Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: CNCCOC
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: COCCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (2-methoxy-ethyl)-methyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (t, 2H, J=7 Hz); 3.22 (s, 3H); 3.28 (s, 3H); 3.58 (m, 4H); 3.85 (m, 2H); 7.21 (m, 2H); 7.50 (m,2H); 7.93 (d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]OS(C)(=O)=O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K].O>CN(C=O)C>[F:1][CH2:2][CH2:3][CH2:4][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCCF
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCF
Temperature: 75 °C
Yield: 99.1 %

Procedure:
A solution of methanesulfonic acid 3-fluoro-propyl ester (34.5 g, 221 mmol) in 250 mL of anhydrous DMF was treated with solid potassium phthalimide (49 g, 265 mmol, 1.2 equiv) at 25° C. The resulting suspension was warmed to 70-80° C. for 2 hours. When 1H NMR showed that the reaction was complete, the reaction mixture was treated with H2O (200 mL). The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired 2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 45.5 g theoretical, 99.7% yield) as a white powder.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](\[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C.O>C1COCC1>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[C:22](/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21]\[CH2:20][OH:19])=[CH:34][CH:33]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OC/C=C(/c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 1.2 M solution of DIBAL-H in toluene (84 ml, 100 mmol) was added dropwise, at −15° C. over 20 min, to a stirred solution of (Z)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester (11.1 g, 33.5 mmol) in dry THF (150 ml), and the mixture stirred for 30 min. Rochelles salt and water was carefully added, and the resulting mixture extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give 9.3 g of (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2c(F)cccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution (14 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetate was added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→8:2) to give the title compound as yellow crystals (yield 10.0 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH:6]=1.[BH4-].[Na+]>>[OH:7][CH:5]1[C:4]([CH3:9])([CH3:8])[C:3](=[O:10])[C:2]([CH3:1])=[CH:6]1
Reactant: CC1=CC(=O)C(C)(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC1=CC(O)C(C)(C)C1=O

Procedure:
The known 2,5,5-trimethyl-cyclopent-2-en-1,4-dione of formula IV is dissolved in an organic solvent (e.g. an alkanol) and reduced at a temperature below 0° C. with sodium borohydride. The desired 4-hydroxy-2,5,5-trimethyl-cyclopent-2-en-1-one of formula V is isolated by rectification from the isomeric mixture which occurs during the working-up.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH2:6][O:7][CH3:8].Cl.O.C1C[O:23][CH2:22]C1>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:22]1=[O:23])[CH2:6][O:7][CH3:8]
Reactant: COCC(CC(=O)OC)Nc1ccccc1N
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COCC(CC(=O)OC)n1c(=O)[nH]c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of 3-(2-Amino-phenylamino)-4-methoxy-butyric acid methyl ester (320 mg, 1.3 mmol) in THF (5.0 mL) is added CDT (440 mg, 2.7 mmol) at room temperature. The mixture is stirred at the same temperature for 16 hours. Then 5 mL of 1.0 M HCl solution is added along with 20 mL of water. The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 205 mg (58%) of 4-Methoxy-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester.
Reaction SMILES: C1(COC([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:30])[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:31])[CH:10]2[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CO>[SH:8][CH:9]1[N:12]([C:13](=[C:27]([OH:30])[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C:11](=[O:31])[CH:10]1[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCC1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 80.7 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (218 mg) in methanol free methylene chloride (2.1 ml) is added aluminum chloride (220 mg) under ice cooling, and the mixture is stirred under argon atmosphere. After 35 minutes, the reaction mixture is poured into ice water containing 4 N-hydrochloric acid (4 ml), stirred for 10 minutes, and is extracted with chloroform. The extract solution is washed with water, dried and evaporated to give p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (150 mg). Yellow foam. Yield: 94.6%. IR: νmaxCHCl3 3400, 1780, 1692, 1610, 1603 cm-1. NMR: δCDCl3 2.25d(10 Hz)1H, 4.25d(2 Hz)2H, 4.58s2H, 5.20-5.37m4H, 6.84-8.24m9H, 12.1s1H.
Reaction SMILES: [OH:1][C:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[C:3]=1[C:20](=[S:23])[NH:21][CH3:22].O1CCCC1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[CH:3]1[C:20](=[S:23])[NH:21][CH3:22]
Reactant: CNC(=S)C1=C(O)C2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC2(CCOCC2)C1O
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a mixture of 3.7 g of 3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide, 100 ml of tetrahydrofuran and 100 ml of methanol was added 2.8 g of sodium borohydride (NaBH4) with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 24 hours. The reaction solution was vacuum-distilled, water was added therein and the resultant mixture was extracted with methylene chloride. An organic layer was washed with water and dried. The solvent was distilled to obtain 1.7 g of 3,4-dihydro-3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide. Subsequently, to 1.5 g of it were added 2.1 g of p-toluenesulfonyl chloride and 60 ml of pyridine. After the mixture was refluxed with heating for 1 hour, the solvent was distilled. Ice water was added to the residue and the reaction solution was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 1.2 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide with a melting point of 183°-184° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([NH2:19])=O)[CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]#[N:19])[CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCc1cccc(C(N)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cccc(C#N)n1
Yield: 99.6 %

Procedure:
Phosphorus oxychloride (86.9 ml) was dropwise added to a mixture of 6-acetoxymethyl-2-pyridinecarboxamide (93.0 g) and N,N-dimethylformamide (74.2 ml) in ethyl acetate (930 ml) under ice-cooling with stirring and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was added to a water and adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 6-acetoxymethyl-2-cyanopyridine (84.0 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][C:12]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:13])=[O:7])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-[(1,2-diphenylethyl)amino]butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1,2-diphenylethylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(COc2nc(N)nc(-c3ccc(Br)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-(5-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 98).
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1.O>C(Cl)Cl>[F:27][C:21]([F:26])([C:22]([F:23])([F:24])[F:25])[CH2:20][CH2:19][CH2:18][S:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12]
Reactant: FC(F)(F)C(F)(F)CCCSCCCCOCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: OCCCCSCCCC(F)(F)C(F)(F)F
Temperature: -78 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
BBr3 (1M in DCM, 2.9 mL, 2.9 mmol) was added dropwise to a solution of (4-(benzyloxy)butyl)(4,4,5,5,5-pentafluoropentyl)sulfane (340 mg, 0.95 mmol) in DCM (5 mL) cooled to −78° C. The temperature was allowed to warm up to room temperature and the mixture was stirred for 18 h. Water was slowly added and the reaction mixture was stirred for 10 min. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 50 to 100% EtOAc/hexanes to afford 171 mg of 4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol as a colorless oil.
Reaction SMILES: O.[OH-].[Li+].O.[C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[CH3:12])=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:7][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH3:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccc3)cc2)cc1)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=NOCCOc1ccc(CC(Nc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of 72 mg of lithium hydroxide monohydrate and 3 ml of water was added to a solution of 282 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(phenylamino)propionate obtained in Example 9 in 3 ml of dioxane. The mixture was stirred at 60° C. for one hour. After the reaction, the reaction mixture was concentrated and diluted with water. Then, 1.71 ml of 1N hydrochloric acid was added to the resulting mixture, and the product thus obtained was extracted with a large amount of hot ethyl acetate. The extract was concentrated to about 5 ml, and 229 mg of the desired compound was obtained by filtration.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.29 min; [M+H]+=496.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Br:24][C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[Cl:33].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][C:26]=1[Cl:33])[CH2:31][C:14]([CH3:13])([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CCC(C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)(Cc1ccc(Cl)c(Br)c1)C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 5.8 ml (41.6 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 16.6 ml (41.6 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 5.06 g (32.0 mmol) of tert-butyl 2-methylbutanoate in 20 ml of THF was added, the reaction temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 10.0 g (35.2 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, and the temperature was once more kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 7.62 g (65.9% of theory) of the title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.C(N(CC1C=CC=C(CN(C(C)C)C(C)C)C=1B(O)O)C(C)C)(C)C.B(O)O>CCCCCCC>[C:4]1(=[O:6])[O:12][C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: CC(C)N(Cc1cccc(CN(C(C)C)C(C)C)c1B(O)O)C(C)C
Agent: OBO
Solvent: CCCCCCC
Product: O=C1OC(=O)c2ccccc21
Temperature: 25 °C
Yield: 72 %

Procedure:
Phthalic acid (2.5 mmol), 2,6-bis(diisopropylaminomethyl)phenylboronic acid (hereinafter, referred to as “boronic acid compound A”, 0.25 mol) as an arylboronic acid catalyst, and heptane (10 mL) as a solvent were added in a flask having a volume of 20 mL, and a column (small Soxhlet extractor) filled with dried molecular sieves 3A (approximately 3 g) was fitted to the flask. The mixture was heated for 12 hours under azeotropic reflux conditions with the removal of water. After the reaction mixture was cooled to room temperature, heptane was evaporated under reduced pressure. The crude product of phthalic anhydride thus obtained was analyzed by 1H NMR (CDCl3), and the yield thereof was calculated. When the same procedure was repeatedly performed a plurality of times, the yield was 72% to 81%.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[F:16][C:17]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)([F:19])[F:18]>>[C:22]1([C:20]2([C:17]([F:16])([F:18])[F:19])[C:5]3[CH:6]=[C:1]([CH3:15])[CH:2]=[CH:3][C:4]=3[O:7][C:8]3[C:13]2=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Product: Cc1ccc2c(c1)C(c1ccccc1)(C(F)(F)F)c1cc(C)ccc1O2

Procedure:
The parent monomer (II, Rf =CF3) was prepared (Scheme VI) using the single-bridging process by reaction of p-tolyl ether (X) and trifluoromethylphenyl ketone in HF at 130° C to provide 9-phenyl-9-trifluoromethyl-2,7-dimethylxanthene (XIX), followed by oxidation to the dicarboxylic acid (XX) and catalytic decarboxylation to (II). The diacid (XX) could also be converted to the diacyl chloride (XXI), then to the diacyl azide and, finally, to the diisocyanate (XXII) as previously described.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[CH:53]=[N:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:54]4[CH:53]=[N:52][N:51]([CH3:50])[CH:55]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a colorless solid in 44% yield: mp 173-175° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (t, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.38-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.42 (s, 2H), 4.18 (d, J=6.0 Hz, 2H), 3.99 (t, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.45 (t, J=9.0 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:28][CH3:29])[C:14]([NH:16][CH:17]2[CH2:20][N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]2=[O:27])=[O:15])[C@H:6]1[OH:30].Cl>C1COCC1>[O:27]=[C:18]1[CH:17]([NH:16][C:14](=[O:15])[C@H:13]([O:28][CH3:29])[C@H:7]([OH:8])[C@@H:6]([OH:30])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:32])([CH3:31])[CH3:1])[CH2:20][N:19]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CO[C@@H](C(=O)NC1CN(c2ccccc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CN(c2ccccc2)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Reaction time: 0.83 h

Procedure:
0.466 ml of THF, 38.7 mg (86.66 μmol) of product 10 and then 0.932 ml of HCl (1N) are successively introduced into a round-bottomed flask equipped with a magnetic stirrer. After 50 minutes, the reaction medium is evaporated to dryness. The residue obtained is purified by chromatography on 2 preparative silica plates (20×20 cm, e=0.5 mm, Merck), eluent: CH2Cl2/MeOH (96/4). 14 mg (40%) of product Example 3 are collected.