Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)(O)[O-].[Na+].O>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[O:5]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccccc1O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-nitro-benzoyl chloride in 60 mL of diethyl ether was added to an ice-cooled mixture of o-aminophenol (5.4 g) and sodium bicarbonate (8.3 g), water (36 mL) and ether (20 mL) over a period of 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered and washed sequentially with water (3×100 mL), 2N HCl (3×100 mL) and diethyl ether (3×50 mL). Yield 11.2 g (77%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: OCCC1c2ccccc2CCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCC1C2=C(CC=CC2)CCc2ccccc21

Procedure:
A mixture of 80.0 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol, 195.7 ml of dry ethanol, 2.0 l of dry tetrahydrofuran and 3.2 l of dry distilled ammonia, stirred under argon, is treated at -30° to -31° with 25.09 g of sodium (3 to 4 pieces). After the exothermic reaction has faded, the mixture is stirred for about an additional 10 minutes and subsequently treated portionwise with a total of 60 g of ammonium chloride. After removal of the ammonia, the suspension remaining is washed three times with 800 ml of saturated ammonium chloride solution each time. The aqueous extracts are extracted twice with 1.5 l of ether each time. The organic phases are washed with 800 ml of water, combined, dried and evaporated in vacuo. There is obtained crude 4,5,10,11-tetrahydro-1H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil which is used in the next step without further purification.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][C@@H:25]([CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[C:26]([O-:28])=[O:27].[Na+].[Na+].OC1C=CC(NC(=O)C)=CC=1.C(Cl)(=O)OC1C=CC([N+]([O-])=O)=CC=1>C(#N)C.O>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][C@@H:25]([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([OH:28])=[O:27])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: N[C@@H](CS(=O)(=O)[O-])C(=O)[O-]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(=O)Nc1ccc(O)cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)N[C@@H](CS(=O)(=O)O)C(=O)O)cc1
Yield: 43 %

Procedure:
(2R)-2-[(4-Acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a) was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 500 mg (2.35 mmol) of disodium (2R)-2-amino-3-sulfonato-propanoate (9) in approximately one (1) mL of water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (844 mg, 2.67 mmol) dissolved in 5 mL of acetonitrile (MeCN). The mixture was heated to about 55° C. for two (2) hours. After work-up procedures, the aqueous layer was lyophilized off to afford 400 mg (43% yield) of the crude 2-[(4-acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a). The material thus obtained was contaminated with some sodium chloride (NaCl) and other sodium salts. The crude product was further purified by preparative HPLC using a gradient consisting of acetonitrile and water containing 0.1 vol-% of formic acid. Samples eluting at 2% acetonitrile and 98% water were collected, frozen, and lyophilized off to afford 83 mg (9% yield) the target compound (13a) as a colorless solid. Rt=3.10 min. 1H NMR (300 MHz, D2O): δ=7.25 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 4.54-4.50 (m, 1H), 3.32-3.27 (m, 2H), 1.98 (s, 3H). LC/MS (ESI): m/z=347.0 [M+H]+, 714.8 [2M+Na]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)C(C)=NC(O)=C2.CCN([CH2:22][CH3:23])CC.[O:24](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:12][CH2:3][O:2][C:22]([CH3:23])=[O:24].[CH3:5][CH2:4][CH2:3][CH2:12][CH2:11][CH3:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC
Product: CCOC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
6,7-Dimethoxy-1-methylisoquinolin-3-ol (540 mg) and Et3N (0.9 mL, 2 eq.) in DCM were cooled to −78° C. Tf2O (0.64 mL, 1.2 eq.) was slowly added to the mixture and was stirred for 30 minutes at −78° C. Reaction was then quickly diluted with additional DCM and washed with saturated NaHCO3. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a white solid (737 mg, 85% yield). 1H NMR (400 MHz) (CDCl3) δ 7.29 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 4.07 (s, 3H), 4.07 (s, 3H), 2.90 (s, 3H). 13C NMR (100 MHz) (CDCl3) δ 156.54, 153.80, 150.67, 135.47, 123.35, 107.62, 105.39, 103.73, 56.23, 56.11, 22.03.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=O)=O)=[CH:37][CH:36]=4)C(=O)C4C=CC=CC=4)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[Cl:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[Cl:45][C:46]1[CH:47]=[C:48]([S:53]([N:26]([CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH3:25])[C:35]2[CH:36]=[CH:37][C:38]([S:41][CH3:44])=[CH:39][CH:40]=2)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)N(C(=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1ccc(N(C(C)c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To solution of (1-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-(4-methylsulfanyl-phenyl)-amine from EXAMPLE 44 (Step 1) (1.0 eq) in pyridine (0.38M) was added 3,4-dichloro-benzenesulfonyl chloride (3.2 eq). The resulting mixture was stirred at 80° C. for 12 h, cooled to room temperature, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 9:1) afforded the desired compound as a foam.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40 mg, 0.20 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (81 mg, 0.40 mmol) and triethylamine (84 μL, 0.60 mmol) in isopropyl alcohol (0.46 mL) was stirred at 100° C. for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 0-40% EtOAc in hexanes) to give the sub-title compound as light yellow powder (43 mg, 59%). LCMS calc. for C18H27N4O4 (M+H)+: m/z=363.2. Found: 363.2.
Reaction SMILES: [C:1]([CH:8]1[CH2:13][CH2:12][N:11](N)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.C(#[N:30])C>O>[C:1]([C:8]1([NH2:30])[CH2:13][CH2:12][N:11]([CH2:26][CH2:25][O:24][CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)C1CCN(N)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: COCCN1CCC(N)(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4-boc-aminopiperidine (11, 10.0 g, 50 mmol), potassium carbonate (6.5 g, 47 mmol), potassium iodide (7.7 g, 46 mmol), 2-bromoethyl methyl ether (4.4 mls, 46 mmol), and acetonitrile (100 mls) was heated to reflux for 3 hrs. After cooling to room temperature, the reaction mixture was poured into H2O and extracted with EtOAc (4×). The combined EtOAc extractions were washed with sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 4-boc-1-(2-methoxy-ethyl)-piperidin-4-ylamine (12, 12.0 g, 99%) which was used in the next reaction without further purification. LC/MS Calcd for [M+H]+ 259, found 259.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C([Cl:7])(=O)C.[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)#[N:9]>C(Cl)(Cl)Cl>[ClH:7].[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8](=[NH:9])[O:3][CH2:1][CH3:2])[CH:11]=1
Reactant: CCO
Reactant: N#Cc1cccnc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1cccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethanol (200 mL) in chloroform (100 mL) at 0° C. was added acetyl chloride (190 mL) and a solution of 3-cyanopyridine (25 g) in (300 mL) of chloroform. The solution was allowed to warm to 25° C. and to stand for 1 day. A white solid separated from solution. The solvent was removed and the white solid collected and washed with ether to provide pure ethyl 3-pyridine-carboximidate hydrochloride as a white solid; MS: m/z=152(M+1).
Reaction SMILES: [C:1]([S:4]/[CH:5]=[CH:6]\[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:10]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.O>ClCCl>[CH:10]1([NH:22][C:7](=[O:8])/[CH:6]=[CH:5]\[S:4][C:1](=[O:3])[CH3:2])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)S/C=C\C(=O)Cl
Reactant: NC1CCCCCCCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)S/C=C\C(=O)NC1CCCCCCCCCCC1
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 3.0 g (0.0162 mol) of cis-3-(acetylthio)propenoyl chloride in 30 ml of dichloromethane under nitrogen was added dropwise 2.98 g (0.0163 mol) of cyclododecylamine as a solution in 30 ml of dichloromethane. After 15 min, 2.27 ml (0.0163 mol) of triethylamine was added dropwise. After 12 h the reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were washed with water, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave 4.5 g of a 2:1 mixture of cis and trans isomers as a tan solid. Purification by flash column chromatography (Merck 60® silica gel, ethyl acetate/hexane eluant) gave 0.5 g (10% yield) of N-cyclododecyl-cis-3-(acetylthio)acrylamide as a white powder where NMR is reported in Table 2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11]C)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClCCCl>[C:17]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[OH:11])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COc1cccc(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reaction time: 0.5 h

Procedure:
67.5 g (0.41 mol)3-acetamidoanisol are suspended in 200 ml 1,2-dichloroethane and cooled in an ice bath. 217 g (1.64 mol) AlCl3 and after it 38.5 g (0.49 mol) acetylchloride were added successively. Stirring was continued 1/2 hour. After 5 hours the reaction was quenched with ice and ethylacetate and water were added. The organic layer was seperated, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from dioxane and water.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13](Cl)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][S:26][C:20]=2[N:19]=[C:18]1[CH2:27][CH3:28]>>[Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([NH:16][N:17]4[C:22](=[O:23])[C:21]5[CH:24]=[CH:25][S:26][C:20]=5[N:19]=[C:18]4[CH2:27][CH3:28])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CCc1nc2sccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Product: CCc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(Cl)(C3)C1)C2

Procedure:
The product from Example 50A and 3-amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one (Enamine) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3 H) 1.46-1.81 (m, 6H) 1.94-2.13 (m, 6 H) 2.14-2.23 (m, 2 H) 2.23 (s, 2 H) 2.55-2.86 (m, 2 H) 7.41 (d, J=5.5 Hz, 1 H) 7.59 (d, J=5.5 Hz, 1 H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:26]=[CH:25][C:20]2[N:21]=[C:22]([NH2:24])[S:23][C:19]=2[CH:18]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH3:12])[C:29]([NH:24][C:22]3[S:23][C:19]4[CH:18]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:26]=[CH:25][C:20]=4[N:21]=3)=[N:13][C:6]=2[CH:5]=1)=[O:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCNc1ccc(C(=O)OC)cc1N
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Yield: 43.6 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (840.0 mg) was prepared by following General Procedure D starting from 3-amino-4-ethylamino-benzoic acid methyl ester (970.0 mg), 6-trifluoromethyl-benzothiazol-2-ylamine (1.0 g), 1,1′-thiocarbonyldiimidazole (890.0 mg), and EDC (970.0 mg) in DMF (5.0 mL).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>CCCCCC.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:18]([OH:21])[OH:19])[CH:6]=[CH:5]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc(Br)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
First, 5.0 g of 2,6-dibromonaphthalene was placed into a 500-mL three-neck flask, and the air in the flask was replaced with nitrogen. To this compound was added 200 mL of tetrahydrofuran (THF), and this solution was stirred at −78° C. for 20 minutes. Then, 12 mL of a 1.7M hexane solution of n-butyllithium (n-BuLi) was dripped into this mixture solution, followed by stirring at −78° C. for 2 hours. After the predetermined time had elapsed, 3.5 mL of trimethyl borate was added to the mixture and this solution was stirred for 18 hours while the temperature was raised to room temperature. After the predetermined time had elapsed, 80 mL of 1.0M hydrochloric acid was poured into this solution, and the mixture was stirred for 1 hour. Then, the mixture solution was separated into an organic layer and an aqueous layer. Organic substances were extracted with ethyl acetate from the obtained aqueous layer. The solution of the extract was combined with the organic layer that had been first obtained, and the mixture was washed with saturated brine and dried by addition of anhydrous magnesium sulfate. Then, the filtrate obtained by gravity filtration was concentrated to give a white solid. The obtained white solid was washed with ethanol, whereby 6-bromonaphthalene-2-boronic acid was obtained (as a white powder in 35% yield). The synthesis scheme of Step 1 is illustrated in the following (a-4).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([Si:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]I)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:31][CH2:30][CH2:29][CH2:28][O:27][Si:24]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:25])[CH3:26])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: O=C1NCc2c(Cl)c(O)cc(I)c21
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cc(I)c2c(c1Cl)CNC2=O
Yield: 84.1 %

Procedure:
In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (70.0 mg, 0.226 mmol) was dissolved in DMF (2.1 mL), and the solution was treated with potassium carbonate (93.8 mg, 0.679 mmol) and tert-butyl(4-iodobutoxy)dimethylsilane (0.176 mL, 0.679 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1) to obtain 4-chloro-5-[4-(tert-butyldimethylsiloxy)butoxy]-7-iodoisoindolinone (94.2 mg, yield 84%).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.S(Cl)([Cl:22])=O>ClCCl>[S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([Cl:22])=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C(O)c1ccc(C=Cc2cc3ccccc3s2)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C=Cc2cc3ccccc3s2)s1
Yield: 95.4 %

Procedure:
To a stirred suspension of 5-[2-(benzo[b]thiophen-2yl)ethenyl]thiophene-2-carboxylic acid (9.11 g) and dichloromethane (900 ml) was added thionyl chloride (7.56 g) over 5 mins. The mixture was refluxed overnight. The solvent was removed in vacuo to give 9.25 g of 5-[2-(benzo[b]thiophen-2-yl)ethenyl]thiophene-2-carboxylic acid chloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([NH2:10])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=O.[CH:16]([NH2:18])=O>O>[CH2:14]([O:13][C:11]([C:8]1[N:9]2[C:5]([C:3](=[O:2])[NH:18][CH:16]=[N:10]2)=[CH:6][CH:7]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1ccc(C(=O)OC)n1N
Reactant: NC=O
Solvent: O
Product: CCOC(=O)c1ccc2c(=O)[nH]cnn12
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 1-amino-1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester (140 mg) and formamide (1 mL) was stirred at 140° C. overnight. The reaction mixture was then cooled and diluted with water, the solid which crashed out was collected by filtration and dried under vacuum to give 60 mg of 4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][NH2:3].C(=O)(O)[O-].[Na+].[S:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17])(=[O:12])(=[O:11])[NH2:10].[CH:23](O)([CH3:25])[CH3:24]>O>[CH:23]([N:2]([C:13]1[CH:14]=[CH:15][CH:19]=[CH:20][CH:21]=1)[NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:13]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:14]=1)([CH3:25])[CH3:24]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CC(C)O
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)N(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neutralization of the hydrazine hydrochloride of Example 2 was effected by stirring with 19.6 g (0.21 mol) sodium bicarbonate in 100 ml isopropanol. When gas evolution ceased (1 1/2hours) the system was cooled in an ice-water bath, and 25 g (0.1 mol) 3-sulfamoyl-4-chlorobenzoyl chloride was added in several portions. Throughout this addition the temperature was maintained between 5° and 20° C. After the addition the reaction mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0°-5° C., diluted with 80 ml water, and stirred for 2 more hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:46][CH2:47][CH3:48]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.66-1.75 (m, 2 H) 2.49-2.50 (m, 3 H) 4.14 (t, 2 H) 6.20 (s, 1 H) 7.35-7.44 (m, 2H) 7.45-7.49 (m, 1 H) 7.50-7.55 (m, 1 H); MS (ESI) m/z 309 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([NH:13][NH2:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.C[NH:21][C:22](=[NH:24])S.[OH-].[Na+].O>CO>[C:22]([NH:14][NH:13][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12])(=[NH:21])[NH2:24]
Reactant: CNC(=N)S
Reactant: NNC(=O)c1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NNC(=O)c1cccc2ccccc12

Procedure:
The synthesis method of Example 1-(1) was applied. The compound (18.3 g) obtained in (2) above, methylisothiourea sulfate (81.6 g), sodium hydroxide (11.7 g), water (90 ml) and methanol (180 ml) were used as reagents and the mixture was reacted at 60° C. for 48 hours to give 39.7 g of a yellow solid. A portion (21.2 g) from the obtained solid was used in the next reaction.