Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31].[Cl-].[NH4+]>O1CCCC1.O>[Si:5]([O:8][CH2:9][C:10]1[S:11][C:12]([CH:30]=[O:31])=[C:13]([CH2:15][CH3:16])[CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCc1csc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Temperature: 0 °C
Yield: 86 %

Procedure:
To a solution of t-butyl[(4-ethyl-2-thienyl)methoxy]dimethylsilane (1.3 g, 5.6 mmol) that was obtained in Example 10 (10a) in tetrahydrofuran (10 ml) was slowly added a 1.6 M solution of n-butyllithium in hexane (4.2 ml, 6.7 mmol) at −78° C. with stirring, and after raising the reaction temperature to 0° C., the resulting mixture was stirred for 30 minutes. Subsequently, the reaction temperature was lowered to −78° C. again under stirring, and to the reaction mixture was added N,N-dimethylformamide (0.86 ml, 11 mmol) with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (1.3 g) in a yield of 86% as a pale yellow oily product.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[S:17][CH:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:30][N:29]=[C:28]([CH3:31])[N:27]=4)[CH:23]=[CH:22][C:21]=3[CH3:32])[C:10]=2[C:11]([NH2:14])=[N:12][CH:13]=1)=[O:7])C>O1CCCC1.CO>[NH2:14][C:11]1[C:10]2[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:30][N:29]=[C:28]([CH3:31])[N:27]=4)[CH:23]=[CH:22][C:21]=3[CH3:32])=[CH:16][S:17][C:9]=2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=1
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccc(C)c(OCc3csc4c(C(=O)O)cnc(N)c34)c2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hydroxide (2 N, 3.0 mL, 1.5 mmol) was added to a solution of 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 0.78 mmol) (from Example 54 supra) in tetrahydrofuran/methanol (3:1, 8 mL) and the mixture was heated at 50° C. for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1N). After stirring 30 minutes, the solid was collected, washed with water and dried to 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid. (Yield 0.29 g, 94%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:23])[N:19]=[CH:20][C:21]=3[Br:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Br:22][C:21]1[CH:20]=[N:19][N:18]([CH3:23])[C:17]=1[C:15]1[CH:14]=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(-c3c(Br)cnn3C)ccc21
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (37 mg, 0.089 mmol) in methanol (2 mL) was treated with of 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica) resulted in 28 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.50 (s, 1H), 7.25 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.10 (s, 1H), 3.83 (s, 3H), 3.17 (m, 1H), 3.1-2.9 (m, 8H), 2.80 (dd, J=7, 13 Hz, 1H), 2.48 (bs, 1H), 1.40 (d, J=8 Hz, 3H). MS calculated for C15H18BrN3+H: 320, observed: 320.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:13]([OH:15])=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:16]1(C)C(S(O[C@H](C)C(OCC2C=CC=CC=2)=O)(=O)=O)=CC=C[CH:21]=1.[C:39](=[O:42])([O-])[O-:40].[K+].[K+]>C(#N)C>[CH2:16]([O:14][C:13]([C@@H:4]([NH:3][C@H:1]([C:39]([OH:40])=[O:42])[CH3:2])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1S(=O)(=O)O[C@H](C)C(=O)OCc1ccccc1
Reactant: CCN[C@@H](CCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O

Procedure:
Ethyl (S)-homophenylalanine (I') and benzyl (R)-α-toluenesulfonyloxypropionate (II') in the presence or absence of potassium carbonate were added to acetonitrile (15 ml, bp 82° C.), and refluxed for a predetermined time, while stirring. After completing the reaction, the mixture was concentrated under reduced pressure and water (10 ml) was added to the oily residue. Then the mixture was extracted with toluene (10 ml). The organic layer was concentrated under reduced pressure to remove toluene. The oily residue was subjected to silica gel column chromatography to give the compound N-[(lS)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine. The reaction conditions are shown in Table 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32](O)=[O:33])=[CH:26][C:25]2=[O:35]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[O:28][C:29]2[C:24]([C:25](=[O:35])[CH:26]=1)=[CH:23][C:22]([CH3:21])=[CH:31][CH:30]=2)=[O:33]
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1ccc2oc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc(=O)c2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 460.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:24][CH:25]=[O:26])[CH:5](O)[C:6](=[CH2:22])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C=CCCC=C.S(Br)([Br:36])=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:24][CH:25]=[O:26])[CH:5]=[C:6]([CH2:22][Br:36])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OC
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Solvent: C1CCOC1
Product: COC(=O)C(C=C(CBr)CCCCNC(=O)OCc1ccccc1)NC=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran there are added 5.5 ml (46 mmol) of hexa-1,5-diene and then, dropwise at -50°, 2.6 ml (32.5 mmol) of thionyl bromide. The mixture is stirred at from 0° to 5° for 2 hours, poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted twice with 20 ml of methylene chloride each time. The organic phase is washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([O:15][CH3:16])=[CH:13][N:12]([CH:17]([CH3:34])[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:11](=[O:35])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([O:15][CH3:16])=[CH:13][N:12]([CH:17]([CH3:34])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:32][CH:33]=2)=[O:19])[C:11](=[O:35])[CH:10]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1Br
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1Br

Procedure:
72 mg (purity 73%, 0.09 mmol) of tert-butyl 4-({2-[4-(2-bromo-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 20 mg (42% of theory)
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([S:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1

Procedure:
A suspension of 3′-mercaptoacetophenone (Reference compound No. 4-1, 0.50 g, 3.3 mmol), potassium carbonate (0.55 g, 4.0 mmol) and 4-fluoronitrobenzene (0.42 mL, 4.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 8.5 hours. Water (30 mL) was added to the reaction mixture, extracted with mixed solvent (30 mL) which consists of hexane and ethyl acetate (3:1). The organic layer was washed with brine (30 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title reference compound (1.2 g) quantitatively as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cccnc1Nc1ccc(O)cc1
Temperature: 10 °C

Procedure:
A mixture of EXAMPLE 1 (41.05 Kg) and ammonium formate (5 equivalents), with or without 2,6-di-tert-butylphenol antioxidant, was treated with a mixture of 50% wet 5% palladium hydroxide on carbon (7% by weight per weight of EXAMPLE 1), in DMF (6 mL/g catalyst) then DMF (total DMF volume: 5 mL/g EXAMPLE 1) first with moderate agitation to control an exotherm (typically peaking at 85° C.) then with increased agitation for 1 hour (incomplete reactions were treated with additional catalyst/DMF mixture), cooled to 10° C., and filtered. The filtrant was washed with DMF (0.4 mL/g EXAMPLE 1), and the filtrate was added to water (29.4 mL/g EXAMPLE 1) at 10° C. to precipitate a solid which was filtered, washed with water (7.5 mL/g EXAMPLE 1), partially dried under a nitrogen stream, and further dried under vacuum at 50° C. to about 0.5% moisture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Temperature: 45 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
To a solution of 4-chloro-2-fluorophenylacetonitrile (Matrix) (5 g, 30 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood) (5 g, 32 mmol) in methanol (200 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (21 mL, 92 mmol). The reaction mixture was heated and stirred at 45° C. for 5 h. The mixture was cooled to room temperature and filtered. The white precipitate was washed with water, cold methanol, and then dried under reduced pressure to afford (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (8 g, 86%).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:18])[CH2:4][N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[OH2:19].N1[CH:25]=[CH:24]C=CC=1>C(OC(=O)C)(=O)C.C(Cl)(Cl)Cl>[C:24]([O:1][CH2:2][C:3](=[O:18])[CH2:4][N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])(=[O:19])[CH3:25]
Reactant: c1ccncc1
Reactant: O
Reactant: Cc1cccc(C)c1N(CC(=O)CO)S(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)CN(c1c(C)cccc1C)S(C)(=O)=O
Reaction time: 20 h

Procedure:
A solution of N-(3-hydroxy-2-oxopropyl)-2',6'-dimethylmethanesulphonanilide (2.8 g) in pyridine (5 ml) and acetic anhydride (5 ml) was allowed to stand at room temperature for 20 hours. Water was added to decompose excess anhydride, and the oily product was extracted into ether. The ether solution was washed successively with dilute hydrochloric acid and sodium bicarbonate solution, dried (MgSO4), and evaporated to give a yellow oil. A solution of this oil in chloroform was percolated through a short column of silica gel. Evaporation of the eluate gave the product, N-(3-acetoxy-2-oxopropyl)-2',6'-dimethylmethanesulphonanilide, as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[C:18]([CH3:35])[C:17]=1[CH3:36].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[C:18]([CH3:35])[C:17]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)CCOc4ccccc4C)c(C)c3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCCOc4ccccc4C)c(C)c3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-3-(2-methylphenoxy)propaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH 1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 473 (M++1)
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([N:25]([CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)[CH2:23][CH3:24].[OH-:40].[Na+]>C(O)(=O)C.O>[CH2:37]([N:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][C:28]1[C:29]2[C:33]([CH:34]=[CH:35][CH:36]=1)=[N:32][C:31](=[O:40])[CH:30]=2)[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCc1cccc2[nH]ccc12
Reactant: [OH-]
Agent: [Br-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCN(CCC)CCc1cccc2c1=CC(=O)N=2
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of pyridinium tribromide 90% (8.72 g, 24.5 mmol) in acetic acid 50% (50 mL) was added to a solution of 4-[2-(dipropylamino)ethyl]indol (IV) (5 g, 20.5 mmol) in acetic acid 50% (100 mL) and was stirred at 50° C. for 3 h. When the resultant mixture reached room temperature, it was stirred at this temperature for 16 h. The reaction mixture was concentrated to obtain an aqueous residue, which was diluted with water (100 mL), basified with an aqueous solution of NaOH 10% and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 4.3 g (81%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([O:11]C(=O)C)[CH:9]([O:15]C(=O)C)[CH:8]([O:19]C(=O)C)[CH:7]([O:23][CH2:24][C:25]([CH3:63])([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]5[N:48]([CH:49]=4)[C:47]4[CH:50]=[CH:51][C:52]([O:54][CH2:55][CH2:56][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)=[CH:53][C:46]=4[S:45]5)=[CH:38][CH:37]=3)=[O:34])[CH:28]=2)[CH3:26])[O:6]1)=[O:4].CO.O.[OH-].[K+]>C(O)(=O)C>[OH:11][CH:10]1[CH:9]([OH:15])[CH:8]([OH:19])[CH:7]([O:23][CH2:24][C:25]([CH3:63])([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]5[N:48]([CH:49]=4)[C:47]4[CH:50]=[CH:51][C:52]([O:54][CH2:55][CH2:56][N:57]6[CH2:58][CH2:59][O:60][CH2:61][CH2:62]6)=[CH:53][C:46]=4[S:45]5)=[CH:38][CH:37]=3)=[O:34])[CH:28]=2)[CH3:26])[O:6][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1OC(OCC(C)(C)c2cc(NC(=O)Nc3ccc(-c4cn5c(n4)sc4cc(OCCN6CCOCC6)ccc45)cc3)no2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(COC1OC(C(=O)O)C(O)C(O)C1O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
Final compound 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6) is prepared by following a general procedure given in J. Med. Chem. 1995, 38, 1911). To a stirred mixture of 3,4,5-triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester (1 equivalent) in 4:1 MeOH:water at rt, is added dropwise aq potassium hydroxide (1-4 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is acidified with glacial acetic acid and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6).
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[O:6].[C:13]([NH:16][CH:17]([C:23](=O)[CH2:24]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14].CN(C)C1C=CC=CC=1>C(O)C>[C:13]([NH:16][CH:17]([C:23]1[N:10]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:11])[Cl:12])=[O:6])[S:9][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.51 g. of N-(β,β,β-trichloroethoxycarbonyl)thiourea and 2.66 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in 50 ml. of ethanol is added 1.8 g. of N,N-dimethylaniline. The mixture is stirred for 24 hours at room temperature, and condensed under reduced pressure. The residue is dissolved in 30 ml. chloroform and the solution is washed with 3N--HCl, water, and dried. The solid matter which is obtained by removal of chloroform is purified by silica gel chromatography to give ethyl α-acetamido-2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetate. 1.43 g.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][NH2:11].[SH:12][CH:13]([CH2:17][C:18]([OH:20])=[O:19])[C:14](O)=[O:15]>CN(C=O)C.O>[CH3:10][N:11]1[C:14](=[O:15])[CH:13]([CH2:17][C:18]([OH:20])=[O:19])[S:12][CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)CC(S)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(CC(=O)O)SC1c1ccccc1
Temperature: 80 °C

Procedure:
A solution of benzaldehyde (0.75 mmol, 79.6 mg) and methylamine hydrochloride (60.8 mg, 0.9 mmol) in DMF (0.5 ml) with 4 Å molecular sieves was heated at 80° C. for 2 hours. A solution of mercaptosuccinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the reaction was heated at 80° C. for an additional 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N HCl, water and evaporated to dryness to give the desired product which was used without further purification.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([I:15])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:16].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.C(OCC)(=O)C>[OH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([I:15])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:16]
Reactant: COCOc1c(C)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Cc1cc(I)c2c(c1O)CNC2=O
Yield: 52.1 %

Procedure:
In a similar manner to Step. 4 of Example 16, 4-methoxymethoxy-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (500 mg, 1.07 mmol) was dissolved in nitromethane (20 mL), and the solution was treated with trifluoroacetic acid (0.742 mL, 9.63 mmol) and triethylsilane (1.54 mL, 9.64 mmol). The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-hydroxy-5-methyl-7-iodoisoindolinone (161 mg, yield 52%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:30])[N:17]([CH3:29])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[F:31])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:31][C:10]1[CH:11]=[C:12]([C:15]2[C:16](=[O:30])[N:17]([CH3:29])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)c(F)c2)c1=O
Yield: 81.7 %

Procedure:
A solution of 5-(4-(benzyloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (0.139 g, 0.331 mmol) in TFA (1.5 mL) was stirred at 40° C. for 3 hours. The reaction mixture was concentrated to dryness and then purified by flash column chromatography, eluting with 20:1 dichloromethane/MeOH. The desired product (0.089 g, 82%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(OCC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(OCC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-4-phenyl-2-(2,2,2-trifluoro-ethoxy)-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Off white solid (19.2 mg, 17%). LC-MS: 382 (M+H)+.