Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:52]1[CH2:56][CH2:55][C@H:54]([NH:57][C:58](=[O:60])[CH3:59])[CH2:53]1>CN(C)C=O.O>[C:58]([NH:57][C@H:54]1[CH2:55][CH2:56][N:52]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:53]1)(=[O:60])[CH3:59]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (62 mg, 0.45 mmol, 2.92 equiv), potassium iodide (5 mg, 0.03 mmol, 0.20 equiv), and (S)—N-(pyrrolidin-3-yl)acetamide (38.5 mg, 0.30 mmol, 1.96 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 150 mL of water. The resulting solution was extracted with 4×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 38.7 mg (24%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.921-8.938 (d, J=5.1 Hz, 1H), 8.623-8.653 (d, J=9.0 Hz, 1H), 8.429 (s, 1H), 8.070-8.138 (m, 3H), 7.859-7.881 (m, 1H), 7.536-7.799 (m, 7H), 4.719 (s, 2H), 4.526-4.593 (m, 2H), 4.377-7.420 (m, 1H), 3.612-3.648 (t, J=5.4 Hz, 4H), 2.500 (m, 1H), 2.007-2.022 (m, 5H), 1.946 (s, 3H), 1.803-1.818 (m, 2H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CCN(CC)CC.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH3:20][N:21]([CH3:25])[C:22]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:23]
Reactant: CN(C)C=Nc1ccncc1O
Reactant: CN(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1ccncc1OC(=O)N(C)C

Procedure:
4-[[(Dimethylamino)methylene]amino]-3-pyridinol (1.65 g) was refluxed for 1 hour in 20 ml of benzene containing 1.10 g of Et3N and 1.10 g of N,N-dimethylcarbamyl chloride. At the end of this time, the reaction mixture was applied directly to a silica column and eluted with 5% Et3N/ethyl acetate. Concentration of the product-containing fractions gave 2.05 g of chromatographically pure product which was distilled in a bulb to bulb apparatus (oven temperature=175° C.) to give analytically pure material, m.p. 64°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 28] (0.037 g) in DCM (1.0 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.025 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 5 min. Morpholine (0.012 ml) was added and the resultant mixture stirred at room temperature for 15.5 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract was concentrated under reduced pressure and the residue was partially purified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:5) to give an impure sample of the title compound. This sample was repurified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:8) to give the title compound (0.036 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH:9]([F:11])[F:10].[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[C:19]([OH:45])=[N:20][C:21](/[CH:24]=[CH:25]/[C:26]3[N:44]=[C:29]4[C@H:30]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]([F:43])([F:42])[F:41])[CH2:31][CH2:32][CH2:33][N:28]4[N:27]=3)=[CH:22][CH:23]=2)[CH:17]=1.CN(C=O)C>C(OCC)(=O)C.O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]3[N:44]=[C:29]4[CH:30]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]([F:42])([F:43])[F:41])[CH2:31][CH2:32][CH2:33][N:28]4[N:27]=3)=[N:20][C:19]=2[O:45][CH2:8][CH:9]([F:11])[F:10])[CH:17]=1
Reactant: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCC[C@H]4c3ccccc3C(F)(F)F)nc2O)cn1
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2OCC(F)F)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
Cesium carbonate (83.7 mg) and 2-bromo-1,1-difluoroethane (34.1 mg) were added to a mixture of 3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol synthesized in Example 344 (100 mg) and DMF (1.2 mL), and the reaction solution was stirred at room temperature for 48 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of the title compound (80 mg). The resulting racemate (80 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=4:6, flow rate: 11 mL/min) to obtain the title optically active compound with a retention time of 14 minutes and positive optical rotation (33 mg) and the title optically active compound with a retention time of 25 minutes and negative optical rotation (35 mg).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15]=[CH:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[CH:15][CH:16]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-hydrazinobenzoic acid (0.501 g, 3.29 mmol) and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (0.48 mL, 3.4 mmol) in EtOH (15 mL) was heated to 75° C. for 17 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide a solid. The obtained solid was suspended in CHCl3 (15 mL), treated with P2O5 (0.50 g, 3.5 mmol), and heated at 65° C. for 6 hours. After cooling to room temperature, the mixture was treated with 1N NaOH (5 mL) and stirred for 30 minutes. The mixture was quenched with 1N HCl (6 mL) and extracted with CH2Cl2 (3×8 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated to provide the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=2[CH3:34])[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]3[CH2:22][O:21]C4(CCCCC4)[O:19]3)[N:14]=2)=[N:10][CH:11]=1.[ClH:37]>C(O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=2[CH3:34])[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=2)=[N:10][CH:11]=1
Reactant: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Agent: Cl
Solvent: CCO
Product: COCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A flask was charged with (S)-N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (0.200 g, 0.375 mmol), 3M HCl (0.751 ml, 0.751 mmol), and ethanol (5 mL). The reaction was heated to 80° C. for 1 hour and then cooled to ambient temperature. The reaction was concentrated in vacuo and purified using reverse phase chromatography (5 to 95% acetonitrile in water) to afford (S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.165 g, 0.298 mmol, 79.4% yield) as white solid after HCl salt formation. Mass Spectrum (apci) m/z=453.1 (M+H−HCl).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=[O:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([N:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])=[C:21]([O:34][CH3:35])[CH:20]=3)[C:11]=12>CS(C)=O>[C:28]([OH:33])(=[O:4])[CH3:29].[C:28]([OH:33])(=[O:4])[CH3:29].[O:33]1[CH2:2][CH:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]3[C:11]4[C:12](=[N:13][CH:14]=[N:15][C:10]=4[NH2:9])[N:16]([C@H:36]4[CH2:37][CH2:38][C@H:39]([N:42]5[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]5)[CH2:40][CH2:41]4)[N:17]=3)=[CH:20][C:21]=2[O:34][CH3:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N=Cc1ccccc1O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC1COc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Salicylaldehyde (0.034 g, 0.000282 mol) and trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.117 g, 0.000268 mol) were combined in absolute ethanol and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)imino]methylphenol which was used without further purification. Trimethylsulfoxonium iodide (0.145 g, 0.00068 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.027 g, 00068 mol) was added at once. After 10 min., the solution of trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl) imino]methylphenol in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (50 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)-3-methoxyphenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.096 g, 0.000142 mol) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][O:21][CH:15]1[CH2:16][C:17]2[C:12]([CH3:22])([CH:11]3[CH:20]([CH2:19][CH:18]=2)[CH:7]2[CH2:6][CH2:5][CH:4]4[CH:3]([CH3:24])[N:2]([CH3:1])[CH2:23][C:8]24[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CI
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reaction time: 8 h
Yield: 38.4 %

Procedure:
Compound 130A (30 mg, 0.091 mmol) was dissolved in 1.5 mL anhydrous DMF. Sodium hydride (60% dispersion in mineral oil, 6 mg, 0.137 mmol) was added and the mixture was stirred at room temperature for 1 hour before iodomethane (39 mg, 0.274 mmol) was added. The reaction mixture and stirred overnight, quenched with water and extracted with dichloromethane to give the crude product, which was purified on silica gel column eluted with 0.3% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12 mg, 38% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:48][C:49]([F:52])([F:51])[F:50])(=O)=O>O1CCCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:48][C:49]([F:52])([F:51])[F:50])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(CC(F)(F)F)CC1
Yield: 43.7 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (180 mg, 0.41 mmol), (prepared as described for the starting material in Example 11), was suspended in tetrahydrofuran (15 ml), and diisopropylethylamine (108 μl, 0.45 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (98 mg, 0.62 mmol) were added. The mixture was heated at reflux for 1.5 hours. Diisopropylethylamine (36 μl, 0.21 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (45 mg, 0.21 mmol) were added and the mixture was heated at reflux for a further 2 hours. The mixture was concentrated under reduced pressure and column chromatography of the residue, eluting with 1% methanol/methylene chloride gave a sticky solid. This was triturated with diethyl ether and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-ylmethoxy]quinazoline (93 mg, 44%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4=CC=CC=C4C3=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O.NN>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:30][CH:31]=2)[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccc(CN2CCOCC2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NCCCCCCOc1ccc(CN2CCOCC2)cc1

Procedure:
To a solution of N-(6-[4-(morpholinomethyl)phenoxy]hexyl)phthalimide (1.66 g, 3.94 mmol) in 1:1 ethanol/THF (28 mL) under nitrogen atmosphere was added hydrazine hydrate (1.4 mL, 29 mmol). The reaction was heated to reflux overnight, then cooled and concentrated. THF was added (30 mL) and the mixture sonicated for 30 min, followed by filtration. The filtrate was concentrated, redissolved in 10 mL THF, and dried with Na2SO4. Concentration gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21].[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCCC>[CH3:1][O:2][C:3](=[O:24])[CH:4]([OH:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCCC
Product: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 60.9 %

Procedure:
3-(4-Benzyloxy-2-nitrophenyl)-2-oxopropanoic acid methyl ester (4.1 g; 12.4 mmole) was dissolved in methanol (60 ml). Sodium borohydride (0.5 g; 13.12 mmole) was added in portions under stirring. TLC (silica gel, ethyl acetate:heptane, 1:1) after one hour showed remaining starting material and the formation of a by product. The reaction mixture was then cooled in an ice-bath and more sodium borohydride (0.2 g; 5.26 mmole) was added. After addition, the mixture was stirred at 0° C. until the starting material was consumed. The reaction mixture was evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was washed with brine and dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel using a gradient of ethyl acetate in heptane as eluant gave 2.5 g (61% yield) of 3-(4-benzyloxy-2-nitrophenyl)-2-hydroxypropanoic acid methyl ester as an oil product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].[OH:34]OS([O-])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O.[OH2:53]>CO>[NH2:1][CH2:2][CH2:3][S:4]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9])(=[O:34])=[O:53]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Reactant: O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCN)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To an ice-cold solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.064 g, 133 μmol, example 237) in MeOH (2 mL) and water (0.5 mL) was added oxone (205 mg, 334 μmol) and the white suspension was stirred at room temperature for 4.5 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (Flasmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 85:15). Colorless solid (0.016 g; 23%). MS (ESI): m/z=512.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16][O:17]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:17][CH3:16])[CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(C=O)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(OC)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-methoxybenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CS(O)(=O)=O.[CH2:15](O)[C:16]#[CH:17].O.[C:20]1(C)[CH:25]=CC=C[CH:21]=1>>[OH:1][CH:2]([CH2:6][C:7]([O:9][CH2:25][C:20]#[CH:21])=[O:8])[C:3]([O:5][CH2:15][C:16]#[CH:17])=[O:4]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: C#CCO
Reactant: Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Product: C#CCOC(=O)CC(O)C(=O)OCC#C
Yield: 43 %

Procedure:
20.00 g (0.149 mol) of 2-hydroxysuccinic acid and 0.2 mL of methanesulfonic acid were dissolved in 100 mL of toluene, 50.16 g (0.895 mol) of propargyl alcohol was added thereto. Using a Dean-Stark device, this was reacted for 4 hours while water formed as a side product was removed under normal pressure. The disappearance of the starting materials was confirmed through gas chromatography, and sodium acetate was added to the system. The resulting salt was filtered away, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (Wakogel C-200, elution with hexane/ethyl acetate=2/1) to give 13.35 g (yield 43%) of di(2-propynyl) 2-hydroxysuccinate.
Reaction SMILES: FC1C(F)=C(F)C(F)=C2C=1[NH:4]C(=O)C(=O)N2.[Cl:17][C:18]1[C:19]([N+:31]([O-:33])=[O:32])=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[NH:24][C:23](=[O:29])[C:22](=[O:30])[NH:21]2.[OH-].[K+].NOS(O)(=O)=O>O>[NH2:4][N:24]1[C:25]2[C:20](=[C:19]([N+:31]([O-:33])=[O:32])[C:18]([Cl:17])=[C:27]([Cl:28])[CH:26]=2)[NH:21][C:22](=[O:30])[C:23]1=[O:29]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Cl)c(Cl)cc21
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The procedure of Shin, S. C. and Lee, Y. Y., Taehan Hwahakhoe Chi 27 (5): 382-4 (1983) was adapted. A red solution of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (100 mg, 0.36 mMol, Cheeseman, supra) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added to a colorless solution of NH2OSO3H (75 mg, 0.66 mMol, Aldrich) in distilled water (0.5 mL) with stirring. A yellow precipitate came out after 10 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C. and was washed with distilled water (2 ml), then dried at 50° C. overnight, affording 85 mg (80% ) of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, as a yellow amorphous solid (80% of desired 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). A 85 mg sample of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (free base Na+, 0.293 mMol) was dissolved into distilled water (10 mL) at 50° C., then was acidified with AcOH to pH=5. After removal of the insoluble material by filtration, the mixture was heated at 60°-70° C. until a clear solution was obtained, which was slowly cooled, whereupon a yellow precipitate came out. The precipitate was crystallized from hot EtOH and the yellow microcrystals were collected by filtration, washed with cold ethanol (2 mL), and dried in the air at 60° C. for 4 h, affording 31 mg (29% ) of pure 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione. Mp was measured: the color of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 275° C.; the decomposition of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione is obvious at 280° C. and it melted to a black liquid at 290°-1° C. IR (KBr, cm-1): 3442; 3315; 3231; 1747; 1723; 1680; 1632; 1547. NMR (1H, DMSO-d6): δ 5.848 (s, 2H); 7.951 (s, 1H); 12,595 (s, 1H). HRMS: calcd for C8H4N4O4Cl2 (M+) m/z: 289.9623; found 289.9616.