Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: BrCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, intermediate 8) in DMF (3 mL) were added 2-(2-bromoethoxy)tetrahydro-2H-pyran (169 mg, 0.81 mmol, intermediate 1), potassium carbonate (150 mg, 1.08 mmol) and a catalytic amount of TBAI. The mixture was stirred at 50° C. overnight. It was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was washed with ethanol and dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (260 mg, 88.8%) as white solid. LCMS retention time 1.712 min, LCMS MH+-THP 459.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1[CH2:17][CH2:16][NH:15]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:17][CH2:16][NH:15][C:11]2=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NCCO1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1cccc([N+](=O)[O-])c1
Temperature: 195 °C
Yield: 33 %

Procedure:
A mixture of 3-nitrophenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 33 percent of the desired product, m.p. 158° C-160° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH2:50][CH2:49][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CN1CCN(CCO)CC1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 0 °C
Yield: 23.9 %

Procedure:
To a homogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]-triazin-6-ol (100 mg, 0.33 mmol) and triphenylphosphine (129 mg, 0.49 mmol) in 4 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran, cooled to 0° C. under a nitrogen atmosphere, was added dropwise a mixture of 2-(4-methylpiperazin-1-yl)ethanol (71 mg, 0.49 mmol) and diisopropylazodicarboxylate (0.10 μL, 0.49 mmol) in 2mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran. The mixture was stirred and allowed to warm to room temperature. The reaction was stirred for twelve hours before being concentrated in vacuo. The residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with chloroform (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (34 mg, 24%) as a yellow solid. 1H NMR (CDCl3) δ 8.20-8.10 (m, 2H), 7.82 (s, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 4.16 (t, 2H, J=5.7 Hz), 2.87 (t, 2H, J=5.7 Hz), 2.80-2.40 (m, 8H), 2.45 (s, 3H), 2.31 (s, 3H); MS(ESI+) m/z 431.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][CH:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][CH2:15][C:16]([C:25](=[O:36])[NH:26][CH:27]([C:32](=[O:35])[NH:33][CH3:34])[C:28]([CH3:31])([CH3:30])[CH3:29])([OH:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[N:46]1[CH:51]=[CH:50][CH:49]=[C:48](B(O)O)[CH:47]=1.[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC.O>[CH3:1][O:2][C:3](=[O:45])[NH:4][CH:5]([C:10]([NH:12][N:13]([CH2:14][CH2:15][C:16]([C:25](=[O:36])[NH:26][CH:27]([C:32](=[O:35])[NH:33][CH3:34])[C:28]([CH3:31])([CH3:30])[CH3:29])([OH:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:48]2[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CNC(=O)C(NC(=O)C(O)(CCN(Cc1ccc(Br)cc1)NC(=O)C(NC(=O)OC)C(C)(C)C)Cc1ccccc1)C(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: COCCOC
Product: CNC(=O)C(NC(=O)C(O)(CCN(Cc1ccc(-c2cccnc2)cc1)NC(=O)C(NC(=O)OC)C(C)(C)C)Cc1ccccc1)C(C)(C)C
Yield: 43.7 %

Procedure:
A mixture of compound (53) (69 mg, 0.10 mmol), 3-pyridylboronic acid (37 mg, 0.30 mmol), Pd(OAc)2 (1.1 mg, 0.0050 mmol), [(t-Bu)3PH]BF4 (3.0 mg, 0.010 mmol) and K2CO3 (41.5 mg, 0.30 mmol), H2O (0.30 mL) and 1,2-dimethoxyethane (1.0 mL) in a 2.0 mL microwave vial was irradiated to 80° C. for 20 min. The reaction mixture was filtered through celite and the solvent evaporated under reduced pressure. The residue was purified by preparative RP-LC-MS which gave 30.1 mg of the title compound (44% yield) as a colorless solid.
Reaction SMILES: ClC1N=CC=C2C=CNC=12.[F:11][C:12]1[CH:13]=[C:14]([NH:29][C:30]([NH:32][C:33](=[O:41])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[S:31])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[C:24]=12.C(Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CI>>[CH2:28]([N:25]1[C:24]2=[C:19]([O:18][C:17]3[CH:16]=[CH:15][C:14]([NH:29][C:30]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[S:31])=[CH:13][C:12]=3[F:11])[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cn1ccc2ccnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reactant: BrCc1ccccc1
Agent: Clc1nccc2cc[nH]c12
Solvent: CI
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3ccn(Cc4ccccc4)c23)c(F)c1

Procedure:
Starting from the compound 259 and following the procedures described above for the synthesis of compound 262b (scheme 60, step 4, example 219) but using benzyl bromide in step 1 instead of methyl iodide, title compound 262c was obtained. 1H NMR (DMSO-d6) δ (ppm): 12.36 (s, 1H), 11.76(s, 1H), 7.78(m, 1H,), 7.58(t, 1H, J1=J2=2.7 Hz), 7.50(d, 1H, J=5.7 Hz), 7.34(m, 5H), 7.30-7.221(m, 5H), 7.15(dd, 1H, J1=8.1 Hz, J2=0.4 Hz), 7.10(t, 1H), 6.60(d, 1H, J=2.9 Hz), 5.68(s, 2H), 3.82(s, 2H). MS (m/z): 511.2(M+H) (found).
Reaction SMILES: C([O-])(=[O:3])C.[Li+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)(C(F)(F)F)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[C:13](/[OH:3])=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C#Cc1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Agent: [Pd+2]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\O)c1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A mixture of lithium acetate (0.21 g, 3.2 mmol) in 5 mL TFA at room temperature was treated with ethyl 4-(2-chloro-6-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (1.18 g, 3.2 mmol), and palladium(II) acetate (0.036 g, 0.16 mmol). The reaction was stirred at room temperature for 2 hours. The residue was diluted with 100 mL EtOAc, washed with water (3×20 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 0.38 g yellow oil. MS m/e: (M+H)+ 383.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N1CCNCC1)=O.C([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=O.[ClH:38]>C(Cl)Cl>[ClH:38].[CH:32]1([CH2:31][N:28]2[CH2:27][CH2:26][NH:25][CH2:30][CH2:29]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=CN1CCN(CC2CCCCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=CN1CCNCC1
Solvent: ClCCl
Product: C1CCC(CN2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (10.51 g) was added to a methylene chloride (50 ml) solution containing N-formylpiperazine (5.08 g) and cyclohexanecarboxyaldehyde (7.50 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hours to undergo reaction, thereby obtaining 1-formyl-4-cyclohexylmethylpiperazine, which was then acid-treated with hydrochloric acid to obtain 1-(cyclohexylmethyl)piperazine-hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][N:14](CC2C=CC(OC)=CC=2OC)[C:13](=[O:29])[C@@H:12]1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:29])[C@@H:12]1[CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C[C@@H](C)N(C(=O)OCc3ccccc3)[C@@H](C)C2=O)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Temperature: 97.5 °C
Yield: 66.8 %

Procedure:
(2S,6R)-4-(2,4-Dimethoxy-benzyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.13 g, 2.74 mmol) is dissolved in 20 mL of acetonitrile. An aqueous solution of potassium persulfate (2.2 g, 8.23 mmol) and sodium phosphate (2.3 g, 16.5 mmol) in 12 mL of H2O is added, and the resulting mixture is heated to 95-100° C. for two hours. After cooling to room temperature, ethyl acetate (200 mL) is used to extract the aqueous layer and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed (SiO2, 60% ethyl acetate/hexane) to give (2S, 6R)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (480 mg, 67% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][NH:7][C:6]=2[CH:17]=1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](F)=[N:25][CH:26]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Reactant: Fc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.0 g, 3.4 mmol) in DMF (5 mL) was added NaH (280 mg, 6.8 mmol) at 0° C. After 0.5 h, 5-chloro-2-fluoropyridine (540 mg, 4.08 mmol) was added. The mixture was stirred at room temperature overnight. After quenching with H2O (30 mL), the reaction mixture was extracted with ethyl acetate (10 mL*3). The organic layer was washed with brine and dried over sodium sulfate. Concentrated in vacuo gave (R)-8-bromo-6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.0 g, crude) for the next step directly. LRMS (M+H+)+: calcd 403.02. found 404.01.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6](OCC)(=[O:13])[CH2:7][C:8](OCC)=[O:9].Cl.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](=[NH:26])[NH2:25])[CH2:20][CH2:19]1>CCCCCC>[O:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:25]=[C:8]([OH:9])[CH:7]=[C:6]([OH:13])[N:26]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)C1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: Oc1cc(O)nc(C2CCOCC2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (3.0 g, 60% in oil, 75 mmol) in hexane (4 mL) was added ethanol (60 mL) slowly at rt. After 30 min at rt, diethyl malonate (4 g, 25 mmol) were added, followed by tetrahydro-2H-pyran-4-carboximidamide-HCl (4.12 g, 25 mmol). The mixture was heated at 90° C. overnight. Dry molecular sieves (2.5 g) were added, and additional ethanol was added to help stirring. The reaction was heated at 90° C. for 4 days. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was removed in vacuo to give 2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,6-diol as a solid, which was used for next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[S:10][CH:9]=[C:8]([CH2:11][CH2:12][C:13]2[N:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>>[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][CH:9]=[C:8]([CH2:11][CH2:12][C:13]2[N:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:7]=1
Reactant: COC(=O)CCc1cc(CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)cs1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CCc3csc(CCCO)c3)nc2)CC1
Yield: 80.2 %

Procedure:
By a method similar to Production Example 113, step 5, tert-butyl 4-(6-{2-[5-(3-methoxy-3-oxopropyl)thiophen-3-yl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (840.0 mg, 1.828 mg) was reduced with diisobutylaluminum hydride to give tert-butyl 4-(6-{2-[5-(3-hydroxypropyl)thiophen-3-yl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (632.3 mg, yield 80.1%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]2[C:20](=[O:23])[NH:21][S:22][C:4]1=2)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[N:24]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]2[C:20](=[O:23])[NH:21][S:22][C:4]1=2)[CH3:2]
Reactant: CCn1c2s[nH]c(=O)c2c(=O)c2cc(F)c(F)c(OC(F)F)c21
Reactant: c1cnc(N2CCNCC2)nc1
Product: CCn1c2s[nH]c(=O)c2c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Yield: 1.4 %

Procedure:
The same reaction as in Example 1 was carried out by using mg (1.44 mmole) of 9-ethyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-3,4-dione and 1.9 g (11.5 mmole) of 1-(2-pyrimidinyl)piperazine to obtain 10 mg of the title compound as pale yellow powder.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1>Cl.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:16])[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of distilled water were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using a hydrochloride of tetraphenyl phosphonium chloride as a catalyst, and the mixture was heated to 90° C. and stirred for 1 hour to obtain diphenyl carbonate containing 5.8 ppm of hydrolyzable chlorine. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 3.0×10−5 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. A pellet of this polycarbonate was used for the measurement of its physical properties. The conditions and results are shown in Tables I-A and I-B below.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[CH:26]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:25][CH2:24]4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH3:36])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[CH:26]([CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24]4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)Cc3ccc4nc(Nc5ccccc5C)oc4c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc4c(c3)CCC4CC(=O)O)cc2o1
Yield: 99.5 %

Procedure:
A solution of ethyl {5-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-1-yl}-acetate [0.255 g, Reference Example 1(b)] in ethanol, under a nitrogen atmosphere, was treated with sodium hydroxide solution (1.6 mL, 1M) and the mixture was heated at reflux temperature for 1.5 hour. The reaction mixture was evaporated and the residual orange oil was treated with water (20 ml) and a few drops of tetrahydrofuran. The mixture was filtered and the filtrate was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting precipitate was filtered at 0° C., then washed twice with a little water and then dried in a dessicator at 50° C. to give the title compound (0.239 g) as a cream coloured solid. LC-MS: RT=3.22 minutes (100% by ELSD); MS(ES+) 456(MH+), 478(MNa+)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:31]1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C:30]1([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:31][CH2:32]1)[CH3:38]
Reactant: CCOC(=O)CC1(CCBr)CC1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 1.67 g (41.62 mmol) of sodium hydride (60% strength dispersion in mineral oil) are added a little at a time to a solution of 10.87 g (32.70 mmol) of diallyl [4-(methoxycarbonyl)benzyl]malonate in 60 ml of anhhdrous DMF. The mixture is stirred at 40° C. for 30 min, and a solution of 6.99 g (29.73 mmol) of ethyl [1-(2-bromoethyl)cyclopropyl]acetate in 60 ml of anhydrous DMF is then added dropwise at this temperature. The reaction mixture is subsequently heated at 100° C. for 8 hours. After addition of 600 ml of water and 200 ml of ethyl acetate and phase separation, the aqueous phase is extracted twice with ethyl acetate. The organic phase is then washed five times with water and once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product is initially purified by flash chromatography (400 g of silica gel 60, mobile phase: cyclohexane/ethyl acetate 4:1), and then by preparative HPLC. This gives 4.87 g (28% of theory) of the title compound in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:26])[CH3:25]>COCCOC>[CH2:24]([NH:26][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:25]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CCN
Solvent: COCCOC
Product: CCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and ethylamine in DME. ES-MS m/e (%): 250 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28])([O-:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:27]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:26])[F:24])=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:28])=[O:29])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc(N)c2ncccc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc12
Yield: 73.1 %

Procedure:
In a similar fashion using route 18 general procedure 27, 5-methoxy-quinolin-8-ylamine 586 (280 mg, 1.6 mmol), 2-nitro-4-(trifluoromethyl) benzenesulfonyl chloride (600 mg, 2.0 mmol), pyridine (0.39 ml, 4.8 mmol) DMAP (cat.) and DCM (15 ml) gave the title compound (500 mg, 73%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[C:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:10][C:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([C:24](=[O:43])/[N:25]=[C:26]4\[S:27][C:28]5[CH:42]=[CH:41][CH:40]=[CH:39][C:29]=5[N:30]\4[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[CH:12][CH:13]=1.Cl>C1COCC1>[O:1]=[CH:2][CH2:6][CH2:7][C:8]1[C:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:10][C:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([C:24](=[O:43])/[N:25]=[C:26]4\[S:27][C:28]5[CH:42]=[CH:41][CH:40]=[CH:39][C:29]=5[N:30]\4[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCC1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCC=O
Temperature: 48 °C
Yield: 79.7 %

Procedure:
Compound 94D (1.47 g) was dissolved in THF (30 mL). To this solution was added 5% HCl (10 mL). The reaction mixture was heated at 48° C. for 90 min. After cooling to room temperature, the reaction mixture was quenched with sat. NaHCO3 solution until no more CO2 was released. The solution was concentrated under vacuum. The residue was re-dissolved in EtOAc, and treated with water (100 mL). The organic layer was separated, and the aqueous layer was extracted with additional EtOAc (three times). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7:3/Hex:EtOAc to give 1.10 g of the title compound 94E (80%): APCI (+)LC/MS: 673 (M+H)+.