Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10](SC2N=C(C)C=C(C)N=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([O:27][C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C@@H:34]1[CH2:38][C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:36][NH:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:35]2[CH2:36][C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:38][C@H:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[O:11])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-p-Nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (719 mg) was added to 770 mg of (2R,4R)-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine in 7 ml of tetrahydrofuran and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with brine, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [Na].[C@@H:2]1(N2C=C(C)C(=O)NC2=O)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([NH:24][CH:25]=[N:26]2)=[C:22]([NH2:29])[N:21]=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.ClC1N=C2C(NC=N2)=C(N=CN(C)C)N=1>>[CH2:3]1[C@H:2]([N:26]2[C:27]3[N:28]=[C:20]([Cl:19])[N:21]=[C:22]([NH2:29])[C:23]=3[N:24]=[CH:25]2)[O:9][C@H:6]([CH2:7][OH:8])[C@H:4]1[OH:5]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)C=Nc1nc(Cl)nc2nc[nH]c12
Agent: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Na]
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
Stereoselective glycosylation of sodium salts of halopurines and analogues with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride gave β-nucleoside anomers via predominant Walden inversion,17,18 and ammonolysis/deprotection gave CldAdo.19 Although the sodium salt glycosylation usually gave good anomeric stereoselectivity, minor quantities of a anomers and >10% of N7 regioisomers were usually formed.20,21 This requires separations and results in diminished yields of the desired N9 product. Carson et al.1 had reported an enzymatic transfer of the 2-deoxy sugar from thymidine to 2-chloroadenine (ClAde). Holy and coworkers noted that cells of a strain of Escherichia coli performed glycosyl transfer from 2′-deoxyuridine to 2-chloro-6-[(dimethylaminomethylene)amino]purine to give a derivative of CldAdo.22 Very recently Barai, Mikhailopulo, and coworkers23 described an E. coli-mediated glycosyl transfer synthesis of 2,6-diamino-9-(3-deoxy-β-D-erythro-pentofuranosyl)purine,24 and its enzymatic deamination to 3′-deoxyguanosine.24 They reported glycosyl transfer from 2′-deoxyguanosine to ClAde, and claimed a yield of 81% of CldAdo (based on ClAde).23 However, a 3:1 ratio of dGuo/ClAde was employed, so the yield of CldAdo was <27% based on dGuo.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[O:10].C(N(C(C)C)C(C)C)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:3]([NH:8][C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 54.1 %

Procedure:
To a solution of tert-butyl (3S)-3-({[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-pyrrolidinecarboxylate (1.8 g) and N-ethyldiisopropylamine (720 mg) in chloroform (50 ml) was added trityl chloride (1.6 g), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (3S)-3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-pyrrolidinecarboxylate (1.7 g) as a solid.
Reaction SMILES: O1CCN(C[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])CC1.C([O:23]C1C(C)=CC(C(O)=O)=CC=1C)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:8]([NH2:9])(=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(CN1CCOCC1)c1ccccc1
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-morpholino-1-phenylethanamine represented by Formula 113 (38.4 mg, 0.186 mmol) was slowly added to 4-benzyloxy-3,5-dimethylbenzoic acid represented by Formula 144 (52.5 mg, 0.205 mmol, purchased from Medizin Co. Ltd.) and diisopropylethylamine (0.13 mL, 0.745 mmol) in DMF (3 mL) solution at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 77.9 mg, 0.205 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (2 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate (K2CO3) solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using a small amount of ethyl acetate. Impurities were eliminated using methanol (15 mL) then separation and purification were conducted (using ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v) to produce a benzamide compound represented by Formula 74 as a desired product (VVZ-080; 31 mg, 37% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:30]4C(=O)C5=CC=CC=C5C4=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1.O.NN.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][NH2:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Yield: 56.3 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g)in ethanol (5 ml) is added hydrazine monohydrate (0.03 ml), and the mixture is refluxed for one hour, and cooled. To the mixture is added water, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. The aqueous layer is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (110 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH:20]([CH3:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c(N3CC(C)c4ccccc4C3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CC(C)c4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 34 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.10 g of the compound (8.76 mM) prepared in Example 16 and 10 ml of dimethyl-formamide, 2.20 ml of 4-fluoro-2-methylaniline(20 mM) was added, 1.40 g of the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:8]([C:17](=[O:18])[CH2:16][Cl:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Fc1cccc(Nc2ccccc2)c1
Solvent: c1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1cccc(F)c1

Procedure:
N-(3-Fluorophenyl)aniline (7.02 g, 0.0375 mole) and chloroacetyl chloride (3.3 ml, 0.0412 mole) were refluxed in benzene (50 ml) for 3 hours, then evaporated in vacuo to solids and the solids triturated with pentane and ether to yield purified title product, 8.69 g, m.p. 115°-117°.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[CH:26]=[N:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(-c2ccc(F)cc2)cn1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3cnc(-c4ccc(F)cc4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyrazinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=3[C:20]([OH:22])=O)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:20](=[O:22])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[C:14]2=[O:16])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: O=C(O)c1cccc(Nc2ccc3c(c2)OCO3)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Yield: 80 %

Procedure:
A mixture of 3-(3,4-methylenedioxyphenylamino)phthalic acid (0.50 g, 1.7 mmol) and rac-α-aminoglutarimide hydrochloride (0.29 g, 1.7 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.52 g of the product at 95:5 methylene chloride-methanol, in 80% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.57-2.63 (m, 2H), 2.83-2.96 (m, 1H), 5.11 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 6.04 (s, 2H), 6.80 (dd, J=8.3 Hz, J=1.9 Hz, 1H), 6.92-6.95 (m, 2H), 7.16-7.22 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 8.25 (s, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 101.3, 105.5, 108.6, 110.9, 112.7, 116.7, 118.9, 132.3, 133.2, 136.2, 144.1, 144.5, 147.9, 167.1, 168.3, 170.0, 172.8; Anal. calcd for C20H15N3O6.0.2H2O: C, 60.51; H, 3.91; N, 10.58. Found: C, 60.49; H, 3.62; N, 10.50.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.CS(O[CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:13][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: O=C1NCCc2ccc(O)c(Cl)c21
Reactant: CC(OS(C)(=O)=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc2c(c1Cl)C(=O)NCC2)C(F)(F)F
Temperature: 140 °C
Reaction time: 48 h
Yield: 15.1 %

Procedure:
A mixture of 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 120 mg, 0.610 mmol), 1,1,1-trifluoropropan-2-yl methanesulfonate (526 mg, 2.74 mmol), and K2CO3 (420 mg, 3.05 mmol) in dry DMF (8 mL) was stirred in a sealed-tube at 140° C. for 48 hours. To the reaction mixture was added H2O (40 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparatory TLC (EtOAc, Rf ˜0.65) to give 8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58a, 27 mg, 15%) as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])[CH2:25][CH:26]=3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(C3=CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CC=C(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-5-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 167, triethylamine (42.3 uL, 0.30 mmol) and cyclopropanesulfonyl chloride (12.8 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2OS(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Solvent: Cc1cccc(C)n1
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 165 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165° C. in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
Reaction SMILES: C1(=CC[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)CCCC1.C(N(CC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C.[CH3:30]/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(OCC)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]=1[C:26]1([CH:27]=[CH2:22])[CH2:25][CH2:24][CH2:23][CH2:30]1
Reactant: CCN(CC)c1ccccc1
Reactant: COC(=O)c1ccc(OCC=C2CCCC2)cc1
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOCC
Product: C=CC1(c2cc(C(=O)OC)ccc2O)CCCC1
Temperature: 240 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
The reaction mixture of methyl 4-(2-cyclopentylideneethoxy)benzoate 26.2 (0.50 g, 2.0 mmol), N,N-diethylaniline (3.2 mL, 20 mmol) and N,O-bis(trimethylsilyl)acetamide (2.5 mL, 10 mmol) in a 20 mL seal tube was heated at 240° C. for 48 hours. The reaction was then cooled to room temperature. Diethyl ether (60 mL) was added, and the organic layer was washed with HCl (3N, 20 mL). The organic layer was separated and the solvent was removed. The residue was dissolved in MeOH (10 mL) and HCl (3N, 2 mL) and stiffed at room temperature for 30 minutes. Diethyl ether (80 mL) was added, and the organic layer was washed with NaHCO3 (30 mL) and brine (15 mL). The organic layer was dried over MgSO4. After filtration, the solvent was removed, and the residue was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc, 95/5 to give 26.3 (0.15 g, yield 30%). 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (1H, d, J=2.2 Hz), 7.80 (1H, dd, J=8.3, 2.0 Hz), 6.81 (1H, d, J=8.3 Hz), 5.99 (1H, dd, J=17.6, 10.5 Hz), 5.77 (1H, s), 5.18 (1H, dd, J=10.5, 1.0 Hz), 5.08 (1H, d, J=17.6 Hz), 3.82 (3H, s), 1.89-2.03 (4H, m), 1.56-1.78 (4H, m). MS ESI (neg.) m/e: 245.1 (M−H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[CH2:14](O)[CH2:15][CH2:16][OH:17].[OH-:19].[Na+]>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:19][CH:16]([OH:17])[CH2:15][CH3:14]
Reactant: OCCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Na+]
Product: CCC(O)Oc1ccc(N)cc1N

Procedure:
To a mixture of 0.2 mol (40.5 g) of 2,4-dinitro chlorobenzene and of 1.12 mols (81 cm3) of 1,3-propanediol, heated to 90° C. are added in 30 minutes 1.12 mols (81 cm3) of 1,3-propanediol in 20 cm3 of 10 N sodium hydroxide.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].[CH3:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]=O>>[ClH:15].[CH3:16][N:17]([CH2:26][CH:10]1[CH2:11][CH2:12][CH2:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]1=[O:14])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNCCc1ccccc1
Reactant: O=C1CCCCC(c2ccccc2)C1
Reactant: C=O
Agent: Cl
Product: CN(CCc1ccccc1)CC1CCCC(c2ccccc2)CC1=O

Procedure:
A mixture of 2.77g of 3-phenylcycloheptanone, 2.52 g of methylphenethylamine hydrochloride and 1.23 ml of an aqueous formaldehyde solution (36%) were heated on a water bath for 2 hours under vigorous stirring and with the introduction of nitrogen. The mixture was then evaporated under vacuum, the residue was extracted 3 times with diethylether/n-hexane=1/1 and dried under vacuum. 5.4 g of the crude title compound were then obtained.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[CH3:41][C:42]([NH:44][CH:45]1[C:55]2[CH:56]=[C:57](O)[CH:58]=[CH:59][C:54]=2[C:53]2[C:48](=[CH:49][C:50]([O:65][CH3:66])=[C:51]([O:63][CH3:64])[C:52]=2[O:61][CH3:62])[CH2:47][CH2:46]1)=[O:43]>ClCCl>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][O:32][C:57]2[CH:58]=[CH:59][C:54]3[C:53]4[C:52]([O:61][CH3:62])=[C:51]([O:63][CH3:64])[C:50]([O:65][CH3:66])=[CH:49][C:48]=4[CH2:47][CH2:46][C@H:45]([NH:44][C:42](=[O:43])[CH3:41])[C:55]=3[CH:56]=2)[CH2:36][CH2:37]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCCN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
DEAD (0.118 g; 0.75 mmol), triphenylphosphine (0.196 g; 0.75 mmol) and 4-(2-hydroxyethyl)morpholine (61 μl; 0.5 mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5 mmol) in dichloromethane (5 ml) under argon atmosphere. The mixture was stirred at ambient temperature for 6 hours. After evaporation the residue was purified by flash chromatography eluting with a gradient of 2–10% ethanol/dichloromethane to give N-[(5S)-3-(2-morpholinoethoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: CS(O)(=O)=[O:3].[F:6][C:7]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:8]=1[C:9]#N.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>[Zn].O1CCCC1>[F:6][C:7]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:8]=1[C:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Temperature: 5 °C
Yield: 80 %

Procedure:
To a stirred suspension of 125 mg of zinc dust in 5.0. of tetrahydrofuran was added 11.0 mg of methanesulfonic acid and the mixture was heated at reflux. To the mixture was added 200 mg of 2,4,5-trifluorobenzonitrile, and subsequently 276 mg of ethyl bromoacetate was added dropwise over 1 hour. After the completion of the addition, the mixture was stirred at reflux for further 0.5 hour. The reaction mixture was cooled to 0 to 10° C., 1. of 3N aqueous hydrochloric acid solution was added, and the mixture was slowly warmed to room temperature. The reaction solution was stirred for 2 hours. Tetrahydrofuran was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate and purified by silica gel column chromatography (eluent: ethylacetate/n-hexane= 1/10, v/v) to give the title compound in a yield of 80% (250 mg).