Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:51]([O:55][C:56](=[O:67])[NH:57][CH2:58][CH:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:54])([CH3:53])[CH3:52].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6](=[O:50])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:66][CH:59]([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[CH2:58][NH:57][C:56]([O:55][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:67])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(Nc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 132 °C
Reaction time: 7 h

Procedure:
A sealed tube was charged with {4-[3-(6-bromo-pyridin-2-yl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 35 supra) (860 mg, 1.18 mmol), (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 1 supra) (390 mg, 1.65 mmol), Pd2(dba)3 (68 mg, 0.12 mmol), DavePhos (93 mg, 0.24 mmol), K2CO3 (228 mg, 1.65 mmol) and dioxane (30 mL), this mixture was stirred at 132° C. under an atmosphere of N2 for 7 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 26 g, 100-200 mesh, eluting with petroleum ether:ethyl acetate, 1:1) to give crude product which was further purified by prep-HPLC to afford (4-{3-[6-(2-tert-Butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 103 mg, 9.86%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[C:2]([CH3:4])=O.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:20]([OH:19])[CH2:21][NH:22][CH:2]([CH3:4])[CH2:1][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][CH:7]=2)=[CH:28][CH:27]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Product: CC(COc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)c1ccc(OCc2ccccc2)cc1

Procedure:
6-[4-[2-[(4-Benzyloxy-β-hydroxyphenethyl)amino]-propyloxy]phenyl]-4,5-dihydro-3(2H)pyridazinone was prepared from 4,5-dihydro-6-(4-acetonyloxyphenyl)-3(2H)-pyridazinone and 2-hydroxy-2-(4-benzyloxyphenyl)ethanamine in an analogous manner to the compound described in Example 38. 1H NMR (DMSO-d6) ppm:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])=O.[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>[O-]CC.[Na+]>[CH3:1][C:2]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[O:14][C:18](=[O:19])[C:17]=1[C:15]#[N:16]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1c(O)ccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Product: Cc1c(C#N)c(=O)oc2ccc3ccccc3c12
Yield: 37.8 %

Procedure:
To a mixture of sodium ethoxide (100 ml; prepared from 1.38 g sodium and 100 ml ethanol) and 2-hydroxy-1-acetonaphthone (11.29 g, 0.06 mol) was added ethyl cyanoacetate (11.1 ml, 0.1 mol). The resulting mixture was stirred at reflux temperature for 2 h. The reaction mixture was cooled in a ice bath and the precipitate was filtered off and washed with water (20 ml) and cold ethanol (3×20 ml), dried in vacuo at 50° C. for 18 h which afforded (9 g) of crude product. The crude product (9 g) was recrystallised from a mixture of acetone (1 l) and water (25 ml) affording 5.33 g (38%) of 1-methyl-3-oxo-3H-benzo[f]chromene-2-carbonitrile as a solid.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13](/B(O)O)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH:13](/[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCOC(=O)c1ccc(I)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 160 °C
Yield: 84.9 %

Procedure:
To a solution of ethyl 4-iodobenzoate (1.0 g, 3.6 mmol) in DMF (4 mL) was added commercial (E)-styrylboronic acid (538 mg, 3.6 mmol) and catalytic Pd(tBuP)2. The reaction vessel was sealed and heated at 160° C. for 10 minutes in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc:hexanes (2:1, 20 mL) and washed with water (2×20 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (silica gel) using 0 to 10% EtOAc/hexanes to afford (E)-ethyl 4-styrylbenzoate (771 mg, 85%) as a pale yellow solid; 1H-nmr (400 MHz, CDCl3) δ 8.05 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 6.95 (d, 1H), 6.89 (d, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.44 (t, J=6.8 Hz, 3H); LCMS (214 nM) 3.58 min (>98%); MS (ESI) m/z=253.1.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH3:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[CH:14]=[C:15]([C:4]2([OH:5])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:1][C:2]2=[O:3])[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: O=C1Nc2ccccc2C1=O
Product: Cc1cc(C)cc(C2(O)C(=O)Nc3ccccc32)c1
Yield: 81.3 %

Procedure:
Using a method similar to Preparation 18 with isatin (1.47 g, 10 mmol) and 3,5-dimethylphenylmagnesium bromide (0.5M in THF, 42 mL, 21 mmol) gave 2.06 g (81%) of the title compound as a peach-color solid. MS (ES): m/z=236 (M+1−H2O), 252 (M−1); 1H NMR(DMSO-d6): δ10.34 (s, 1H), 7.23 (dt, J=1.3 Hz, J=7.6 Hz, 1H), 7.07 (d, J=6.7 Hz, 1H), 6.95 (dt, J=0.9 Hz, J=7.4 Hz, 1H), 6.88 (m, 4H), 6.51 (s, 1H), 2.21 (s, 6H).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>CN(C)C=O>[S:3]1[CH2:2][CH2:1][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[S:4]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)CCCC[C@@H]1CCSS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
110 mg of (R)-α-lipoic acid were dissolved in 2 ml of anhydrous dimethylformamide, and 97 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 4 hours. At the end of this time, 57 mg of methanesulfonamide and 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue this obtained. The resulting mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1:1 and 3:1 by volume mixtures of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilised, to obtain 68 mg of the title compound, melting at 71° C. to 73° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29](Cl)=[CH:28][CH:27]=3)[OH:25])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(=O)C1C=CC=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(Cl)ncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 49, step 3, 1.15 mg, 3.0 mmol) in THF (30 mL) at −78° C. was added LDA (2M in THF, 6 mL, 12 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then benzaldehyde (636 mg, 6.0 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at −78° C. for 20 min, quenched with aq. NH4Cl (5 mL) then diluted with EA (30 mL) and water (8 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(hydroxy(phenyl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H, 3H)-dione (450 mg, 30.7% yield) as a colorless oil. LCMS: [M+-OH] 472 and TR=2.058 min.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([C:34]([NH:36][NH2:37])=[NH:35])[CH:20]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:32][C:30]([C:21]1[CH:20]=[C:19]([C:34]2[N:36]=[N:37][C:1](=[S:2])[N:35]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:31])[CH3:33]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCOc1c(C(C)(C)C)cc(C2=NC(=S)N=N2)cc1C(C)(C)C

Procedure:
1,1'-Thiocarbonyldiimidazole (0.64 g, 0.0036 mole) is added portionwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (1.0 g, 0.0028 mole) and triethylamine (0.43 ml, 0.003 mole) in tetrahydrofuran (5.0 ml). After the addition is complete the mixture is heated to reflux for 1.5 hours. The solution is cooled and concentrated in vacuo. The residue is dissolved in ether (20 ml) and the solution washed with aqueous 2M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo gives 0.94 g (1.1 g theor., 86%) product after recrystallization from ethyl acetate/isopropyl ether, mp 187° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][NH2:37])[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[C:29]=2[O:28]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]=[CH:22][N:23](C)C)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl.N[OH:28]>CO>[Br:1][C:2]1[C:3]([N:21]=[CH:22][NH:23][OH:28])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1Br
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N=CNO)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-4-(((dimethylamino)methylene)amino)pyrimidin-2-yl)piperazine-1-carboxylate (2.0 g) and methanol (30 mL). To the above solution was added hydroxylamine hydrochloride (0.5 g, 7.3 mmol) in one portion. The resulting mixture was stirred at room temperature for 12 h. Work-up: the solvent was evaporated. The resulting crystalline solid was washed with water and collected by filtration. The solid was washed with ethanol (100 mL) and dried, to afford 1.0 g (80%) of the product as a white solid.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([C:31]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=O)[CH:27]=[CH:28][C:29]=1[F:30]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([C:31]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=[S:10])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Temperature: 110 °C
Reaction time: 4 h
Yield: 116.1 %

Procedure:
Under an argon atmosphere, Lawesson's reagent (1.00 g) was added to a suspension of ethyl 3-(3,4-difluorophenyl)-2-oxopiperidine-3-carboxylate (1.00 g) in toluene (20 ml) at room temperature. The reaction mixture was stirred at 110° C. for 4 hr, and allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (859 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1.[CH:27]1[CH:28]=CC2N(O)N=N[C:31]=2[CH:32]=1>CN(C1C=CN=CC=1)C.C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([O:26][CH2:28][CH2:27][CH2:32][CH3:31])=[O:25])=[CH:5][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(OC)cc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCCCO
Product: CCCCOC(=O)c1cnc2ccc(C(=O)NC)cc2c1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a suspension of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid (0.1 g) in dichloromethane EDC.HCl (1-Ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride, 0.161 g), HOBt (N-hydroxybenzotriazole 0.042 g), DMAP (4-dimethylaminopyridine, 0.17 g) and n-butanol (25 mL) were added, and the reaction mixture was stirred at room temperature for 3 hours. After aqueous work up, the reaction mixture was extracted, concentrated and dried over anhydrous sodium sulphate to afford the crude product which was later purified by column chromatography to afford 0.05 g (55% yield) of butyl 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 10.84 (s, 1H, —NH—), 9.21 (s, 1H, aromatic), 8.05 (d, 1H, J=8.8 Hz, aromatic), 7.97 (d, 1H, J=8.8 Hz, aromatic), 7.80 (s, 1H, aromatic), 7.16 (d, 2H, J=8.7 Hz, aromatic), 6.96 (d, 2H, J=8.7 Hz, aromatic), 5.60 (s, 1H, —NHCH3—), 4.41 (t, 2H, J=6.6 Hz, —O—CH2—), 3.87 (s, 3H, —OCH3), 2.88 (s, 3H, —NCH3), 1.92-1.75 (m, 2H, —O—CH2—CH2—CH2—), 1.65-1.46 (m, 2H, —O—CH2—CH2—CH2—), 1.12-0.98 (m, 3H, —CH3); LC-MS (m/z) 407.9 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]>C(O)C>[C:1]([O:4][C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: CCO
Product: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
mp 129-130° C. (EtOH 95) (lit.(1) mp 130-131° C.) 1H NMR (200 MHz, CDCl3): δ 8.09-7.87 (m, 6H, HArom), 7.62-7.31 (m, 9H, H Arom) 6.43 (s, 1H, H1), 5.91 (dd, 1H, H3, J3,4 6.7 Hz; J3,2 4.9 Hz), 5.79 (pd, 1H, H2, J2,3 4,9 Hz; J1,2<1), 4.78 (m, 2H, H4 and H5), 4.51 (dd, 1H, H5, J5,5′13,1 Hz, J5′,4 5,5 Hz), 2.00 (s, 3H CH3CO); (identical to commercial 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose) Mass analysis (FAB+, GT) m/z 445 (M−OAc)+Elemental analysis C28H24O9 Calculated C, 66.66 H, 4.79. found C, H.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4](I)[CH:3]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([C:16]#[C:15][C:14]([CH3:18])([CH3:17])[CH3:13])[CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: OCCNc1cnc(Cl)cc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc(Cl)ncc1NCCO
Yield: 29.1 %

Procedure:
To a solution of 2-(6-chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g, 49 mmol) in Et3N (200 mL) were added 3,3-dimethyl-but-1-yne (12.0 g, 146 mol), CuI (0.9 g, 4.9 mmol) and Pd(PPh3)Cl2 (3.4 g, 4.9 mmol) under N2 atmosphere. The mixture was refluxed overnight and quenched with H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% ethyl acetate in petroleum ether as eluant) to afford 2-(6-chloro-4-(3,3-dimethylbut-1-ynyl)pyridin-3-ylamino)ethanol (3.6 g, 29%). 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.11 (s, 1H), 4.77 (br s, 1H), 3.92-3.90 (m, 2H), 3.78-3.36 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].[CH2:15]([Li])[CH2:16][CH2:17]C>O1CCCC1.CCCCCC>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(C)C)cc(O)c1=O
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (1.95 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml) and the resultant was cooled to -78° C. in a dry ice/acetone bath. A solution of n-butyllithium in hexane (1.6M, 14 ml) was added dropwise to the solution, then, the dry ice/acetone bath was removed and the resultant was stirred until insoluble matter was dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and the resultant was extracted with methylene chloride. The methylene chloride layer was washed with water, then dried over anhydrous sodium sulfate. Solvent was distilled off to give 2.72 g of 7-(α-hydroxybutyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[O:11][CH2:12][C:13]([NH:15][CH:16]([CH3:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([S:26](=[O:29])(=[O:28])[NH2:27])[CH:19]=1)=O)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:6]([O:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[O:11][CH2:12][CH2:13][NH:15][CH:16]([CH3:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([S:26]([NH2:27])(=[O:28])=[O:29])[CH:19]=1)[CH3:7]
Reactant: CCOc1ccccc1OCC(=O)NC(C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1OCCNC(C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
50 ml of tetrahydrofuran was added to 4.22 g (10 mmol, 1.0 eq.) of 2-(2-ethoxy-phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)-1-methyl-ethyl]-acetamide. 379 mg (10 mmol, 4.0 eq.) of lithium aluminum hydride was added thereto and the whole mixture was stirred at 60° C. for 24 hours. Upon the completion of the reaction, 0.4 ml of water, 0.4 ml of 10% NaOH aqueous solution and 1.2 ml of water were sequentially added to the reaction solution and then, filtered through celite. The filtrate was concentrated under reduced pressure to obtain 3.5 g of 5-{2-[2-(2-ethoxy-phenoxy)-ethylamino]-propyl}-2-methoxy-benzene sulfonamide. Thereto was added 10 ml of 2 M HCl solution in ethanol to obtain 3.56 g (yield: 80%) of 5-{2-[2-(2-ethoxy-phenoxy)-ethylamino]-propyl}-2-methoxy-benzene sulfonamide hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][O:11][CH:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]1[CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=2)[N:9]=[CH:10]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc(-c2cocn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)-1,3-oxazole (469 mg, 2.09 mmol) in dioxane (20 ml) was added tributyl(1-ethoxyvinyl)tin (906 mg, 2.51 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.207 mmol), lithium chloride (221 mg, 5.23 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. To the residue was added THF (10 ml), 2N HCl aqueous solution (10 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (256 mg, 65% yield).