Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:24][CH2:23][CH2:22][C@H:19]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:9][CH:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH2:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:8][CH2:7]4)[C:21]=3[C:20]1=2
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (120 mg, 0.35 mmol, 1.00 equiv) in distilled DMF (5 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (75 mg, 0.51 mmol, 1.50 equiv) and potassium carbonate (26 mg, 0.19 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with methanol/DCM (1:10) to afford the desired 2-[(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (130 mg, 82%) as a white solid. MS (ES): m/z 459 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.20 (1H, m), 3.66 (2H, t), 3.58 (2H, t), 3.50-3.41 (3H, m), 3.37 (2H, s), 3.15-3.05 (1H, m), 3.00-2.92 (1H, m), 2.75-2.60 (2H, m), 2.37 (3H, s), 2.33-2.15 (4H, m), 2.03-1.88 (6H, m), 1.71-1.54 (4H, m).
Reaction SMILES: O1CCOCC1.Cl.Cl[C:9]1[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)=[CH:13][C:12]([O:23][CH3:24])=[CH:11][N:10]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[C:9]([NH:25][C:26]2[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:10][CH:11]=1
Reactant: COc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Reactant: COc1ccc(N)cn1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1
Temperature: 140 °C

Procedure:
1,4-dioxane (0.1 mL, 1.169 mmol) and 2 N HCl (0.219 mL, 0.437 mmol) was added to a mixture of 4-(2-chloro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 0.437 mmol) and 5-amino-2-methoxypyridine (Aldrich, St. Louis, Mo.) (81 mg, 0.656 mmol) in a microwave reaction vessel and the mixture was sealed and heated at 140° C. for 60 min in a Personal Chemistry microwave unit under microwave irradiation. After cooling, the resulting dark mixture was concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided the title compound mixed with starting material. This was washed with methanol several times and finally the solid was recrystallized from MeOH to give 4-(5-methoxy-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (21 mg, 0.062 mmol, 14.16% yield) as a yellow-green powder. LCMS (API-ES) m/z 340 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.47 (s, 1H) 8.52 (d, J=2.74 Hz, 1H) 8.39 (d, J=3.33 Hz, 1H) 8.13-8.18 (m, 1H) 8.12 (d, J=3.13 Hz, 1H) 7.86 (br. s., 1H) 7.73 (br. s., 1H) 6.79 (d, J=8.80 Hz, 1H) 3.83 (s, 3H) 3.82 (s, 3H) 2.44 (s, 3H).
Reaction SMILES: Cl.N#N.C(OC([NH:11][C@H:12]([C:17]([NH:19][CH:20]([CH3:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:11])[CH3:31])=[CH:28][CH:27]=1)#[N:30]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(C#N)cc1
Agent: Cl
Agent: N#N
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)NC(C)COc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Hydrogen chloride gas was introduced into a solution containing 15.0 g of N2 -tert-butoxycarbonyl-N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-isoleucinamide dissolved in 300 mL of methylene chloride for 1 hour at room temperature. After completion of the reaction, the methylene chloride was removed under reduced pressure, thus obtaining a crude crystal. 200 ml of a saturated aqueous solution of sodium bicarbonate and 200 ml of methylene chloride were added to the crude crystal, and the mixture was stirred for 30 minutes and extracted with methylene chloride. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The methylene chloride was removed under reduced pressure. The obtained crude product was washed with acetone to afford 10.0 g of the desired product (yield: 90%). Melting point: 64°-67° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][N:31]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CN(C)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.3 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 5.83 grams of 4-dimethylamino-piperidine dihydrochloride and 32 grams of sodium carbonate in 100 milliliters of water and 75 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, the resultant solid washed with water, dried and recrystallised from ethanol/water to give 6.28 grams of the title compound. Melting point 230°--231°C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[C:25]1([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.7 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (0.3 g, 1.2 mmol) in acetonitrile (5 mL) was added 2-(trimethylsilyl)phenyl trifluoromethane sulfonate (397 mg, 1.33 mmol, 1.1 eq) and cesium fluoride (365 mg, 2.4 mmol, 2.0 eq). The mixture was stirred at room temperature for 3 days. Ethyl acetate was then added and the organic layer washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column (eluted with 10% ethyl acetate in hexane) to give tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate as a white solid (400 mg, 99%). M.p.=139-141° C. 1H NMR (DMSO) 400 MHz δ 7.33 (m, 2H), 7.18 (dd, J=1.2 and 7.6 Hz, 2H), 7.09-6.87 (m, 4H), 6.68-6.58 (m, 2H), 3.80 (s, br, 1H), 3.64 (m, 1H), 3.29 (m, 1H), 2.94 (dd, J=5.2 and 10.8 Hz, 1H), 2.72 (m, 1H), 1.34 (s, 9H). LCMS m/e 325 (M+H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27]C.IC(C)C>O1CCCC1>[CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([N:15]([CH:26]([CH3:27])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)I
Product: COc1ccc(N(c2cc3c(c(C(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 7 %

Procedure:
Following general procedure L and using 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.6 g, 2.7 mmol), 1.6M solution of n-butyllithium in hexanes (2.2 mL, 3.5 mmol) and 2-iodopropane (0.9 g, 5.4 mmol) in 10mL of anhydrous tetrahydrofuran, the title compound (0.077 g, 7%) was obtained as a brown oil after separation from recovered 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, CDCl3): δ 6.75 (d, 2H, J=9.2 Hz), 6.62 (s, 1H), 6.38 (d, 2H, J=9.2 Hz),4.25-4.11 (m, 3H), 3.73 (s, 3H), 3.19 (heptet, 1H, J=7.0 Hz), 2.06 (s, 3H), 1.33 (d, 6H, J=7.0 Hz), 1.27 (s, 6H), 1.11 (br m, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:31]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), iodomethane (0.081 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give 3-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 30% yield) as a white solid: mp 193-195° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.74 (3H, s), 6.61 (1H, d, J=7.9 Hz), 6.91 (1H, dd, J=2.3, 8.3 Hz), 7.25 (1H, s), 7.33-7.40 (3H, m), 7.45-7.52 (4H, m), 8.12 (1H, d, J=7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m/z 397 [M+H]+. Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.56; H, 3.88; N, 14.09.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[CH:25][CH:26]=2)[C@@H:9]([OH:10])[CH2:8]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 g of 5-iodo-2′-deoxyuridine (5.65 mmole) was dissolved in 30 ml of pyridine, 5 ml of TEA and 2.16 g of MMTr-Cl (6.99 mmole) were sequentially added thereto, and stirred at room temperature for 4 hours. Then, pyridine was removed under a reduced pressure with a rotary evaporator, the residue was treated with a mixture of water and CH2Cl2, the CH2Cl2 layer was separated, dried under MgSO4, and then, CH2Cl2 was removed under a reduced pressure. The resulting residue was subjected to column chromatography (silica gel 60, 230˜400 meshes, Merck) to obtain the title compound as a pale yellow solid. The chromatography was conducted using a mixture of CH2Cl2 and methanol as an eluting solution whose mix ratio was gradually changed from 100:1 to 50:1 (v/v).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[C:4]1=[O:14])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.COC(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:13][C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([N:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c(=O)c(C)nc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: CCn1c(=O)c(CBr)nc2ccccc21
Yield: 40.3 %

Procedure:
4.2 g (22.3 mM) of 1-ethyl-3-methyl-quinoxalin-2(1H)-one, 3.97 g (22.3 mM) of N-bromosuccinimide and 53.3 mg of benzoylperoxide in 220 ml of carbon tetrachloride were refluxed for 4 h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (70/30) as eluant to give a solid, which was taken up in methylterbutyloxide. After filtration, 2.4 g of 3-(bromomethyl)-1-ethyl-quinoxalin-2(1H)-one were obtained as a tan solid. Yield: 40.3%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:9]([O:8][P:6]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
2.1 g of sodium hydride (60% in oil) was suspended in DMF, and 10 g of ethyl diethylphosphonoacetate was dropwise added thereto at -20° C. under argon atmosphere. The mixture was stirred at room temperature for 30 minutes, and then 9.2 g of benzyl bromide was added thereto 50° C. The mixture was stirred at 50° C. overnight. The reaction solution was poured into a saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=6/1) to obtain 5.7 g of ethyl 2-diethylphosphono-3-phenylpropionate as colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]([C:17]([OH:19])=O)=[CH:10]2)=[O:5].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH2:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@@H:57]([NH:58][C:17]([C:11]1[N:12]([CH3:16])[C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[OH:1])=[CH:15][CH:14]=2)=[O:19])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1
Reactant: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1cc2cc(NC(=O)c3ccccc3O)ccc2n1C)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The product of step (b) (1.36 g, 4.38 mM), PyBrOP (2.45 g, 5.26 mM), and (S)-N-benzyl-N-methyl-2-phenylglycinamide (1.91 g, 6.57 mM) were placed in a 50 mL round bottom flask. DMF (20 mL) was added and the mixture was cooled to 0° C. and treated with diisopropyl ethylamine (3 mL, 17.52 mM). After the addition was complete the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (120 mL) and the mixture was washed with 1N HCl (20 mL), water (20 mL) and brine (20 mL). The ethyl acetate was dried with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% diethyl ether in CH2Cl2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of 0.53 g (2.0 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.44 g (2.2 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 10 ml of pyridine was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the solid was filtered and washed with ethanol to yield 0.39 g of the title compound, mp 273°-276° dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC(NC2N(C)C3C=CC(O[C:31]4C=CN=[C:33]([C:37](NC)=[O:38])[CH:32]=4)=CC=3N=2)=CC=1[N+]([O-])=O.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:33]1[CH:32]=[CH:31][O:38][CH:37]=1
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c([N+](=O)[O-])c2)n3C)ccn1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccoc1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A suspension of 3-bromo-4-methyl nitrobenzene 1 (421 mg, 2.0 mmol), 3-furan boronic acid 2 (452 mg, 4.0 mmol), diisopropylethylamine (1.4 mL, 8.0 mmol), and Pd(dppf)Cl2—CH2Cl2 (162 mg, 0.2 mmol) in dry NMP (10 mL) was sparged with Ar for 20 min. The reaction mixture was heated to 80° C. and maintained at that temperature for 16 h. The reaction was allowed to cool to rt and was then partitioned with water and EtOAc. The resulting mixture was filtered through Celite and the phases partitioned and separated. The aqueous portion was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried (MgSO4), and concentrated. The crude residue was adsorbed onto SiO2 and purified by flash chromatography (9:1 hexanes-EtOAc) to furnish 319 mg (1.57 mmol, 80%) of an off-white solid as 3: 1H NMR (300 MHz, CD3OD) δ 8.16 (d, J=2.5 Hz, 1H), 8.04 (dd, J=2.5, 8.5 Hz, 1H), 7.77 (dd, J=0.8, 1.7 Hz, 1H), 7.63 (app t, J=1.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.72 (dd, J=0.8, 1.9 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]([NH2:25])=[O:24]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[NH:22][C:23](=[O:24])[N:25]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 47.4 %

Procedure:
(E)-3-(3-(4-Hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)benzoic acid (15.0 g, 53.0 mmol) and urea (16.0 g, 0.27 mol) was suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol, filtered and washed with 50 mL of 2-propanol, dried in the air. 8.1 g (48%) of a yellowish powder was obtained. 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.60 (s, 1H), 8.35 (m, 1H), 8.18 (m, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 6.95 (m, 1H), 2.18 (s, 3H). MS (EI): 323 (MH+).
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Si](C=[N+:15]=[N-:16])(C)(C)C>C(Cl)Cl.CO>[C:1]([NH:15][NH2:16])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CCCCCC(=O)O
Solvent: CO
Solvent: ClCCl
Product: C=CCCCCC(=O)NN
Reaction time: 0.5 h

Procedure:
To a solution of 6-heptenoic acid (1.24 g, 9.68 mmol) in methylene chloride (40 mL) and MeOH (10 mL) was added slowly TMSCHN2 (2M, 12.1 mL) at room temperature. The reaction mixture was stirred for additional 30 minutes. After the reaction was completed, the mixture was evaporated in vacuo. The residue was directly used for the next step without further purification. To the above residue in MeOH (20 mL) was added hydrazine monohydrate (5 mL) at room temperature. The reaction mixture was stirred at the same temperature overnight. The mixture was evaporated in vacuo. The residue was further dried by high vacuum overnight to provide the title compound. MH+143.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:26]=3)[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)OC(C)(C)[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C

Procedure:
7-Methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3-chromene (1 kg) was dissolved in acetic acid (10 l) by heating to 60° C. Palladium on carbon (10%, 50% wet, 100 g) was added and the mixture hydrogenated at 60° C., 2-3 atmospheres hydrogen pressure for 24 hours. The mixture was cooled down to 40-50° C. and the catalyst filtered off. The filtrate was evaporated in vacuum to an oil. It was dissolved in 2-propanol (4 l) and sodium hydroxide was added (ca. 1.2 l, 36%) in order to adjust the pH of the mixture to 10-11. The solution was seeded at 40-50° C. The mixture was cooled down to ca. 5° C. and the product filtered off and washed with water (3 l) and dried at 50° C. Yield 0.9 kg, 95%.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH:25][C:1](=[O:11])[CH:2]=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C=Cc2ccccc2)cn1
Yield: 4 %

Procedure:
Prepared as in Example 4-8 from cinnamic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 4%. MS M+H calculated 322.6. Found 322.4.