Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])=[O:11])=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-dimethylaminocarbonylmethyl-4-acetylthiopyrrolidine (100 mg) was dissolved in 3 ml of methanol, and 0.24 ml of 1N sodium hydroxide solution was added thereto under nitrogen stream at room temperature, followed by stirring at the same temperature for 15 minutes. 1N Hydrochloric acid (0.24 ml) was added thereto, followed by concentration under reduced pressure. The concentrate was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonylmethyl-4-mercaptopyrrolidine.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([Cl:38])[C:7]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[C:13]([CH3:24])[CH:12]=1)(=[O:3])[NH2:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([Cl:38])[C:7]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH2:19][CH2:18]2)=[C:13]([CH3:24])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-3-chloro-6-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (578 mg), 1-methylpiperazine (175 μL), and 1,2-dichloroethane (8.67 mL) was added sodium triacetoxyborohydride (338 mg), followed by stirring at room temperature for 3 hours. To the reactant was added 1-methylpiperazine (82 μL), followed by stirring at room temperature for 4 hours. To the reactant were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, and followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-300:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-chloro-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (560 mg) as a yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15](=S)[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2].S1CC(=O)NC1=S.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(COc1ccc(C=C2SC(=S)NC2=O)cc1)OCC
Agent: O=C1CSC(=S)N1
Solvent: CCO
Product: CCOC(COc1ccc(C=C2SC(N3CCCCC3)=NC2=O)cc1)OCC
Yield: 69 %

Procedure:
A mixture of 5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (which was obtained in Intermediate 37)(1.19 g, 5 mmol), rhodanine (0.67 g, 5 mmol) and piperidine (1.72 g, 20.2 mmol) in ethanol (50 mL) was refluxed for 2 hours. After cooling to room temperature hexanes (70 mL) were added and the solid which was formed was collected to give the title compound as a yellowish solid (1.4 9, 69%); 1H NMR (300 MHz, DMSO-d6) δ1.14(t, J=7.1 Hz, 6 H), 1.55-1.75(m, 6 H), 3.40-3.80 (m, 6 H), 3.85-3.95(m, 2 H), 4.20(d, J=5.2 Hz, 2 H), 4.82 (t, J=5.2 Hz, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 7.57 (d, J=7.6 Hz, 2 H), 7.58(s, 1 H); MS (ES) m/z: 404.9 (MH+, 100%); HRMS Calcd. for C21H28N2O4S (M+): 404.1770. Found: 404.1780.
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([O-:28])=[CH:26][CH:25]=1.[Na+].CC1C=CC(O)=CC=1>C1COCC1>[C:24]1([CH3:23])[CH:30]=[CH:29][C:27]([O:28][C:2]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Reactant: Cc1ccc([O-])cc1
Agent: Cc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(OC(=CC(=O)c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di (4-bromobenzoyl) ethane (11.1 g, 0.02 mole) in 35 ml of THF was added a suspension of sodium 4-methyl phenoxide [prepared from 0.92 g (0.04 mole) Na and 4.32 g (0.04 mole) 4-methylphenol in 30 ml THF by refluxing for 4-5 hr]. The yellow mixture was refluxed for 2-3 hr (TLC followed) after which the THF was removed under reduced pressure. The residue was treated with water, and the solid was filtered, washed with water, dried (Na2SO4), and dissolved in chloroform. The chloroform solution was passed through a silica column (elution with 2-5% ether in hexane). The result was an of f white crystalline solid, 4.95 g (50%), mp 137°-8° C. IR (KBr) 3087, 3035, 2868, 1687, 1646, 1587, 1572, 1557, 1502, 1399, 1364, 1194, 1068, 1009, 971, 876, 815, 772, 526. 1H NMR (CDCl3 /35° C.) 7.92 (d, 2H, J=8.8), 7.65 (d, 2H, J=8.8), 7.55 (d, 2H, J=8.8), 7.48 (d, 2H, J=8.8), 7.27 (d, 2H, J=8.3), 7.11 (d, 2H, J=8.3), 6.32 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3 /35° C.) 189.4, 187.6, 168.4, 150.9, 136.6, 136.0, 133.4, 132.3, 131.8, 130.9, 130.3, 129.6, 129.2, 128.2, 120.6, 101.8, 20.95. MS m/e 500 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>C1COCC1>[CH2:31]([NH:33][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)[CH3:32]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3ccccc3F)c2n1

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was combined and stirred with 5 mL of a 2M solution of ethylamine in THF. After 5 min the solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-2% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a light-yellow crystalline solid. mp 176-177°, LC MS m/z=393 (MH+) Retention time=2.38 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C2C(=CC=CC=2)C=CC=1>[C:12]1([S:18][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[CH3:11])[C:5]([OH:7])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Sc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc(C(=O)O)cc1Sc1ccccc1
Yield: 95 %

Procedure:
Reaction of 3-bromo-4-methylbenzoic acid 1 with thiophenol and cuprous oxide in quinoline at 180° C produces 3-phenylthio-4-methylbenzoic acid 5 in 95-96% yield. Generation of the dianion of 5 is ccomplished by sequential treatment with sodium ydride and then lithium diisopropylamide in a olvent mixture of tetrahydrofuran and 1,3-dimethylmidazolidinone at -20° C. Carboxylation at -15° with carbon dioxide at a pressure of one atmosphere produces the diacid 6 in 90% yield.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]1[C:22](=[O:28])[NH:23][C:24](=[O:27])[NH:25][CH:26]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:25]2[CH:26]=[C:21]([F:20])[C:22](=[O:28])[NH:23][C:24]2=[O:27])=[CH:14][CH:15]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=c1[nH]c(=O)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)cc1F

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 5-fluoropyrimidine-2,4(1H,3H)-dione. M/e+ 371 for C18H13ClFN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.36 (m, 1H), 6.96 (m, 1H), 6.69 (d, J=5.5 Hz, 1H), 5.45 (s, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]([CH3:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)([OH:3])=O.[OH2:22]>C(Cl)Cl.C(OCC)(=O)C>[O:3]=[C:1]1[C:13]2[CH:12]=[CH:11][C:10]([CH:14]([CH3:17])[C:15]([NH2:16])=[O:22])=[CH:9][C:8]=2[CH2:7][CH2:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: CC(C#N)c1cccc(CCc2ccccc2C(=O)O)c1
Reactant: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C

Procedure:
2-[3-(2-Carboxyphenethyl)phenyl]propionitrile (26 g.) is added to polyphosphoric acid (135 g.) [prepared from orthophosphoric acid (d = 1.7; 430 g.) and phosphorus pentoxide (500 g.)] and the emulsion obtained is heated for 1 hour at 100°C. After cooling, the reaction mixture is taken up in water (200 cc.) and methylene chloride (200 cc.). The organic layer is decanted, washed with a saturated solution of sodium bicarbonate (2 × 100 cc.) and then with water (2 × 100 cc.) and is finally dried over anhydrous sodium sulphate (50 g.). After evaporation of the solvent under reduced pressure (20 mm.Hg) at 60°C., the oil obtained is taken up in ethyl acetate (80 cc.). The product which crystallises is filtered off to give 2-(5-oxo-10, 11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (6 g.), melting at 175°C. After recrystallisation from ethanol, the product melts at 181°C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=2[F:26])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[F:26][C:17]1[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:16]=1[O:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: Fc1c(F)c(F)c(OC2CCN(Cc3ccccc3)CC2)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.1 %

Procedure:
To 2.0 g of 10% palladium on carbon was added 6.0 g of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 250 ml of methanol. The reaction mixture was pressurized to 50 psi with hydrogen and shaken on a Parr apparatus at room temperature for five hours. The mixture was then filtered and concentrated. Recrystallization of the concentrate from hot isopropanol afforded 1.9 g (42%) of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride, m.p. 187°-190° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[C:42]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([CH2:48][CH2:49][CH2:50][NH:51][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)=[O:10])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCc1ccccc1)c1ccc(O)cn1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (0.103 g, 0.74 mmol) in dichloromethane was added diisopropylethylamine (0.279 mL, 1.6 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.012 g, 0.8 mmol) and EDCI (0.153 g, 0.8 mmol). The resulting mixture was stirred for 15 minutes and 3-phenyl-1-propylamine (0.108 g, 0.8 mmol) was added. After stirring for 22 h, the reaction mixture was diluted with dichloromethane (80 mL), washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded 5-hydroxypyridine-2-carboxylic acid (3-phenylpropyl)amide as white crystals (0.116 g, 61% yield). MS (ES+) m/z 257.2 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[N:3]=1.[CH2:28]([OH:31])[C:29]#[CH:30].O>N(CC)CC.[Cu]I.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[C:10]=12
Reactant: C#CCO
Reactant: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: O
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1nc2ccccc2n1-c1ccccc1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of 3-iodo-1-((1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 141 (1.5 g, 3.2 mmol), prop-2-yn-1-ol (0.4 g, 6.4 mmol), CuI (0.2 g, 0.64 mmol) and Pd(PPh3)2Cl2 (0.25 g, 0.32 mmol) in Et2NH (30 mL) was stirred at 25 for 2 hrs. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (30 mL×3). The combined organic layers were concentrated in vacuo. The residue was treated with CH2Cl2 and filtered to give 152 (400 mg, yield 32%) as a yellow solid. LCMS (ESI), M+H+=394.15. 1HNMR (400 MHz, DMSO) δ 4.322-4.337 (d, J=6 Hz, 2H), 5.395-5.425 (t, J=6 Hz, 1H), 5.710 (s, 2H), 5.735 (s, 2H), 7.090-7.107 (d, J=6.8 Hz, 1H), 7.223-7.249 (m, 2H), 7.414-7.491 (s, 5H), 7.643-7.663 (d, J=8 Hz, 1H), 8.092 (s, 1H)
Reaction SMILES: [C:1]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([F:19])=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:20](OC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].Cl.C(OCC)(=O)C.[C:34]([N:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)CCO)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1.[Pd].C(O)(=O)C.O>[CH2:45]([NH:41][CH2:34][CH2:20][N:10]1[CH:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][C:17]2[C:12](=[CH:13][C:14]([F:19])=[CH:15][CH:16]=2)[CH2:11]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccccc1
Reactant: COC(=O)N1Cc2cc(F)ccc2CC1C(=O)c1ccccc1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)CN(CCNCc1ccccc1)C(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
A solution of 12 mg of 3-benzoyl-7-fluoro-2-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline in 2 mL of a 6 N aqueous hydrochloric acid solution was reacted under reflux for 16 hours. Under ice-cooling, the reaction liquid was diluted by addition of water, alkalized with 5 N sodium hydroxide, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily substance. 10 mg of the obtained yellow oily substance and 3 mg of 10% Pd-C were dissolved in 2 mL of ethanol and 0.2 mL of a 4N hydrochloric acid/ethyl acetate solution, followed by stirring at room temperature for 48 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 8 mg of a yellow oily substance. To a solution of 8 mg of the yellow oily substance and 9 mg of N-Boc-2-benzylaminoethanol in 1 mL of toluene were sequentially added 9 mg of sodium triacetoxyborohydride and 5 mg of acetic acid, followed by stirring at room temperature for 2 hours. It was alkalized by addition of an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 10 mg of a yellow oily substance. To this yellow oily substance was added 2 mL of 4N hydrochloric acid/ethyl acetate, followed by stirring at room temperature for 30 minutes. The organic layer was washed with an aqueous sodium bicarbonate solution and then with brine, and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue obtained was purified using silica gel chromatography (chloroform: methanol=10:1) to obtain 2 mg (yield 41%) of a title compound as a yellow oily substance.
Reaction SMILES: C[C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH3:14])[C:5]([C:11]([OH:13])=[O:12])=[N:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+]>O.CO>[CH3:14][C:4]1[C:5]([C:11]([OH:13])=[O:12])=[N:6][C:7]([C:8]([OH:10])=[O:9])=[CH:2][C:3]=1[O:15][CH3:16]
Reactant: COc1c(C)c(C(=O)O)nc(C(=O)O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)nc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3.0 g of dimethyl 4-methoxy-pyridin-2,6-dicarboxylic acid (compound F6) are dissolved in 280 ml of water and 420 ml of methanol. After cooling to 0° C., 14.65 ml of a sodium hydroxide solution (strength 1.0 M) is added dropwise (15 min). After 1 h, the mixture is allowed to warm up to room temperature and is stirred for further 21 h during which time 2.0 ml of sodium hydroxide solution are gradually added. Subsequently, 6.5 g of acidic ion exchange resin (Amberlite IR-120 [H+]) are added for neutralization. Thereafter, the mixture is filtered and the filtrate is concentrated in vacuum to yield 2.8 g of the title compound as a colorless oil. TSP-MS: 212.1 [MH+]. TLC: Rf=0.1-0.2 (dichlormethane/methanol 5:1, 3.0 vol.-% acetic acid).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:21])[C:6]2=[O:20].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC.O>[C:16]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:21])[C:6]2=[O:20])=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O

Procedure:
A mixture of 48.4 g (137 mmol) of 4-bromo-5-isobutoxy-6-tertbutyl-2-methylindanone, 25.0 g (205 mmol) of phenylboronic acid, 40.5 g (382 mmol) of Na2CO3, 1.90 g (8.22 mmol, 6 mol %) of Pd(OAc)2, 4.30 g (16.4 mmol, 12 mol %) of PPh3, 180 ml of water, and 520 ml of DME was refluxed for 6 h. Then, this reaction mixture was quenched with water, solvents were evaporated. The residue was dissolved in 500 ml of dichloromethane, this solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness, the crude product was obtained from the residue by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=2:1, vol.). This crude product was re-crystallized from n-hexane to give 40.3 g (84%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH2:21][C:22]([O:24]C)=O)[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[NH3:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:30][C:22](=[O:24])[CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Reactant: N
Solvent: CC#N
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2
Temperature: 22 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of intermediate 3, 5-benzyloxy-2-methanesulfonyl-1-methoxycarbonylmethyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester, (1.10 g, 2.59 mmol) in acetonitrile (20 ml) was treated with a freshly prepared solution of ammonia in acetonitrile (20 ml) and the resulting mixture stirred at 22° C. for 2 h. The reaction was monitored by LC/MS and rapid formation of the amino intermediate followed by cyclization was observed. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by recrystallization of the solid residue from ethyl acetate/hexane gave 0.770 g (82% yield) of the title ester as white crystals; mp 196° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.2 Hz, CH3), 4.39 (2H, q, J=7.2 Hz, OCH2), 4.57 (2H, s, CH2), 5.24 (2H, s, OCH2), 7.3–7.55 (5H, m, aromatics), 9.6 (1H, broad, NH). Anal. Calcd for C16H15N3O5: C, 58.35; H, 4.59; N, 12.76. Found: C, 57.99; H, 4.27, N, 12.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11]>C(OCC)(=O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: COc1cc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)ccc1OS(C)(=O)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)ccc1OS(C)(=O)=O
Yield: 7.3 %

Procedure:
1.5 g (33.4 mmole) 5-(4-[2-(3-methoxy-4-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated on Pd/C (10%) in 150 ml ethyl acetate and 5 ml acetic acid at atmospheric pressure over night. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was crystallized in ethanol to give 1.1 g (yield 73%) of the desired product.