Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:18])C.C=O.[OH-].[K+]>CCCCCC>[OH:18][CH2:16][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: NC(=O)CCC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(CCC(=O)OCc1ccccc1)NCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To astirred solution of 20.7 g. (0.10 mole) of benzylsuccinamate in 150 ml. ethyl acetate at 25°C. is added 3.0 g. of paraformaldehyde and 1 ml. of a 20% (by weight) solution of ethanolic potassium hydroxide. After stirring at 25°C. for 20 hours, hexane is added to the cloudpoint and the mixture is cooled at 5°C. for 24 hours. Solvents are decanted off and the residue is washed with 25 ml. hexane to give benzyl N-hydroxymethylsuccinamate.
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]([NH2:17])[N:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([Cl:35])=[C:23]([NH:25][S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:24]=1>>[NH2:17][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:19]2[CH:20]=[CH:21][C:22]([Cl:35])=[C:23]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:24]=2)=[CH:6][N:5]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1cc(Br)ccc1Cl)c1cccnc1
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(NS(=O)(=O)c2cccnc2)c1

Procedure:
This compound is prepared as described for Example 3-25 (step 2) from 4-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-pyrimidin-2-ylamine (Intermediate G) and pyridine-3-sulfonic acid [5-bromo-2-chloro-phenyl]-amide.
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:8].C(O)(=O)C>C(O)C>[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1
Reactant: C/C=C(\N)C#N
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To an ice-cold solution of aminocrotononitrile (82 g, 1.0 mol) and 2-hydrazinopyridine (120 g, 1.1 mol) in ethanol (300 mL) was added acetic acid (132 g, 2.2 mol), and the mixture was heated under reflux for 3.5 hours. After the mixture was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure and water was added to the residue. After the solution was made basic by the addition of an aqueous sodium hydroxide solution, organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (156.3 g, 90% yield).
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O:27]([CH2:34][CH2:35][CH2:36]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)CCC>[O:27]([CH2:34][CH2:35][CH2:36][N:18]1[CH2:17][CH2:16][CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCOc1ccccc1
Reactant: c1ccc(Cc2ccccc2C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1ccc(Cc2ccccc2C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4.40 g of 4-(α-phenyl-2-tolyl)piperidine hydrochloride of Example 35 and 14 g K2CO3 in 50 ml of n-butanol are heated to reflux with stirring. To this is added 5.66 g 3-phenoxypropylbromide in 10 ml of n-butanol dropwise. The mixture is then refluxed for 24 hours. After cooling the suspension is suction filtered, washing the flask and filter cake with n-butanol. The combined filtrates are evaporated to an oil which is dissolved in 20 ml of isopropanol and made acid with HCl/ether. The hydrochloride is collected by suction filtration and washed with ether. The resultant product is recrystallized from isopropanol/ether to yield 1-(3-phenoxypropyl)-4-(α-phenyl-2-tolyl)piperidine, mp 139°-140° C.
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:22]([NH2:31])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>CO>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:20]2[C:34](=[O:35])[CH2:33][C:32](=[O:37])[NH:31][C:22]3[C:23]4[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=4[CH:29]=[CH:30][C:21]2=3)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1c(Nc2cccc(OCc3ccccc3)c2)ccc2c1CCCC2
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(=O)N(c2cccc(OCc3ccccc3)c2)c2ccc3c(c2N1)CCCC3
Reaction time: 1 h
Yield: 32 %

Procedure:
To an anhydrous tetrahydrofuran (15 mL) solution of N2-(3-benzyloxyphenyl)-5,6,7,8-tetrahydronaphthalene-1,2-diamine (151 mg, 0.44 mmol) was added malonyl chloride (50 μL, 0.53 mmol) while stirring in ice-bath. The mixture was stirred at room temperature for 3 hours. To the mixture was added methanol (5 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour, and at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the titled compound as yellow oil (58 mg, yield 32%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>C(OCC)C>[CH2:1]([C:3]1[O:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1)[CH3:2]
Reactant: O=C=O
Reactant: CCc1ccco1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccc(C(=O)O)o1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
2-Ethylfuran (9.1 g) was dissolved in diethyl ether, and the mixture was cooled to -70° C. under nitrogen atmosphere. n-Butyllithium (1.6M in hexane, 60 ml) was slowly added dropwise. The mixture was stirred at room temperature for 2 hours, and then cooled to -70° C. The mixture was stirred for 30 minutes with introducing carbon dioxide gas, and then warmed to room temperature. The mixture was stirred at room temperature for 30 minutes, poured into ice-water, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was crystallized from water and collected by filtration to give 5-ethyl-2-furancarboxylic acid (9.0 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][N:25]([CH3:43])[C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:30]5[CH:31]=[CH:32][C:27]([C:26]([N:25]([CH3:43])[CH3:24])=[O:42])=[CH:28][CH:29]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Temperature: 150 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (0.10 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 mmol), K2CO3 (240 μL, 1M), Pd-FibreCat (7 mg), and DMF (1 mL) were combined. The mixture was heated at 150° C. for 5 min (5 min ramp time) in a microwave reactor. After cooling, the mixture was filtered and purified by prep-HPLC to provide 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,N-dimethyl-benzamide. ESI-MS m/z calc. 442.2, found 443.5 (M+1)+; Retention time 3.12 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.02-1.08 (m, 2H), 1.37-1.44 (m, 2H), 2.17 (s, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 6.01 (s, 2H), 6.87-6.93 (m, 2H), 6.98 (d, J=1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H), 7.40-7.52 (m, 4H), 8.75 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][CH3:15])[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of 3-ethylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 1.5 mmol) in DMF (5.0 mL) was added drop wise a solution of 4-chlorophenyl isocyanate (0.23 g, 1.51 mmol) in DMF (2.5 mL) at room temperature and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified on silica using hexane/ethyl acetate (50%) followed by ethyl acetate (100%) to give the desired product as white foamy solid.
Reaction SMILES: [O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].Cl>>[O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of methyl 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-propylbenzimidazole-7-carboxylate (703 mg) in 0.3N-NaOH (12 ml) was stirred at 60° C. for one hour, and then adjusted to pH 3 with 0.1N-HCl. Resulting precipitates were extracted with a mixture of chloroform-ethanol (10:1; 150 ml). The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as colorless prisms (550 mg, 90%), m.p.169-171° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])=[CH:18][N:17]=3)[C:14]=2[OH:15])[C:5]([CH3:25])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: C1COCCN1
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 3.40-3.87 (m, 8 H) 7.79 (d, J=7.07 Hz, 1 H) 7.88 (d, J=10.86 Hz, 1 H) 8.10 (dd, J=8.59, 2.02 Hz, 1 H) 8.27 (br. s., 1 H) 8.44 (br. s., 1 H) 8.57 (dd, J=2.27, 0.76 Hz, 1 H) 13.47 (br. s., 1 H); ESI-MS m/z [M+H]+408.3.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=O>>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(Br)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (60 mg, 0.185 mmol; Example 1, Step 2) and 3-bromo-4-chlorobenzaldehyde (48.6 mg, 0.222 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (91 mg) that was used without any further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>CN(C=O)C.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>[CH3:11][C:8]1[CH:9]=[C:10]2[C:2]([C:17](=[O:19])[CH3:18])=[N:3][NH:4][C:5]2=[CH:6][N:7]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2c(Br)n[nH]c2cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1n[nH]c2cnc(C)cc12

Procedure:
A solution of 3-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (2.13 g, 10.04 mmol), tri-butyl(1-ethoxyvinyl)tin (6.78 mL, 20.09 mmol) and PdCl2(PPh3)2 (0.705 mg, 1 mmol) in DMF (12.6 mL) was heated at 80° C. overnight under argon atmosphere. Then concentrated under reduced pressure and diluted with EtOAc. HCl (2N) was added, the layers were separated and the aqueous layer was basified by addition of NaHCO3 (1N in water) and extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The yellow oil thus obtained was used without further purification in the next step. TLC, Rf (c-hexane/EtOAC 1:1)=0.05; MS (UPLC/MS): 176 [M+H]+, 174 [M−H]−.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][O:19][C:13]4=[CH:12][C:11]=3[N:10]=[C:9]([C:20]([O:22]CC)=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26].CO>>[CH3:25][NH:26][C:20]([C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[N:10]=1)=[O:22]
Reactant: CCOC(=O)c1cc(N2CCCCC2)c2cc3c(cc2n1)OCO3
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(N2CCCCC2)c2cc3c(cc2n1)OCO3

Procedure:
After a mixture of ethyl 8-(1-piperidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate as obtained in Reference Example 31 (60 mg) and a 40% methylamine-methanol solution (5 ml) was stirred at room temperature for 3 hours, the solvent was distilled off under reduced pressure to yield the title compound as a colorless powder (33.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[CH:11]12[O:16][CH:12]1[CH2:13][CH2:14][CH2:15]2>O1CCCC1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[OH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: C1CC2OC2C1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2CCC[C@H]2O)c1
Yield: 56.3 %

Procedure:
To a solution of 3-methoxyphenyl magnesium bromide 1.0M (59.4 ml, 59.4 mmoles) and copper(I) iodide (0.762 g, 4.0 mmoles), add (dropwise) a solution of cyclopentene oxide (5.2 ml, 59.4 mmoles) in tetrahydrofuran (5 ml) over 40 minutes. The reaction is exothermic and the temperature rises to 45° C. Cool the reaction to ambient temperature and quench with a 25% solution of ammonium chloride (40 ml), extract with ether and shake with brine. Dry the organic layer over sodium sulfate and concentrate in vacuo to yield an oil which is flash chromatographed on silica with 14-25% ethyl acetate/hexanes to yield 6.43 g of the titled compound. 1H NMR (CDCl3): 7.23 (d, J=8.4, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.81 (s, 1H), 6.77 (m, 1H), 4.15 (m, 1H), 3.81 (s, 3H), 2.86 (m, 1H), 2.18-2.04 (m, 2H), 1.9-1.6 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:6][CH:7]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8]2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: COc1cc(OC2CCN(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC2CCN(C)C2)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
To a stirred solution of 3-(3-methoxy-4-nitro-phenoxy)-1-methyl-pyrrolidine (Intermediate 46; 5.50 g, 20.68 mmol) in ethanol (125 mL) under nitrogen was added in one portion the Pd/C catalyst (10%, 500 mg). The resulting mixture was evacuated and backfilled with nitrogen (×4) before hydrogen gas was introduced via a balloon. The reaction mixture was stirred at room temperature for 18 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give a the title compound as a light red oil (4.74 g, 100%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)[C@@H](C)O
Yield: 94.6 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (2.88 g, 17 mmol), 3-methoxy-4-nitrobenzoic acid (3 g, 15.2 mmol), WSC hydrochloride (3.83 g, 20 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (2.58 g, 20 mmol) and dichloromethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0) to obtain 4.49 g of the title compound as a light yellow amorphous solid (95%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=CC=CCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of the 6-(4-chlorophenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.44 g, 1.64 mmol) in distilled THF (9.0 mL) containing 50% aqueous hydroxylamine (1.0 ml, 15.2 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.6 mL, 2.6 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 h, distilled water (9.0 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.21 g, 48%) as a pale brown powder, mp 120-122° C. (decomp).
Reaction SMILES: [C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]1=[O:30])(=[O:3])[CH3:2].[CH3:31]I.[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:31])[C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]1=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1NC(=O)N2C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1N(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
3'-Acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'trione (3.06 g) is dissolved in dimethylformamide (20 ml) and thereto is added methyl iodide (1 ml) and further added in portions sodium hydride (60%) (0.3 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent: chloroform) to give 3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (3 g, yield: 94.5%) as an oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[CH3:3][CH:4]([O:7][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]#[CH:6]
Reactant: C#CC(C)O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: C#CC(C)OCC(=O)OC

Procedure:
Sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol), (±)-3-butyn-2-ol (21 g, 0.30 mol), and methyl bromoacetate were processed as described in Example 43A to provide the title compound. 1H NMR (CDCl3) δ 1.51 (d, 3H), 2.46 (d, 1H), 3.76 (s, 3H), 4.25 (AB q, 2H), 4.39 (dq, 1H).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:14]/[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:19]=1[CH3:20])/[C:5](=[O:13])[NH:6]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd]>[CH3:12][O:11][C:10]1[C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:13])/[C:4]/2=[CH:14]\[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:19]=1[CH3:20]
Reactant: COc1ccc2c(c1Br)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2c(c1-c1ccccc1)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a mixture of 4-bromo-5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (223 mg, 0.5 mmol) and phenylboronic acid (73 mg, 0.6 mmol) in DME/water (5 mL) were added Palladium catalyst Pd(PPh3)2Cl2 (10.5 mg) and sodium carbonate (106 mg, 1 mmol). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 85° C. oil bath for overnight. TLC showed some de-bromination of the starting material. The degass procedure was repeated for three more times and the heating was continued for 3 more days. The mixture was cooled to room temperature, the unreacted starting material was filtered off and the mother liquor was concentrated. The residue was purified on a silica gel column to give 21 mg of 5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [BrH:1].[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[C:11]1=[O:22].[H][H]>[Pd].O>[BrH:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[CH:11]1[OH:22]
Reactant: O=C1c2ccc(O)c(O)c2CCC1NCC1CCC=CO1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NCC1CCCCO1)C2O

Procedure:
In the presence of 2 parts of 5% palladium-on-carbon, 2 parts of 2-(3,4-dihydro-2H-pyran-2-yl)methylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide is catalytically reduced in 50 volume parts of water at ordinary temperature and pressure until no more hydrogen is absorbed. The catalyst is filtered off and the filtrate is freeze-dried. The above procedure yields 2 parts of 2-(tetrahydropyran-2-yl)methylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals melting at 155°-158° C (decomposition). The product was identified as that of Example 5 by mixed melting point)