Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1>O1CCOCC1.[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reaction time: 34 h

Procedure:
17 (1.6 g, 3.08 mmol) was dissolved in dioxane (45 mL), transferred in a hydrogenation bottle and Pd on carbon (10%, 1.0 g) was added. Hydrogenation was done at 65 psi for 34 h. Following this period, additional Pd on carbon (10%, 0.6 g) was added and hydrogenation was allowed to continue for another 18 h. Catalyst was filtered through a bed of Celite® and solvent was evaporated. The residue was purified by column chromatography on reverse phase silica gel (C-18) using acetonitrile-water (1:1) mixture to elute 18 as white solid (0.60 g, 38%): mp 125-128° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.04 (br s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.6 Hz, 4H), 6.30 (d, J=2.0 Hz, 2H), 6.29 (t, J=2.0 Hz, 1H), 4.90 (dd, J=9.2 and 4.4 Hz, 1H), 3.98 (t, J=8.0 Hz, 1H), 3.67 (s, 6H), 3.56 (s, 3H), 3.37 (dd, J=13.6 and 4.0 Hz, 1H), 3.21 (dd, J=14.0 and 8.8 Hz, 1H); 3.11 (dd, J=14.0 and 9.2 Hz, 1H) and 2.90 (dd, J=13.6 and 7.6 Hz, 1H); MS (EI) m/z 522[M]+; Anal. (C28H27NO7S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][NH:34][CH2:35][CH:36]([OH:43])[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH2:35][CH:36]([OH:43])[CH2:37][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:33])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CNCC(O)CN1CCCC1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC(O)CN1CCCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-hydroxy-3-pyrrolidin-1-yl-propyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and 1-Methylamino-3-pyrrolidin-1-yl-propan-2-ol following General Procedure B.
Reaction SMILES: [C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:21][CH:22]=[CH2:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:21][CH2:22][CH3:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 95.5 %

Procedure:
0.51 g of 6-t-butyl-5-hydroxy-4-(2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 8 was dissolved in 5 ml of ethanol and the solution was vigorously stirred with 0.05 g of 10% palladium on carbon overnight under a hydrogen stream. After the palladium on carbon was filtered off, the mixture was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 0.49 g of 6-t-butyl-5-hydroxy-4-n-propyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a white solid (yield 95%).
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]3[CH2:16]CC[C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1[C:20](O)=[O:21]>>[CH3:20][O:21][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2
Reactant: O=C(O)[C@@H]1CCCN1
Product: COc1cccc2c1C(=O)N(C)CC(=O)N2

Procedure:
(S)-6-methyl-1,2,3,11a-tetrahydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine-5,11(10H)-dione by reaction with L-proline. M.p. 207.6°-209.9° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15](F)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]1=[O:30])[CH:7]=[CH2:8].C(N(CC)CC)C>C(#N)C>[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:11]1=[O:30])[CH:7]=[CH2:8]
Reactant: C=CCOn1c(=O)c2cc(F)c(F)cc2n(Cc2ccccc2)c1=O
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOn1c(=O)c2cc(F)c(N3CCCC3)cc2n(Cc2ccccc2)c1=O
Yield: 94.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-allyloxy-1-benzyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example A-4, 0.15 g, 0.4 mmol) and triethylamine (0.12 mL, 0.9 mmol) in 15 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid, mp 148-150° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10](Cl)[CH:11]=[CH:12][C:4]=2[O:3]1.N[C:15]1C=C(Cl)C=CC=1O>>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[C:4]=2[O:3]1
Reactant: CC1Oc2ccc(Cl)cc2NC1=O
Reactant: Nc1cc(Cl)ccc1O
Product: Cc1cccc2c1OC(C)C(=O)N2

Procedure:
2-Methyl-6-chloro-1,4-benzoxazin-3-one from 2-amino-4-chlorophenol
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:6]=1)(=O)=O.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][OH:36]>>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][O:36][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:6]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CCOc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(Methylsulfonyl)-4-ethoxy-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (LRf from Example 123) was reacted with 2 equivalents each of sodium hydride and 3,4-difluorobenzyl alcohol by the procedure described in Example 16 to afford the title compound: HPLC/MS: m/e=521 (M++1); Rt=4.90 min. 1H-NMR 400 MHz (CDCl3): δ 1.35 (t, 3H), 4.45-4.55 (dd, J=9 Hz, J=7 Hz, 2H), 5.20 (s, 2H), 7.02-7.21 (m, 9H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:34][C:29]1[NH:30][C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:33][CH:32]=2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2C=CC(N)=NC2=O)[O:9][C@H:6]([CH2:7]O)[C@@H:4](O)[C@H:2]1O.[C:18](OC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>CN(C=O)C>[C:1]([NH2:10])(=[O:9])[C:2]1[CH:4]=[CH:6][CH:7]=[CH:19][CH:18]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 282.4 %

Procedure:
To a suspension of cytidine (100 g, 0.411 mol) in DMF (2.06 L) is added benzoic anhydride (102.4 g, 0.452 mol). The mixture was stirred at room temperature for 20 hours. The DMF was removed in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by suction filtration and washed with diethyl ether (2×200 mL). Further drying in vacuo at room temperature gave the N4 benzamide (140.6 g, 98.3%). A portion of this material (139.3 g, 0.401 mol) was dissolved in anhydrous pyridine (1.2 L) and was treated with 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (141.4 mL, 0.441 mol) at room temperature. The solution was stirred at room temperature overnight. The mixture was concentrated to near dryness in vacuo and coevaporated with toluene (3×200 mL). The residue was treated with EtOAc (1.8 L) and washed with HCl (2×200 mL, 0.05 N), NaHCO3 (5%, 2×400 mL). The organic layer was washed dried (Na2SO4), filtered, and evaporated to dryness. Compound 701 (256.5 g, >100%) was isolated as a white foam and used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[Br:16][CH2:17][CH2:18]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][CH2:17][Br:16])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: OCCBr
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Product: O=C(O)c1cc(OCCBr)c2ccccc2c1O
Temperature: 90 °C
Yield: 50 %

Procedure:
60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added to 150 ml of 2-bromoethanol and, under heating at 90° C. with stirring, hydrogen chloride gas was bubbled into the mixture during a reaction period of 2 hours. The mixture was cooled to from 10° to 20° C. and the crystals precipitated were collected by filtration to obtain 47.4 g (50% yield) of 1-hydroxy-4-(β-bromoethoxy)-2-naphthoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CC#N>[CH3:23][O:22][C:18](=[O:21])[CH:19]=[CH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(C2=CCCc3ccccc32)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=CCCc3ccccc32)cc1
Yield: 74 %

Procedure:
Prepared by Heck coupling 4-(4-bromophenyl)-1,2-dihydro-naphthalene (2i) and methyl acrylate in accordance with the general method described in Example IV (J. Chem. Soc. B, 1969, 638–643). Yield 74%; APcI m/z: 332 (M+H+CH3CN+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:24])[N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:13](=[O:24])[N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2ccc(OCc3cccc(Cl)c3)cc21
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7-((3-chlorobenzyl)oxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (34 g, 0.09 mol) in THF (50.09 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.06 M in THF, 99.24 mL, 0.11 mol) at −78° C. The reaction was stirred at that temperature for 30 minutes after which ethyl bromoacetate (9.70 mL, 0.09 mol) was added. The reaction was allowed to warm to ambient temperature, stirred overnight and quenched into water (250 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with brine and dried over MgSO4. The organics were concentrated under reduced pressure to afford a yellow-brown oil and carried on crude to the next step. 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.27-7.22 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.59 (dd, J=8.3, 2.5 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.95 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.06-2.91 (m, 1H), 2.87-2.70 (m, 2H), 2.60 (d, J=7.5 Hz, 1H), 2.37 (d, J=8.9 Hz, 1H), 1.54-1.44 (m, 9H), 1.26-1.19 (m, 3H). [M+H]=374.2.
Reaction SMILES: [Mg].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:13](Cl)(=[O:15])[CH3:14].S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:4]([CH:3]([C:13]([CH3:14])=[O:15])[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C(C)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
5 ml of tetrachloromethane were added to 24.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 177.7 g (1 mol) of tert-butyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at the reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of acetyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice-water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure tert-butyl 2-acetylacetoacetate were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17](Cl)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[CH3:23]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.O1CCCC1.O>[CH3:11][C:10]1[N:9]([C:12]2[C:17]([CH3:23])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][N:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CB(O)O
Reactant: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1-n1ncc(C(=O)O)c1C
Temperature: 120 °C
Yield: 27.2 %

Procedure:
A suspension of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3 g) in Reference Example 123 (2), methylboronic acid (807 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (185 mg), palladium acetate (101 mg) and tripotassium phosphate (5.72 g) in 1,4-dioxane (20 ml) was stirred at 120° C. After completion of the reaction, the mixture was allowed to cool to room temperature, 4 N aqueous solution of sodium hydroxide (30 ml), water (30 ml), tetrahydrofuran (10 ml) and methanol (20 ml) were added thereto, and stirred at room temperature overnight. The organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (697 mg) as a brown solid. MS (ESI) m/z: 286 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][S:28]([CH:31](O)[CH3:32])(=[O:30])=[O:29].C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(O)S(C)(=O)=O
Agent: [Cu+2]
Agent: CC[SiH](CC)CC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCOCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 21 %

Procedure:
To a suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (52 mg, 0.108 mmol) obtained in Step F of Example 1 in methylene chloride (anhydrous, 5 mL) were added copper trifluoromethanesulfonate (20 mg, 0.005 mmol), methanesulfonylethanol (200 μL), and triethylsilane (500 μL, 3.13 mmol) under a nitrogen atmosphere, and the mixture was stirred thoroughly for a whole day and night. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with 2% aqueous EDTA, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-ethoxymethyl)-benzamide (13.3 mg, 21%) as a white solid.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:12]([OH:14])=[O:13].C(N(CC)CC)C.O>C(#N)C>[CH:12]([O:14][CH:2]([CH3:11])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:13]
Reactant: O=CO
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(OC=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-1-phenylpropan-1-one (25 g) in acetonitrile (250 ml) was added formic acid (7.7 ml), and thereto was added dropwise triethylamine (25 ml) under ice-cooling. Then, the mixture was stirred at room temperature for 5 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered and concentrated to give the title compound (19 g). The obtained crude product was used in the next reaction without further purification.
Reaction SMILES: CC(CC([C:7]1[C:12](O)=[CH:11][C:10]([OH:14])=[C:9]([CH2:15][CH:16]=[C:17](C)C)[C:8]=1[O-])=O)C.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[CH2:15]([C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][C:10]=1[O:14][CH2:9][CH:10]([OH:14])[CH2:11][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26])[CH:16]=[CH2:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Product: C=CCc1ccccc1OCC(O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared from compound X (R=2-allylphenyl) and phthalimide by the general procedure described above for the 1-naphthyl derivative (Compound XII).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: c1ccc(COC2CCCNC2)cc1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC(OCc3ccccc3)C2)ccc1Cl

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid is reacted with 3-benzyloxypiperidine by the method of Example 1. Recrystallization from ether-hexane yields the product, m.p. 173°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si](C)(C)C)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][CH2:11][CH2:12][C:13]#[CH:14]
Reactant: COc1ccc(CCCCC#C[Si](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A mixture of 3.20 g (12.3 mmol) [6-(4-methoxy-phenyl)-hex-1-ynyl]-trimethyl-silane, 50 ml methanol and 12.3 ml (24.6 mmol) 2N NaOH was stirred for 2 h at r.t. After neutralization with 13 ml 2N HCl methanol was distilled off and the aqueous phase extracted with diethyl ether. Drying (Na2SO4) and removal of solvents in vacuo gave 1.80 g (78%) of the title compound.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4][CH2:5][CH:6]([S:10][C:11](CC1C=CC=CC=1)=S)[C:7]([OH:9])=[O:8].Cl>C(O)C>[O:1]=[C:11]1[NH:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[S:10]1
Reactant: NCC(SC(=S)Cc1ccccc1)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(C(=O)O)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.0 ml of a 1N aqueous solution of sodium hydroxide were added to a suspension of 1.2 g of 3-amino-2-(benzylthiocarbonylthio)propionic acid hydrochloride in 35 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes, after which 12.0 ml of 1N aqueous hydrochloric acid were added, whilst ice-cooling. The solvent was then removed by distillation under reduced pressure, the resulting residue was dissolved in diethyl ether and the solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 0.50 g of a colorless powder. This powder was recrystallized from ethyl acetate, to give 0.25 g of the title compound as colorless columnar crystals, melting at 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-])[C:6]=2[CH:20]=1.[C:24](O)(=O)C>[C].[Pd]>[CH3:11][C:9]1([CH3:12])[CH2:8][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:20]=[C:2]3[NH:1][CH:24]=[N:21][C:3]3=[CH:4][C:5]=2[O:10]1
Reactant: CC(=O)O
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c([N+](=O)[O-])cc2O1
Agent: [Pd]
Product: CC1(C)CN(c2ccccn2)c2cc3[nH]cnc3cc2O1

Procedure:
To a solution of 500 mg 2-(6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine 1-oxide in 25 ml acetic acid, was added a catalytic amount of 10% palladium-carbon to perform catalytic hydrogenation. The catalyst was filtered off from the reaction mixture, the solvent was distilled off from the filtrate under reduced pressure, the residue was dissolved in 10 ml formic acid, and the solution was heated under reflux for 18 hours with stirring. After distilling off the solvent from the reaction mixture, water was added to the residue, and the resulting mixture was neutralized by addition of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off from the dried solution, the residue was subjected to column chromatography on silica gel, elution was conducted by the use of a 20:1 mixture of chloroform and methanol, and the crude product thus obtained was recrystallized from ethanol, thus giving 119 mg of 1,6,7,8-tetrahydro-6,6-dimethyl-8-(2-pyridyl)imidazo[4,5-g][1,4]benzoxazine.