Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4].[CH3:32]I>CN(C)C=O.C(OCC)(=O)C.[Ag]>[CH3:1][O:2][C:3]([CH:5]([N:24]([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [Ag]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCc1cn(C(=O)OC(C)(C)C)c2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
295 g of silver(l) oxide are added, with stirring, to a solution of 75 g of N-tert-butyloxycarbonyl-amino-3-(1-tert-butyloxycarbonyl-indol-3-yl)-propanecarboxylic acid methyl ester in 770 ml of N,N-dimethylformamide. 75 ml of methyl iodide are then added dropwise. The reaction mixture rises to a temperature of 40° and is stirred at room temperature for 2 days and then diluted with 800 ml of ethyl acetate, filtered and concentrated by evaporation. The residue is purified by chromatography (silica gel, hexane/ethyl acetate 3:2). In this way the title compound is obtained in the form of a yellow oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([O:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:22][OH:23])[C:18]2[C:14](=[CH:15][N:16]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:17]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([O:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:22]=[O:23])[C:18]2[C:14](=[CH:15][N:16]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:17]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To solution of Methyl Sulfoxide (0.197 ml, 2.77 mmol) in DCM (12 ml) at −78° C. was added oxalyl chloride (0.694 ml, 1.387 mmol) dropwise. The solution was stirred at −78° C. for 0.5 h. A solution of Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (400 mg, 0.631 mmol) in DCM (12 ml) was then added dropwise. The slurry was stirred at −78° C. for 2 h before addition of N,N-Diisopropylethylamine (0.549 ml, 3.15 mmol) dropwise. The solution was slowly warmed up and stirred at room temperature for 3 h. It was then washed with iced 1M HCl and brine, dried over MgSO4, filtered and concentrated. The residual light yellow oil was purified by Biotage LC (35% EtOAc/Hexane) to afford title compound (286.3 mg, 0.453 mmol, 71.8% yield) as yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 9.61 (s, 1H), 8.05, s, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.33 (m, 2H), 7.04 (m, 2H), 7.02 (buried, 1H), 5.67 (m, 2H), 3.60 (app t, J=8.3 Hz, 2H), 3.45-3.85 (m, 3H), 3.45 (d, J=9.1 Hz, 1H), 2.18 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.43 (s, 9H), 0.91 (app t, J=8.2 Hz, 2H), −0.04 (s, 9H). LC/MS (HPLC method 3): tR=4.11 min, 632.3(MH)+.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCCC1.O>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])(=[O:4])=[O:3]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoyl chloride (1.5 g) in tetrahydrofuran (12 mL) were added benzyl alcohol (712 mg) and pyridine (370 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:16:1) to give benzyl 3-(chlorosulfonyl)benzoate as a colorless oil (yield 1.70 g, 87%). To a suspension of sodium hydride (60% in oil, 120 mg) in tetrahydrofuran (8 mL) were added dropwise a solution (12 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (646 mg) in tetrahydrofuran, 15-crown-5 (660 mg) and benzyl 3-(chlorosulfonyl)benzoate (684 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-yellow oil (yield 1.09 g, 91%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[CH3:14].[OH-:15].[Na+].[CH3:17]O>C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][O:15][CH3:17])[CH:4]=2)[N:9]=1
Reactant: Cc1cc(Cl)nc2ccc(CBr)cc12
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCc1ccc2nc(Cl)cc(C)c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-methylquinoline (0.40 g) in methanol (8 mL) was added 1 M aqueous sodium hydroxide (4 mL) at room temperature, and the mixture was stirred at 70° C. for 30 min. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, the organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 2-chloro-6-methoxymethyl-4-methylquinoline (0.31 g).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11][C:10]=2[CH:21]=1)#[N:2].[NH:29]([C:31]1[N:36]=[N:35][C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=1)[NH2:30]>CC(O)C>[N:35]1[C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=[C:31]([N:29]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[CH2:15][CH2:14][C@@H:13]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH2:12][CH2:11][C:10]=4[CH:21]=3)=[N:30]2)[N:36]=1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Reactant: N#CN=C(Nc1ccc2c(c1)CCC(N1CCCC1)CC2)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc3c(c2)CC[C@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Phenyl (S)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate and phenyl (R)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate were treated with 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine in a similar manner as described above in Synthetic Example 2 to yield 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine. For example, a suspension of a single enantiomer of phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate (0.06 g, 0.16 mmol) and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90° C. for 18 h. After cooling to ambient temperature, the solvent was evaporated and the residue was purified by HPLC to provide enantiomerically pure 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09-1.82 (m, 5H) ppm; MS (ES) 507 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([CH2:7][CH3:8])[CH:6]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=C[CH:24]=1>>[CH2:7]([N:5]1[CH:6]=[C:2]([N:1]([CH3:24])[S:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])[CH:3]=[C:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc(N)cn1CC
Product: CCOC(=O)c1cc(N(C)S(=O)(=O)c2cccs2)cn1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of ethyl 4-amino-1-ethyl-1H-pyrrole-2-carboxylate (7.1 g) and pyridine (50 mL) was added 2-thiophen-sulfonyl chloride (8.4 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. To a solution of the residue in N,N-dimethylformamide (50 mL) was slowly added sodium hydride (60%, oily, 1.7 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (2.7 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, 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 to give ethyl 1-ethyl-4-[methyl(2-thienylsulfonyl)amino]-1H-pyrrole-2-carboxylate (11.9 g, yield 88%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]=[C:14]([CH:16]=[CH2:17])[CH:13]=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[C:30](I)[CH:29]=[CH:28][C:27]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:35](=[O:46])[CH2:34]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH:15]=[C:14]([CH:16]=[CH:17][C:30]2[CH:29]=[CH:28][C:27]([N:33]3[CH2:34][C:35](=[O:46])[N:36]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:37]3(=[O:39])=[O:38])=[C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:31]=2)[CH:13]=[N:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([CH:17]=[CH:16][C:14]2[CH:15]=[N:11][NH:12][CH:13]=2)[CH:29]=[CH:28][C:27]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:35](=[O:46])[CH2:34]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=Cc1cnn(C(=O)OCc2ccccc2)c1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cn[nH]c3)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cnn(C(=O)OCc4ccccc4)c3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 4-vinylpyrazole-1-carboxylic acid benzyl ester and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to Example 39, step D. The deprotected pyrazole, 5-{2-benzyloxy-4-[2-(1H-pyrazol-4-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one, is also isolated.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[ClH:3].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: Nc1ccc(CCC(=O)O)cc1
Product: COC(=O)CCc1ccc(N)cc1
Product: Cl

Procedure:
12.96 g (0.11 mol) of thionyl chloride (7.93 ml) are added dropwise to a solution of 15 g (0.0991 mol) of 3-(4-amino-phenyl)-propionic acid in 100 ml of methanol, while stirring and cooling with methanol/ice. When the addition has ended, the mixture is stirred for a further 30 minutes, while cooling, and is then stirred overnight at room temperature. It is then concentrated to dryness in vacuo and the residue is crystallized from methanol/ether.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.C(O)CC>CCOC(C)=O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: N#Cc1ccc(F)nc1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(C#N)cn2)C1
Temperature: 150 °C
Yield: 89.6 %

Procedure:
A heavy-walled, screw-cap glass tube was charged with (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (3.30 g, 17.7 mmol), 2-fluoro-5-cyanopyridine (1.63 g, 13.2 mmol), i-Pr2NEt (6.3 mL, 35.5 mmol) and n-PrOH (3 mL). The mixture was heated at 150° C. in an oil bath for 2 h. The mixture was diluted with EtOAc (180 mL), washed with 1% aq HCl (3×40 mL), satd aq NaHCO3 (40 mL) and brine (40 mL), and dried over Na2SO4. Removal of the solvent left an oil (3.28 g) which was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxylate (3.41 g, 88% based on 2-fluoro-5-cyanopyridine). LC-MS Method 1 tR=1.57 min, m/z=289.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1
Product: CCOC(=O)c1cccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 79 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (100 mg) was reacted with imidazole to obtain the desired (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (19.9 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1>>[S:1]1[C:5]([C:16]2[C:17]([CH3:21])=[CH:18][N:19]=[C:14]([NH:22][CH:23]3[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)[N:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: OB(O)c1cc2ccccc2s1
Product: Cc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1cc2ccccc2s1

Procedure:
The title compound was prepared analogous to Steps B and C of Method A, starting from benzo[b]thiophene-2-boronic acid, 2,4-dichloro-5-methyl-pyrimidine and 4-amino-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:24].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:9]1[C:10]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:24])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccc([N+](=O)[O-])cc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccc([N+](=O)[O-])cc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-8-nitro-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.77 (s, 2H); 7.24-7.40 (m, 5H), 8.29 (dd, J1=9 Hz, J2=2 Hz, 1H); 8.40 (d, J=9 Hz, 1H); 8.71 (d, J=2 Hz, 1H); Ret. time=2.56 min., m/z=368.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].S(Cl)([Cl:19])=O.ClCCl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][Cl:19])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ccc(CCCl)cc1
Yield: 92.3 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (1 g) prepared in the Examples 1-3, thionyl chloride (2.7 g) and dichloromethane (15 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Toluene (30 mL) was added, the mixture was condensed under reduced pressure, and the solvent was removed. Dichloromethane (50 mL) and sodium hydrogen carbonate solution (30 mL) were added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propionic acid methylester (1.0 g, yield 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CC(N(C)C)=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: II
Reactant: Cc1cccc(C)c1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (25 gm) in 1,4-dioxane (200 ml) and dimethylacetamide (20 ml) was added iodine (79 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 45 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:22]([C:21]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=3[Cl:19])=[O:23])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)cc4Cl)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Dichlorobenzoyl chloride (85.9 mg; 0.41 mmol) to obtain 48.1 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br d, 1H), 7.76 (s, 1H), 7.54 (s, 2H), 7.41 (m, 2H), 7.07 (br d, 1H), 6.98 (br d, 1H), 6.83 (t, J=7.6 Hz, 1H), 4.58 (br d, 1H), 3.42 (m, 2H), 3.16 (m, 2H), 2.99 (m, 1H), 2.74 (m, 2H). ESIMS+419.3 m/z
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][CH2:16][C@@H:17]([OH:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12].O.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26]>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:19][C@@H:17]([CH3:18])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:29]=1)[C:25]#[N:26]
Reactant: C[C@H](O)COC(C)(C)C
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:23])O[C:20](=[O:21])[CH2:19][CH2:18]1.C([N:26](CC)CC)C.Cl>ClCCl>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:17](=[O:23])[CH2:18][CH2:19][C:20]([NH2:26])=[O:21])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)CCC(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The compound (100 mg) obtained in the above (5) is dissolved in dichloromethane (2 ml), and thereto are added succinic anhydride (53 mg) and triethylamine (73 μl), and the mixture is stirred at room temperature for 45 minutes. To the mixture is added 1N hydrochloric acid, and the mixture is extracted three time with ethyl acetate. The extract is washed twice with a saturated brine, and the organic layer is dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (139 mg).