Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:21][CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (5.0 g, 30.1 mmol) and imidazole (2.4 g, 35.4 mmol) in dry DMF (20 mL) was added chlorotriisopropylsilane (6.8 mL, 31 mmol) dropwise at 0° C. The mixture was stirred at rt for 16 h. Then water was added (100 mL), and the product was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the remaining crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 10:1→1:1) to afford the title compound (9.66 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 2H), 6.89 (d, 2H), 4.33 (quart, 2H), 1.38 (t, 3H), 1.27 (m, 1H), 1.10 (d, 18H); DCI(NH3)-MS m/z 323 (MH)+; HPLC RT (Method G) 6.19 min.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[C:6](O[C:9](=[O:11])[CH:10]=1)=[O:7].NN>C1COCC1>[Br:4][C:5]1[C:6](=[O:7])[NH:2][NH:3][C:9](=[O:11])[CH:10]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(Br)c(=O)[nH][nH]1
Yield: 76.9 %

Procedure:
Hydrazine hydrate (28 ml, 576 mmol) was added dropwise to a stirred solution of bromomaleic anhydride (100 g, 565 mmol) in THF (1 l) cooled in an ice-bath so that the internal temperature did not exceed 10° C. After complete addition of the hydrazine the mixture was refluxed for 18 h. Solvent was removed by evaporation and the residues were dried by azeotroping with toluene. The residue was triturated and washed with diethyl ether to give the title compound as an orange solid (83 g, 77%). 1H NMR (250 MHz , d6-DMSO) δ 7.68 (1H, br s). MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: [C:1]([NH:18][C:19]1[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.Cl>O1CCCC1>[CH2:1]([NH:18][C:19]1[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)o1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)o1

Procedure:
A mixture of 1.1 g. of ethyl 5-hexadecanamido-2-furancarboxylate and 5 ml. of 1 M borane in tetrahydrofuran is refluxed on the steam bath for 3 hours. After cooling, the reaction is poured into dilute hydrochloric acid and the resulting solid filtered. The solid is dissolved in methylene chloride and the solution is filtered through Magnesol. The solvent is evaporated to yield the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:30]([O-])([OH:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[C:13]([N+:30]([O-:32])=[O:31])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C2(C#N)CCC2)ccc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
A solution of 1-(4-(benzyloxy)-3-methoxyphenyl)cyclobutanecarbonitrile (5 g, 17.04 mmol), from Step 1, in acetic acid (20 mL)/acetic anhydride (20 mL) was cooled in an ice bath to 0° C. and treated slowly with 65% nitric acid (2.54 mL, 34.1 mmol). The reaction was stirred at 0° C. for 20 min, poured into ice and extracted with EtOAc. Organic layer was washed with saturated aqueous NaHCO3 and water. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-50% EtOAc/hexane) afforded 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (5.29 g, 92%). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:49][CH2:50][O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60][CH3:61])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:61][O:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCOCCc4ccccc4OC)cc3)cc21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
The mixture of 0.133 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d), 0.106 g of 2-[2-(2-methoxyphenyl)ethoxy]ethyl toluene-4-sulphonate and 0.173 g of potassium carbonate in 2.5 ml of N,N-dimethylformamide is stirred at 60° C. for 20 hours. The reaction mixture is subsequently cooled, poured onto water (25 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (2:1 EtOAc-heptane); Rt=5.87.
Reaction SMILES: O=[C:2]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:13]=2)[CH:8]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.[OH-].[Na+]>O1CCCC1>[CH2:18]([O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:5]1[S:43][C:2]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:3][N:4]=1)[CH:16]=[CH:15]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)NCC(=O)CCCCCC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(-c3ncc(CCCCCC)s3)ccc2c1
Temperature: 0 °C
Yield: 52.7 %

Procedure:
Then, 0.40 g (0.88 mM) of 2-oxooctyl-(6-decyloxy-2-naphthoyl)amine, 0.38 g (0.94 mM) of Lawesson's reagent and 6 ml of tetrahydrofuran were placed in a 30 ml-round-bottomed flask, followed by heat-refluxing for 45 minutes under stirring. After the reaction, the reaction mixture was poured into a solution of 0.27 g of sodium hydroxide in 70 ml of ice water to precipitate a crystal. The crystal was recovered by filtration washed with water and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) and recrystallized from a mixture solvent of acetonemethanol to obtain 0.21 g of 2-(6-decyloxy-2-naphthyl)-5-hexylthiazole (Yield: 52.7%). ##STR236##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: BrCCCBr
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12

Procedure:
A suspension of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 2.18 g of potassium carbonate in 20 ml of acetone was admixed with 3.2 ml of 1,3-dibromopropane and the mixture was refluxed for 90 minutes and was filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1 to obtain 2.37 g of N-[2-[3-bromopropoxyl]phenyl]-1H-indole-4-carboxamide melting at 145° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH:11]3[CH2:13][CH2:12]3)[C:9]([C:14]3[C:15]([NH2:19])=[N:16][O:17][N:18]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:11]1([N:10]2[C:3]3[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=[C:9]2[C:14]2[C:15]([NH2:19])=[N:16][O:17][N:18]=2)[CH2:13][CH2:12]1
Reactant: Nc1nonc1-c1nc2cncc(Br)c2n1C1CC1
Reactant: OB(O)c1ccccc1
Product: Nc1nonc1-c1nc2cncc(-c3ccccc3)c2n1C1CC1

Procedure:
The title compound was prepared from the product of Step 5 and phenylboronic acid using the method of Example 101; MS (ES+) m/e 319 [M+H]+.
Reaction SMILES: S1C2C=C(NC(=O)C3C=C([N+]([O-])=O)C(F)=CC=3Cl)C=CC=2N=C1.[NH4+].[OH-].[NH2:26][C:27]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:30]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]3[N:38]=[CH:39][S:40][C:36]=3[CH:35]=2)=[O:32])=[C:29](Cl)[CH:28]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>O1CCOCC1>[NH2:26][C:27]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:30]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]3[N:38]=[CH:39][S:40][C:36]=3[CH:35]=2)=[O:32])=[C:29]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:28]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C(Nc1ccc2ncsc2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3ncsc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of N-benzothiazol-6-yl-2-chloro-4-fluoro-5-nitrobenzamide (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (12 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-6-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc(NC(C)=O)ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)ccc1OCCN1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
1.07 g of 4-(2-fluorophenyl)piperazine and 1.5 ml of triethylamine are added to a solution of 1.5 g of 2-(4-acetamido-2-methoxyphenoxy)-1-(p-toluenesulfonyloxy)ethane in 10 ml of anhydrous dimethylformamide, and the mixture is stirred at 100° C. for 6 hours. After the reaction, the mixture is poured into ice-water, and the aqueous mixture is extracted with chloroform. The extract is washed with water and an aqueous saturated sodium chloride solution, successively. Said extract is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent; 2% methoanol/chloroform), and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.3 g of 1-[2-(4-acetamido-2-methoxyphenoxy)ethyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless scales. Yield: 85%
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:37][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.036 g, 0.18 mmol), 1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]-4-phenylpiperidin-4-ol (0.035 g, 0.092 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in ethanol (0.32 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product as the free base. LCMS calculated for C27H27ClN7O (M+H)+: m/z=500.2; Found: 500.1.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH2:12])[CH2:3][CH2:2]1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[CH2:3][CH2:2]1
Reactant: NCC1CCOc2ccccc21
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCC1CCOc2ccccc21
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from 1-(3,4-dihydro-2H-chromen-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.74 (br s, 1H), 7.50 (d, 1H, J=5.0 Hz), 7.23 (d, 1H, J=7.4 Hz), 7.04 (t, 1H, J=7.1 Hz), 6.78 (t, 1H, J=7.3 Hz), 6.69 (d, 1H, J=8.0 Hz), 4.06-4.17 (m, 2H), 3.59-3.65 (m, 1H), 3.41-3.47 (m, 1H), 3.04-3.09 (m, 1H), 1.79-1.96 (m, 2H). [M+H] calc'd for C16H16N2O3, 285. Found 285.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[NH:8][CH2:7][CH2:6]2.[F:23][C:24]([F:29])([F:28])[C:25]([NH2:27])=[O:26].F.O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][OH:15])[NH:8][CH2:7][CH2:6]2.[F:23][C:24]([F:29])([F:28])[C:25]([NH2:27])=[O:26]
Reactant: COc1ccc2c(c1)CCN[C@@H]2CCO[Si](C)(C)C(C)(C)C
Agent: F
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)CCN[C@@H]2CCO
Yield: 74.3 %

Procedure:
To a solution of 6-methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (1.14 g, 2.73 mmol) obtained in step (a) of Example 190 in acetonitrile (10 ml) was added dropwise 48% solution of hydrofluoric acid in water (0.5 ml, 13.67 mmol) gradually with stirring under cooling in a water bath. The resulting mixture was further stirred at room temperature, and after confirming the disappearance of the starting material by thin layer chromatography, saturated aqueous sodium hydrogen carbonate solution was added with stirring, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1) as the eluent to afford the title compound (0.65 g, yield: 79%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][CH:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:35]=[N:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:22][N:21]([CH3:23])[S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:37]=[N:36][CH:35]=[C:34]([NH:38][S:39]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)(=[O:41])=[O:40])[CH:33]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CN(C)S(=O)(=O)C1CCN(c2cnc3ccc(Br)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)C1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A slurry of 1-(7-bromo-2-quinoxalinyl)-N,N-dimethyl-4-piperidinesulfonamide (0.43 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.47 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 18 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (5% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (102 mg, 43% yield) as a yellow solid. MS(ES)+ m/e 539.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[C:6]([N+:23]([O-:25])=[O:24])[N:5]=1.[CH3:26]I>CN(C=O)C>[CH3:26][C:10]([C:9]1[C:4]([CH3:3])=[N:5][C:6]([N+:23]([O-:25])=[O:24])=[CH:7][CH:8]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% in oil, 0.8 g, 19 mmol) in DMF (50 mL) was added tert-butyl ethyl (2-methyl-6-nitropyridin-3-yl)propanedioate (4 g, 13 mmol) at room temperature. The mixture was stirred for 1 hour and CH3I (3.7 g, 26 mmol) was added. The mixture was heated to 40° C. for 2 hours. Cooled to ambient temperature, the mixtue was poured to ice/water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatograph silca gel to give tert-butyl ethyl rnethyl(2-methyl-6-nitropyridin-3-yl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 4.19-4.27 (m, 2H), 2.59 (s, 3H), 1.85 (s, 3H), 1.45 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)(=O)C.C(O)C.[OH-].[K+]>O>[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Reaction time: 0.25 h

Procedure:
To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3-acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[F:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[OH:24].[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[CH:22][C:23](=[O:24])[C:18]([F:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: Oc1ccncc1F
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
First, 127 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 96 mg of 3-fluoro-4-hydroxypyridine, and 55 mg of powdered potassium hydroxide were added to 12 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 3 hours in a nitrogen atmosphere. Then, 50 ml of ice water was added to the reaction mixture, and the mixture was neutralized with 2N hydrochloric acid. The resultant precipitate was filtered and washed with water. The precipitate was dissolved in 3 ml of 1N sodium hydroxide. The solution was treated with activated carbon and filtered. The filtrate was neutralized with conc. hydrochloric acid. The precipitated crystals were filtered and dried to give 147 mg of 6-nitro-7-(3-fluoro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:16][Br:29])=[CH:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Br)c(C)cc1OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c(CBr)cc1OCC

Procedure:
After dissolving ethyl 5-bromo-2-ethoxy-4-methylbenzoate (19.72 g) in carbon tetrachloride, azobisisobutyronitrile (1.13 g) was added and the mixture was heated to reflux for 30 minutes. N-bromosuccinimide was added and the mixture was further heated to reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (10.54 g) as a colorless oil.