered off under reduced pressure. The crude product was washed sequentially with 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 3-methoxyphthalimide (8.95 g, 37%) as an off-white solid. 1H NMR (DMSO-d6) 11.08 (1H, br s), 7.78 (1H, dd), 7.45 (1H, d), 7.36 (1H, d), 3.93 (3H, s). MS: [M+H]+ 178.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[C:15]1([C:19](OCC)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][C:15]4([C:19](=[O:20])[N:13]=1)[CH2:18][CH2:17][CH2:16]4)([CH2:4]3)[CH2:2]2
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Product: O=C1N=C(NC23CC4CC(CC2C4)C3)SC12CCC2

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42]([NH:12][CH2:11][C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:46][CH:47]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)Cl)ccc2c1O
Reactant: NCc1cccc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)NCc3cccc4ccccc34)ccc2c1O
Reaction time: 18 h

Procedure:
To a stirred solution of 44 μL of 1-naphthylmethylamine and 51 μL of diisopropylethylamine in 0.5 mL of pyridine is added 100 mg of 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-7-quinolinesulfonyl chloride from Preparation No. 31. After 18 h, the solution is added to 3.5 mL of rapidly stirred 2 N HCl, and the resulting solid is filtered, washed well with water, and dried under vacuum. Flash chromatography of the solid on silica gel using 2-5% methanol in dichloromethane provides 48 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (23, 58 mg, 0.059 mmol) and K2CO3 (139 mg, 1.008 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (61 μL, 0.590 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. The crude product was purified by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.6 min) to afford 7 (15 mg, 32%) mp 101-104° C.; 1H NMR (500.13 MHz, CDCl3) δ 9.54 (br s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.42 (br s, 1H), 8.01 (t, J=5.7, 1H), 7.82 (t, J=5.7 Hz, 1H), 6.39 (d, J=6.4 Hz, 1H), 5.36 (d, J=4.7 Hz, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 3.11 (m, 2H), 2.93-2.84 (m, 3H), 2.39-2.28 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.4 Hz, 2H), 1.97-0.94 (m, 36H), 0.92 (s, 3H), 0.86 (d, J=6.5 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.82 (d, J=2.4 Hz, 3H), 0.61 (s, 3H); 13C NMR (125 MHz, DMSO d6) δ 171.9, 170.9, 145.1, 144.4, 144.1, 138.5, 137.9 122.4, 120.5, 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8 (×2), 41.6, 40.5, 36.4, 36.1 (×2), 35.6, 35.5 (×2), 35.3, 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.3, 26.0, 24.9, 24.4, 23.8, 23.2, 22.6, 22.4, 20.4, 18.7, 18.5, 11.6; IR (film) νmax 3257, 3093, 2940, 2858, 1636, 1548, 1377 cm−1; CI m/z 790.5605 (MH+, C45H72N7O5 requires 790.5595).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([NH:15]C2C=CC=CC=2)C=CC=CC=1.[S-]C#N.BrBr>>[NH2:15][C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: BrBr
Agent: N#C[S-]
Product: Nc1nc2ccccc2s1

Procedure:
If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3. This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8-scheme 4 with a strong base like NaOH in a protic solvent (i.e., EtOH).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(R)-Thiazolidine-4-carboxylic acid (309.9 mg, 2.33 mmol) was dissolved in DMF (10 mL) and distilled water (10 mL). The solution was cooled to 0° C., and DIEA (0.590 mL, 3.39 mmol) was added followed by benzyl chloroformate (0.485 mL, 3.40 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.