Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:27][CH2:26][CH:5]([N:6]([C:8]3[C:17]([F:18])=[C:16]4[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]4[CH2:19][CH3:20])=[CH:10][C:9]=3[F:25])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[CH2:28]=O>C(O)=O>[CH2:19]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:25])=[C:8]([N:6]3[CH2:7][CH:1]4[N:27]([CH3:28])[CH2:26][CH:5]3[CH2:4][CH2:3][CH2:2]4)[C:17]=2[F:18])[C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4C)c(F)c21

Procedure:
A mixture of 0.20 g (0.52 mmol) of 7-(6,8-diazabicyclo[3.2.2]non-6-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml of 37% formaldehyde solution, and 5 ml of formic acid was heated under reflux for 3.6 hr. The reaction mixture was evaporated to dryness and the residue was suspended in ethanol/HCl. The solid was collected by filtration to give 0.16 g of the title compound as the hydrochloride salt, mp>300°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)C(=O)N1CCCC1C(=O)N2C
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CN1CCCC1C(=O)N2C

Procedure:
When (+)-7,10-dimethyl-1,2,3,11a-tetrahydro-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (melting point 137°-139°C., prepared from L-proline and N,5-dimethylisatoic anhydride as described in Example 1) is treated with 1M borane in tetrahydrofuran as described in Example 1, the above compound, melting point 80°-82° is obtained. The hydrochloride salt melts at 213°-215°C.
Reaction SMILES: CO.O.C[O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[OH-].[Na+:25]>O>[Na+:25].[CH3:22][O:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([O-:23])=[O:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: COCCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCN1CCN(c2ccc(C(=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To 4 ml of MeOH/H2O (1:1) is added 0.52 g (1.87 mmol) of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl]benzoic acid methyl ester and 0.078 g (1.96 mmol) of NaOH (30%). The resulting reaction mixture is stirred 1 hour at 80° C., then cooled to room temperature and diluted with H2O. The H2O-layer is extracted 3 times with diethyl ether and then lyophilised to yield 0.47 g of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl)-benzoic acid sodium salt as a white solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7].[N:39]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:48]2[CH2:49][CH2:50][CH:45]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:46][CH2:47]2)=[O:19])[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7]
Reactant: O=C(O)CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-carboxypropyl)-2-(1H-indol-3-yl-methyl)piperazine (180 mg), 4-piperidinopiperidine (56 mg) and 1-hydroxybenzotriazole hydrate (45 mg) in dichloromethane (4 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg) at ice-bath temperature. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature and was stirred for 2 hours and 40 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous saturated sodium bicarbonate and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(4,1'-bipiperidin-1-yl-carbonyl)propyl]-2-(1H-indol-3-yl-methyl)piperazine, which was converted to the corresponding dihydrochloride salt (0.18 g) by treatment with 4N hydrogen chloride in dioxane solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]=1[N+:13]([O-])=O.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]=1[NH2:13]
Reactant: [H][H]
Reactant: COCCOc1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COCCOc1cccc(F)c1N
Yield: 99.8 %

Procedure:
A mixture of 1-fluoro-3-(2-methoxy-ethoxy)-2-nitro-benzene (675 mg) and Pd/C (10%, 30 mg) in ethanol was shaken under 50 psi of hydrogen for 4 hours. The reaction mixture was filtered through celite and concentrated to afford 580 mg of 2-fluoro-6-(2-methoxy-ethoxy)-phenylamine: 1H NMR (300 MHz, CDCl3) δ 6.8-6.7 (m 3H), 4.2 (t, 2H), 3.9 (bs, 2H), 3.8 (t, 2H), 3.5 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]=[CH2:3].O.NN>[Ni].O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1NCCCC
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1cccc(N)c1NCCCC

Procedure:
A suspension of 0.5 g of Raney nickel in 50 ml of tetrahydrofurane is warmed to 50°, whilst stirring, and a solution of 10.0 g of 1-allyloxy-2-butylamino-3-nitrobenzene and 10 ml of hydrazine hydrate in 100 ml of tetrahydrofurane is added dropwise in the course of 40 minutes. The reaction mixture is then heated to the boil for 1 hour, whilst stirring and under reflux. After cooling, the catalyst is filtered off, the filtrate is evaporated under reduced pressure and the oily residue is subjected to distillation in a bulb tube, 1-allyloxy-2-butylamino-3-aminobenzene being obtained at 100°/0.1 mm Hg (external temperature) as a yellowish distillate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>COCCOC.O>[N:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])=[CH:17][CH:16]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2ccncc2)c1
Yield: 93.5 %

Procedure:
3-Bromoaniline (0.24 ml, 2.2 mmol) and sodium carbonate (0.70 g, 6.6 mmol) were suspended in a mixture of 1,2-dimethoxyethane (16 ml) and water (4 ml). The reaction mixture was then treated with 4-pyridyl boronic acid (0.27 g, 2.2 mmol), and flushed with Argon. Tetrakis (triphenylphosphine)-palladium (0) (0.35 g) was then added, and the mixture was heated to reflux under Argon for 24 hours. The reaction mixture was allowed to cool after which it was partitioned between dichloromethane and water. The aqueous layer was again extracted with dichloromethane. The combined extracts were then dried (Na2SO4) and concentrated in vacuo to afford a pale yellow solid (0.35 g). This was chromatographed on silica gel eluting with ethyl acetate to afford the title compound as a white solid (0.15 g, 41%).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.O.[N:27]1([CH2:33][CH:34]=O)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].O>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: O=CCN1CCOCC1
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(CCN3CCOCC3)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 127, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then morpholine-4-ylacetaldehyde monohydrate hydrochloride (1 g, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 225 mg (38% yield) of ethyl 6-iodo-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: F[C:2]1C=CC(COC2C=C(C)N(C3C=C(C=CC=3C)C(O)=O)C(=O)C=2)=C(CNC(OC)=O)C=1.Br[C:35]1[C:36](=[O:69])[N:37]([C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=2[CH3:68])[C:62]([OH:64])=[O:63])[C:38]([CH3:58])=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH2:50][NH:51][C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53]>>[CH:55]1([NH:54][C:52]([NH:51][CH2:50][C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[CH2:42][O:41][C:40]2[CH:39]=[C:38]([CH3:58])[N:37]([C:59]3[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=3[CH3:68])[C:62]([O:64][CH3:2])=[O:63])[C:36](=[O:69])[CH:35]=2)=[O:53])[CH2:57][CH2:56]1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2CNC(=O)NC2CC2)c(Br)c1=O
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)NC3CC3)cc2=O)c1

Procedure:
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid. 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.12 (m, 1H), 7.01 (m, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 5.19 (s, 2H), 4.44 (s, 2H), 2.48 (m, 1H), 2.11 (s, 3H), 1.90 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ES HRMS m/z 480.1921 (M+H calculated for C26H27FN3O5 requires 480.1929). Step 3: Preparation of 3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[O:15]([C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:30]3[CH2:31][CH2:32][N:27]([C:25]4[CH:26]=[C:17]([O:15][CH3:16])[CH:18]=[C:19]5[C:24]=4[N:23]=[CH:22][CH:21]=[CH:20]5)[CH2:28][CH2:29]3)[C:7]=2[CH:14]=1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Product: COc1cc(N2CCN(CCc3coc4ccc(OC)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxyl-8-piperazino quinoline (243 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 90 mg, (21%); (M+H): 418; 1HNMR (400 MHZ, CDCl3): δ 8.73˜8.71 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H) 8.03˜8.00 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 7.50˜6.71 (m, 7H); 3.91 (s, 3H), 3.87 (s, 3H), 3.55˜2.82 (12H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:35]=[CH2:36]>>[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([C:22]2[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([S:11][C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)=[C:13]([C:24]([F:25])([F:26])[F:27])[CH:14]=3)[CH:19]=[CH:20][N:21]=2)[CH2:39][CH2:38]1)[CH:35]=[CH2:36]
Reactant: C=CCN1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: C=CCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-allylpiperazine. A yellow solid 136 was obtained (0.037 g, 73%). 1H-NMR (CDCl3, 400 MHz) δ 2.10–2.55 (br m, 6H), 3.24–3.45 (br m, 2H), 3.7 (d, J=7.0 Hz, 2H), 4.06–4.20 (br, 2H), 4.28–4.34 (m, 4H), 5.54 (d, J=7.2 Hz, 1H), 5.61 (d, J=10.2 Hz, 1H), 6.06 (m, 1H), 6.88 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.02–7.06 (m, 2H), 7.09 (d, J=1.9 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.82 (s, 1H), 8.26 (d, J=5.9 Hz, 1H); MS (APCI) m/z 514 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].ClC1C=CC2[O:30][CH2:29]CC(CC(OCC)=O)C=2C=1>O1CCCC1>[CH3:29][O:30][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:14]=1
Reactant: CCOC(=O)CC1CCOc2ccc(Cl)cc21
Reactant: OCCC1CCOc2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)CCO2

Procedure:
2-(6-Chloro-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanol may be prepared by proceeding as in Example 1, but starting with lithium aluminium hydride (1.97 g), and ethyl (6-chloro-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanoate (6.6 g) in tetrahydrofuran (120 cc). 2-(6-methoxy-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanol (5.5 g) is thus obtained in the form of a colourless oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)[CH3:2].C(O[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41]C(=O)C)[C@@H:33]([O:34]C(=O)C)[C@H:28]([O:29]C(=O)C)[C@H:23]1[O:24]C(=O)C)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:7]1[CH:16]=[CH:17][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[C@@H:22]1[O:39][C@H:38]([CH2:40][OH:41])[C@@H:33]([OH:34])[C@H:28]([OH:29])[C@H:23]1[OH:24]
Reactant: CCSc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCSc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 60.1 %

Procedure:
To a solution of 2-(4-ethylthiobenzyl)phenol (0.51 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (2.4 g) in toluene (6.3 mL) and dichloromethane (2.7 mL) was added boron trifluoride diethyl ether complex (0.78 mL), and the mixture was stirred at room temperature for 9 hours. To the reaction mixture were added ethyl acetate (70 mL) and a saturated aqueous sodium hydrogen carbonate solution (25 mL), and the organic layer was separated. The organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10.5 mL), sodium methoxide (28% methanol solution, 0.08 mL) was added to the solution, and the mixture was stirred at 25° C. for 18 hours. To the reaction mixture were added ethyl acetate (75 mL) and water (20 mL), and the organic layer was separated. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained colorless solid was washed with diethyl ether and dried under reduced pressure to give 2-(4-ethylthiobenzyl)phenyl β-D-glucopyranoside (0.51 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[O:17])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of 2-[4-(benzyloxy)-2-chlorophenyl]ethanol (1.50 g) in dichloromethane (30.0 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.70 g) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture was added a 1 M aqueous sodium thiosulfate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [4-(benzyloxy)-2-chlorophenyl]acetaldehyde (1.01 g).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:3]#[CH:4].Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[C:3]#[C:4][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(O)cc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne (120 mg, 0.84 mmol) (from Example 17 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-hydroxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 62 mg, 47%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)c1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)c1
Yield: 57.8 %

Procedure:
A solution of the compound (104 mg, 0.2 mmol) obtained in Example 23-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (47 mg, 58%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(C)c2)n1C
Yield: 60.64 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-04) (250.0 mg, 60.64%) was synthesized as a white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (400.0 mg, 0.905 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:24])(=[O:3])[CH3:2].C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:44]N1C(=O)CCC1=O>C(OCC)C>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@:13]32[C@H:8]([C@H:9]([C:21](=[O:23])[CH2:22][Br:44])[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=O)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(=O)CBr)CC[C@@H](C)[C@@]23OC(C)(C)O[C@@H]13
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a stirred, cooled (0° C.) solution of the product of (3aS,4R,6aS,7R,10S,10aS)-7-acetyl-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 148, 1.8 g) in diethyl ether (30 ml) was added triethylamine (1.8 ml) and trimethylsilyltrifluoromethanesulfonate (2.3 ml). After 30 minutes, N-bromosuccinimide (1.2 g) was added and the reaction mixture was allowed to warm to room temperature over three hours. The reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried (MgSO4), evaporated and purified by flash column chromatography on silica gel using a gradient elution ethyl acetate:hexane (1:9 to 2:8) to give the product as a gum (1.81 g).