Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][CH2:1][CH:2]=[CH2:3])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Allylamine (0.45 mL, 0.34 g, 6.0 mmol), acetic acid (0.300 mL, 315 mg, 5.24 mmol), and 3 Å molecular sieves (2.00 g) were added to a solution of 1-(t-butyoxycarbonyl)-4-piperidone (1.00 g, 5.01 mmol) in 1,2-dichloroethane (14 mL). The resulting mixture was stirred for 30 min at rt, then treated with sodium triacetoxyborohydride (1.62 g, 7.6 mmol). The reaction was stirred at rt for 3 h, then partitioned between EtOAc (30 mL) and sat'd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (30 mL) and the organic layers were washed with 20 mL of sat'd NaCl, combined, dried over Na2SO4, and evaporated to give 1.20 g of crude 1-(t-butoxycarbonyl)-4-(N-prop-2-enyl)aminopiperidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Cl:9][CH2:10][C:11](Cl)=[O:12].O.Cl>C(Cl)Cl>[Cl:9][CH2:10][C:11]([C:5]1[S:1][C:2]2[CH:8]=[CH:7][S:6][C:3]=2[CH:4]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: c1cc2sccc2s1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)c1cc2sccc2s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
Thieno[3,2-b]-thiophene (38.5 mmol) was solubilized in anhydrous DCM (77 mL) and the chloroacetylchloride (39.66 mmol) was added. The reaction mixture was cooled down to 0° C. and A1Cl3 (43.12 mmol) solubilized in DCM (385 mL) was added slowly. The mixture was stirred at room temperature during 5 hrs. The reaction mixture was cooled again to 0° C. and water and 2N HCl were added until pH=1. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give intermediate E71 as a yellow solid in 43% yield. MS (ESI, EI+) m/z=216.8 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17](=[S:19])[NH:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CCO.O>[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17]([S:19][CH2:2][C:3]([OH:5])=[O:4])=[N:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1
Reactant: S=c1[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc2[nH]1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetic acid (43.4 mg, 0.312 mmol) in EtOH (1 mL) was added dropwise to a 20 mL scintillation vial equipped with a stirring bar and a septum cap containing a solution of compound 2-3 (52.6 mg, 0.156 mmol) in EtOH (0.5 mL). To this solution, 1M KOH (1.5 mL) was added dropwise, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with water (4 mL) and acidified with 10% aqueous HCl. The solution was extracted with EtOAc (3 mL, then three times 1 mL). Extracts were combined and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1 mL), filtered and purified by reverse-phase HPLC with to give the title compound as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.70-7.76 (4H, m), 7.64 (1H, s), 7.46-7.55 (4H, m), 7.45 (1H, s), 7.36-7.40 (1H, m), 4.12 (2H, s); LRMS (API-ES): calculated for C21H15ClN2O2S 394.1, observed m/e 395.0 (M+H)+ (Rt 3.14 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 97 %

Procedure:
Prepared according to Procedure H utilizing ethyl 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoate ( 0.50 g) and aqueous sodium hydroxide (2M, 2 mL) in THF (6 mL) to afford the title compound ( 0.46 g). Electrospray MS m/z 516 (MH+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25](Br)[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B1OC(C)(C)C(C)(C)O1>C1(C)C=CC=CC=1.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>[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[Cl:37])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: CC1(C)OB(c2ccccc2Cl)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3Cl)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 229 mg (1.08 mmol) potassium phosphate to a mixture of 220 mg (0.49 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 17 mg (0.03 mmol) bis(triphenylphosphine)palladium(II) chloride in 2.2 ml toluene. Next, add 176 mg (0.74 mmol) (2-chlorophenyl)boronic acid pinacol ester and stir the mixture for 15 h at 80° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 101 mg (42% of theor.) of the desired product is obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH2:21][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C=O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(CN2CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a 2 ml 1,2-dichloroethane solution of 61 mg (0.166 mmol) of the compound obtained in Example 233, 37 μl (0.332 mmol) of N-methylpiperazine, 10 μl of acetic acid, and 53 mg (0.252 mmol) of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 57 mg (76%) of the captioned compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[CH2:19][CH2:20]Cl.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([N:27]2[C:2]3[N:7]4[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]4[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=3[CH2:19][CH2:20]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1nc2c([N+](=O)[O-])cnn2c(Cl)c1CCCl
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c([N+](=O)[O-])cnn2c2c1CCN2C1CCCC1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
In 12 ml of anhydrous dimethylformamide were dissolved 1.16 g (3.48 mmol) of ethyl 7-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine-5-carboxylate, and 2.4 ml (d=0.863, 24.32 mmol) of cyclopentylamine were added to the solution, and the resultant mixture was stirred for 4 hours at room temperature. The reaction mixture was then poured into ice water. Insoluble solids were collected by filtration, washed with water and air-dried to obtain 1.15 g (yield: 95.7%) of the intended product.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:19][I:29])([CH3:18])[CH2:16][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: C=C(C)Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
In 200 ml of a mixed solvent of diethyl ether-water (3:1) was dissolved 10.0 g of 4-acetoxy-3,5-di-t-butyl-2-(2-methyl-2-propenyl)phenol synthesized according to the procedure described in JP 7-330759/95 and combined with 5.3 g of sodium bicarbonate and 12.0 g of iodine, and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was combined with a saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to give 13.2 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Br:11])=[CH:9][C:10]=1[I:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1ccc(Br)c(C)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1cc(C)c(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 5.00 g (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester in 50 mL acetonitrile were added at 0° C. 4.84 g N-iodosuccinimide and 0.18-mL trifluoromethanesulfonic acid. The mixture was stirred 18 h at room temperature. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 5.800 g of the title compound as white crystals melting at 140-141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]C2C=CC=CC=2)=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:41]1([CH2:47][CH2:48][S:49][CH:50]([C:54]([OH:56])=O)[C:51]([OH:53])=[O:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[OH:56][C:54]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[O:53][C:51](=[O:52])[C:50]=1[S:49][CH2:48][CH2:47][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ccccc1COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]phenylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 138-139° C.; 1H NMR (400 MHz, DMSO-d6) δ2.77 (t, 2 H), 2.98 (t, 2 H), 3.83 (s, 3 H), 5.14 (s, 2 H), 6.68 (s, 1 H), 6.97 (t, 1 H), 7.08 (d, 1 H), 7.20 (m, 7 H), 7.53 (t, 1 H), 7.40 (d, 1 H), 7.76 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31](N)=[O:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH-:34].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31]([OH:32])=[O:34])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [OH-]
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(N)=O)C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This compound was prepared utilizing the same procedures as those used for the synthesis of cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylic acid amide except the reaction was monitored at short intervals to minimize the amide formation. The reaction generated a mixture of ester and amide (2:1), which was treated with NaOH (0.15 mL) in THF (0.95 mL) and MeOH (1 mL). The reaction was left to stir at rt for 3 h. The mixture was concentrated in vacuo, diluted with DCM and washed with water. The product was purified by MDP, to afford the title compound as a yellow solid; MS (ES+): m/z 436.27 (40) [MH+]; 1H NMR (400 MHz, DMSO-d6) δ 2.62-2.67 (m, 5H) 3.16 (s, 1H) 3.90-3.91 (m, 1H) 6.21 (s, 1H) 7.10 (d, J=5.2 Hz, 1H) 7.50-7.59 (m, 4H) 7.93 (dd, J=6.8, 1.6 Hz, 1H) 8.10 (d, J=8.4 Hz, 1H) 8.18 (d, J=8.8 Hz, 1H) 8.25 (s, 1H) 8.30-8.33 (m, 2H) 8.51 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Reactant: CC[C@H](N)C(=O)O
Product: CC[C@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using L-2-aminobutyric acid (310 mg, 3 mmol) to give (S)-2-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4S)-5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17]>CN(C)C(=O)C>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])#[N:17]
Reactant: COc1ccccc1S
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Sc3ccccc3OC)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 231.2 %

Procedure:
2-Methoxythiophenol (0.0322 g, 0.230 mmol) and potassium carbonate (0.158 g, 1.14 mmol) were stirred in N,N-dimethylacetamide. 3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.248 g, 0.571 mmol) was added to the reaction mixture portion-wise and the mixture stirred under a nitrogen atmosphere at ambient temperature for 2 hours. The reaction was quenched with a 1M aqueous solution of sodium hydroxide (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was separated and washed with water (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel column chromatography (ethyl acetate elution) to afford the title compound (0.295 g, 93%) and this was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:20]2[CH:25]=[CH:24][C:23]([N:26]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:26]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[C:23]2[CH:22]=[CH:21][C:20]([N:19]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:16]3[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO)cc3)cc2)cc1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
7. To a dry 250 mL round bottom flask under nitrogen was added N1-(4-(3-(tert-butyldimethylsilyloxy)propoxy)phenyl)-N1,N4,N4-tris(4-methoxyphenyl)benzene-1,4-diamine (9.06 g, 13.1 mmol), tetrahydrofuran (12.4 mL), and tetrabutylammonium fluoride (8.21 g, 31.4 mmol). The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 150 mL of cold water. The product was extracted using 3×75 mL ether. The organic layers were combined and dried over MgSO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The material was purified by flash chromatography (silica gel, 1:2 hexanes:ethyl acetate) and recrystallization (methanol) to yield a white solid (5.93 g, 78.6%). 1H NMR (400 MHz, C3D6O) δ 6.97 (m, 8H), 6.85 (m, 8H), 6.81 (s, 4H), 4.07 (t, J=6.3 Hz, 2H), 3.78 (s, 9H), 3.71 (q, J=5.7 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 1.93 (q, J=6.3 Hz, 2H). 1H NMR (400 MHz, C3D6O with D2O) δ 6.95 (m, 8H), 6.84 (m, 8H), 6.79 (s, 4H), 4.03 (t, J=6.3 Hz, 2H), 3.74 (s, 9H), 3.68 (t, J=6.2 Hz, 2H), 1.92 (q, J=6.3 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.29, 155.77, 143.59, 143.53, 142.22, 142.13, 126.17, 123.68, 123.64, 115.98, 115.37, 65.74, 58.80, 55.62, 33.11. HRMS-EI (m/z): [M]+ calcd for C36H36N2O5, 576.26; found, 576.4). Anal. Calcd for C36H36N2O5: C, 74.98; H, 6.39; N, 4.86. Found: C, 74.80; H, 6.25; N, 4.82.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:19])=[N:4][C:5]2[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1>CN(C)C=O.[Pd]>[NH2:16][C:7]1[C:8]2[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:19])=[N:4][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c1CCCC2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc2nc(O)c(O)nc2c2c1CCCC2

Procedure:
A solution of 7,8,9,10-tetrahydro-2,3-dihydroxy-6-nitrobenzo(f)quinoxaline (1.5 g, 5.7 mmol) in 50 ml of N,N-dimethylformamide was hydrogenated at atmospheric pressure and room temperature in the presence of 5% palladium-on-charcoal. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was triturated with water, the solid was collected and washed with water, and ethanol affording 1.2 g (90%) of the amino compound; m.p. > 300° C.; 1H-NMR (DMSO-d6): 1.7-2.0 (m,4H,2×CH2), 2.5-2.8 (m,4H, 2 × CH2), 4.97 (broad s, 2H, NH2), 6.53 (s, 1H, H-5), 10.5 (broad s, 1H, 0H), 11.4 (broad s, 1H, 0H).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>C(Cl)Cl.O>[OH:3][NH:2][C:4](=[O:5])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NO
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NO)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
hydroxylamine hydrochloride (6.0 g, 86 mmol) in CH2Cl2 (250 mL) and water (100 mL) at 0° C. After 10 mins, solid FmocCl (21 g, 81 mmol) is added portionwise with vigorous stirring. After 1 h a white precipitate forms and more CH2Cl2 (100 mL) is added. The solution is allowed to warm to 20° C. and left to stir for 3 d. The white solid that remains is filtered away, re-dissolved in ethyl acetate (300 mL), washed with brine and dried over MgSO4 to yield (9H-fluoren-9-yl)methyl hydroxycarbamate (Mellor, S. L.; McGuire, C.; Chan, W. C.; Tet. Lett., 1997, 38, 3311-3314) as a white solid (15 g, 68%). Furthermore, the mother-liquor is concentrated and purified by column chromatography (silica gel, ethyl acetate/CH2Cl2 1:1 to 1:0) to yield the title compound (by-product) as a white solid (0.55 g, 1%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CS(O[CH2:19][C:20]1[S:28][C:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=2[CH:21]=1)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:19][C:20]2[S:28][C:27]3[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=3[CH:21]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)CC1
Yield: 50 %

Procedure:
Potassium carbonate (26.5 mmol) and N-methylpiperazine (6.36 mmol) was added to a solution of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) in toluene (30 ml). The reaction mixture obtained was heated under reflux for 16 hours. The reaction temperature was then reduced to 25° C. and the reaction mixture was diluted with ethyl acetate. The reaction mixture was washed with water and saturated sodium chloride solution and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the crude product obtained was purified by column chromatography (5% methanol in methylene chloride). The desired product was obtained in a yield of 50%.