Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](SCC=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(=[O:14])C.C(NC=CSCC1C=CC=CC=1)(=O)C.[CH3:30][C@@H:31]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1>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.C1COCC1>[CH2:1]([OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C@@H:31]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1
Reactant: CC(N)=O
Reactant: O=CCSCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)NC=CSCc1ccccc1
Agent: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Solvent: C1CCOC1
Product: OCc1ccccc1
Temperature: 250 °C

Procedure:
0.10 mol of 2-(benzylthio)acetaldehyde and 0.20 mol of acetamide are heated together at 100° C. with stirring, and the product solid is heated in a sublimator at 250° C. and 1 mm Hg until formation of the enamide 1-acetamido-2-benzylthioethene is complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), D-menthol (0.5 mmol), (PPh3)2PdCl2 (36 mg, 0.05 mmol), and 1-acetamido-2-benzylthioethene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a mixture of two diastereomeric cysteine derivatives, N-acetyl-L-benzylcysteine D-menthyl ester and N-acetyl-D-benzylcysteine D-menthyl ester. These diastereomers are separated by column chromatography on silica gel with benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100° C. in 1N HCl for 2 hours to give pure L- and D-cysteine, benzyl alcohol, acetic acid, and D-menthol, which is thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH3:11])[CH2:4][N:3]1[CH2:12][CH3:13].[Br:14]Br>C(Cl)Cl>[Br-:14].[O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH3:11])[CH2:4][NH+:3]1[CH2:12][CH3:13]
Reactant: BrBr
Reactant: CCN1CN(CC)C(=O)N(C)C1=O
Solvent: ClCCl
Product: CCN1C[NH+](CC)C(=O)N(C)C1=O
Product: [Br-]
Yield: 86.4 %

Procedure:
18.5 g (0.1 mol) of 2,4-dioxo-hexahydro-1,5-diethyl-3-methyl-s-triazine are dissolved in 20 ml of methylene chloride and 24 g (0.15 mol) of bromine are added dropwise. The temperature is kept at 20° C to 30° C by occasional cooling. After a few minutes, an orange-coloured precipitate separates out. This is filtered off and recrystallised from isopropanol. 23 g (87%) of 2,4-dioxo-1,2,3,4-tetrahydro-1,5-diethyl-3-methyl-s-triazinium bromide of melting point 198° C are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (100 mg, 0.552 mmol) in methylene chloride (5 mL) was added thiophene-2-carbaldehyde (62 mg, 0.552 mmol), sodium triacetoxyborohydride (351 mg, 1.66 mmol) and drop of acetic acid. The solution was stirred for 4 hr. The solvent was removed under vacuum, and the crude product was loaded on a Isco 12 g column. Elution with 0% to 10% methanol in methylene chloride over 15 column volumes afforded the title compound (95 mg, 61% yield). Exact mass calculated for C13H15N3O2S 277.3. found 278.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.58 (d, J=5.05 Hz, 1H) 7.33 (d, J=3.03 Hz, 1H) 7.07-7.16 (m, 1H) 4.63 (s, 2H) 4.47 (s, 2H) 4.24 (s, 2H) 3.94 (t, J=5.56 Hz, 2H) 2.73 (t, J=5.56 Hz, 2H).
Reaction SMILES: O=S(Cl)Cl.C([N:12]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:17][C@@:13]1([CH3:29])[C:14]([OH:16])=[O:15])(OC(C)(C)C)=O.[CH3:30]O>>[CH3:30][O:16][C:14](=[O:15])[C@:13]1([CH3:29])[CH2:17][C@@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:19][NH:12]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@@]1(C)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@]1(C)C[C@@H](OCc2ccc(Br)cc2)CN1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
SOCl2 (0.27 mL) was carefully added dropwise to 2.7 mL of MeOH at −5° C. To this mixture was added (2S,4R)-N-Boc-4-(4-Bromobenzyloxy)-2-methyl-proline (0.25 g) in 2.7 mL of MeOH. The reaction mixture was allowed to warm to 20° C. and stirred overnight. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated in vacuo to afford the titled compound (85 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)=[O:23].[CH2:40](O)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:20][O:21][C:22]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])=[CH:33][CH:32]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: CCCCCCCCO
Reactant: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1

Procedure:
A solution of triphenylphosphine (3.78 g, 0.014 mol) in dry tetrahydrofuran (50 ml) was added to a stirred solution of compound 4 (3.92 g, 0.014 mol), octan-1-ol (1.88 g 0.014 mol) and diethyl azodicarboxylate (DEAD) (2.51 g 0.014 mol) in dry tetrahydrofuran (100 ml) under an atmosphere of dry nitrogen. The addition was such that the triphenylphosphine was added over 30 seconds in which time the solution became hot and the white solid (4) and orange colour (DEAD) disappeared. The resultant solution was stirred overnight, the solvent was removed in vacuo and the viscous, oily residue was purified by column chromatography (10% petrol/dichloromethane) to give a colourless solid which was recrystallised from ethanol to leave colourless plates.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: Oc1c(Br)cccc1Br
Reactant: COCCl
Product: COCOc1c(Br)cccc1Br
Yield: 99.9 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 19.16 g (76.1 mmol) of 2,6-dibromophenol with 7.35 g (91.3 mmol) of chloromethyl methyl ether, 22.50 g (100%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)=[O:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.O1CCCC1.CO.[OH-].[Li+]>O>[CH3:15][C:13]1[CH:14]=[C:6]([CH2:5][CH:4]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:23][CH2:24]2)=[O:18])[C:3]([OH:36])=[O:2])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reaction time: 0.02 h
Yield: 75 %

Procedure:
A suspension of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (240.0 mg, 0.489 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) at room temperature was treated with a solution of lithium hydroxide (140.5 mg, 7 equiv) in water (10 mL). Within 1 min, the mixture became homogeneous and it was left to stand at 4° C. overnight. The solvents were evaporated at ca. 30° C. and the pH was adjusted to ca. 1 with 1N hydrochloric acid. The resulting white suspension was stored at 4° C. for several hours and the product was collected by filtration, washed with a small amount of water, and dried in vacuo (169.0 mg, 73%). Solid sodium chloride was added to the filtrate resulting in precipitation of more product (5.2 mg, total yield 75%). 1H-NMR (CD3OD, 500 MHz) δ 1.2-1.7 (4H, m), 2.58 (3H, s), 2.5-3.2 (4H, m), 3.35 (2H, m), 4.15 (2H, m), 4.36 (1H, m), 4.60 (1H, m), 6.79 (1H, d), 6.96 (1H, t), 7.18 (3H, m), 7.49 (1H, s), 8.00 (1H, s). Mass spec.: 477.13 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](OC(N1CCN(C(=O)C2C=CC(C=O)=CC=2)CC1)=O)([CH3:32])(C)[CH3:30].N1CCOCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH:32]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[O:28])[CH2:10][CH2:9]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CO
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaB(OAc)3H (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (1.22 g, 48%). MS (ESI): mass calcd. for C21H31N3O4, 389.23; m/z found, 390.4 [M+H]+. 1H NMR (CDCl3): 7.39-7.33 (m, 4H), 3.75-3.66 (m, 6H), 3.50 (s, 2H), 3.51-3.33 (m, 6H), 2.45-2.41 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.[CH:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCCCCC>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[C:31]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C1CCCCC1)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A solution of 2.88 mL (20.5 mmol) of diisopropylamine (iPr2NH) in 50 mL of tetrahydrofuran (THF) was flushed with argon and cooled to −78° C. To this solution was added dropwise 8.2 mL (20.5 mmol) of n-butyllithium (nBuLi) 2.5 M solution in hexane, and the resulting mixture was stirred at −78° C. for 20 min, after which time a solution of 4.5 g (16.3 mmol) of (4-iodo-phenyl)-acetic acid methyl ester in 25 mL of THF was added dropwise. The mixture was allowed to warm up to rt for 40 min, then it was cooled again to −78° C., and 2.62 mL (19.6 mmol) of cyclohexanecarbonyl chloride was added dropwise, and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight under argon. The reaction mixture was quenched on ice by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated to give 7 g of a burgundy oil which was chromatographed on silica gel (Biotage; 10% ethyl acetate in hexane) to afford 5.06 g (80% yield) of desired 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo-propionic acid methyl ester as a pale yellow solid as indicated by 1H NMR (1:2.6 keto:enol ratio). LC-MS—calcd for C16H19IO3 [M++H]+: 387.04, found: 387.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[NH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[N:25]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=c1[nH]cnc2cc(Cl)ccc12
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](n1cnc2cc(Cl)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (2.46 g, 9.8 mmol, obtained as described in Tasaka et al., Chem.Pharm.Bull. 1993, 41, 1035-1042) in N-methylpyrrolidone (10 mL), 7-chloro-3H-quinazolin-4-one (1.77 g, 9.8 mol) and K2CO3 (1.35 g, 9.8 mmol) were added. The resulting solution was heated at 80° C. for 3 days. The mixture was cooled to room temperature, water was then added and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (4×). The combined organic extracts were washed with water (4×), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to a reduced volume and was allowed to crystallize at 0° C. The resulting product was filtered, dried and dissolved in hot ethanol (10 mL/g). The insoluble material was filtered off, and the filtrate was then poured over cold water (120 mL/g of UR-9825) under stirring. The resulting precipitate was filtered and dried in vacuo (50° C.) to give the desired product as a white amorphous powder (3.1 g, 75%).
Reaction SMILES: [NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[OH:22])[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.Cl[CH2:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:22][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: CC(C)(C)OC(=O)CC[C@@H](C(N)=O)N1Cc2c(O)cccc2C1=O
Reactant: ClCc1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@@H](C(N)=O)N1Cc2c(OCc3ccc(CN4CCOCC4)cc3)cccc2C1=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
(S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm.
Reaction SMILES: [C:1]1(=[O:20])[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=[O:11])[C:5](=[O:19])[CH2:4][CH2:3][CH2:2]1.Cl.[OH-:22].[Na+]>>[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=1)[NH:6][C:5](=[O:19])[CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:22])([OH:12])=[O:11]
Reactant: [OH-]
Reactant: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
3'-Carboxy-5'-nitroglutaranilic Acid [F; Y is CH2CH2CH2, Z is OH] was prepared by warming gently a solution of 5.0 g. of 3-glutarimido-5-nitrobenzoic acid in excess 10% aqueous sodium hydroxide. The solution was acidified with 3N hydrochloric acid and the product collected and recrystallized from ethyl acetate to give 3'-carboxy-5'-nitroglutaranilic acid, pale yellow prisms, m.p. 182°-184° C.
Reaction SMILES: [CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][C:4]1=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)cc(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Temperature: 100 °C

Procedure:
A suspension of 1-ethyl-4-hydroxy carbostyril (1.09 g; 0.00575 mole) in glacial acetic acid (5 ml) was swirled during the rapid addition of concentrated nitric acid (1.25 ml; d 1.42) and the dark liquid heated for 5 minutes at 100°C. The yellow solid which separated on cooling was filtered off and washed well with ethanol m.p. 154°-5°C (decomp). (Found;C, 56.54; H, 4.52; N, 11.56; C11H10N2O4 requires; C, 56.41; H, 4.30, N, 11.96%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH:3]2[CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: COc1ccc2c(c1)C(CO)CN(C(=O)OC(C)(C)C)C2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step G (10.5 g; 36 mmol) is dissolved in 150 ml of dichloromethane and then triethylamine (8.5 ml) is added. The solution is cooled to 0° C. and methanesulphonyl choride (4.8 ml; 62 mmol) is added dropwise. The reaction mixture is stirred at ambient temperature for 2 hours and then poured into 150 ml of water. The solution is extracted with dichloromethane, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The title compound is purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18](=[S:20])[NH2:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].Cl[CH:34]([CH:40]=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(O)(=O)C.CN(C)C(=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:20][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:40][N:19]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=S)cc3c2)cc1
Reactant: CCOC(=O)C(Cl)C=O
Agent: [K]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (280 mg), ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg), acetic acid (0.5 mL) and N,N-dimethylacetamide (5 mL) was stirred at 100° C. for 4 h. Ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg) and acetic acid (0.5 mL) were added again, and the mixture was stirred at 100° C. for 3 h. Furthermore, ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg) and acetic acid (0.5 mL) were added and the mixture was stirred at 100° C. for 7 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 50/50, volume ratio) to give the title compound (242 mg, crude yield 71%) as a yellow solid. MS 549 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2)cc1OC

Procedure:
The 1-(4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane prepared in (2) above in an amount of 5.5 g (0.015 mol) was dissolved in methanol (200 ml) and ethyl acetate (200 ml) and, thereafter, 10% Pd/C (2 g) was added to the resulting reaction solution and the reaction mixture was stirred in hydrogen gas for 8 h, followed by filtration and concentration under vacuum to yield the end compound 1-(4-aminophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (5 g).