Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37](N(CC)CC)[CH3:38].C(Cl)(=O)C.O=P(Cl)(Cl)Cl>C1COCC1.C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37]([CH3:38])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) and triethylamine (0.038 mL) in THF (0.65 mL) at rt was added acetyl chloride (8.5 mg, 0.108 mmol), and the reaction was stirred at rt overnight. The volatiles were removed and the residue was chromatographed on a SiO2 column to provide acetyl product, which was mixed with POCl3 (60 mg, 0.4 mmol) and acetonitrile (0.14 mL), and was stirred at 80° C. for 3 h. The volatiles were removed, and the residue was purified by SiO2 column chromatography to provide the title compound. LC/MS: m/e 544.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.21 (1H, d, J=1.9 Hz), 8.02 (1H, dd, J=8.5, 2.1 Hz), 7.63 (1H, d, J=7.5 Hz), 7.15 (1H, d, J=7.6 Hz), 7.13 (1H, d, J=8.7 Hz), 7.04 (1H, br s), 6.96 (2H, J=8.5 Hz), 6.90 (1H, d, J=8.6 Hz), 4.65-4.95 (2H, br), 2.67 (3H, s), 1.26 (9H, s).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
1-(6-Mesitylpyridin-2-yl)pentan-2-ol (2.91 g, 10.3 mmol) in 100 mL of dichloromethane and 20 mL of acetonitrile was combined with 4 angstrom crushed molecular sieves (2.5 g) and N-methylmorpholine-N-oxide (1.80 g, 15.4 mmol). Tetrapropylammonium perruthenate (0.54 g, 1.54 mmol) was added last. The reaction stirred at room temperature for 1 h. The reaction was filtered and concentrated. Flash chromatography (10% ethyl acetate/hexanes) gave 0.87 g (30%) of the title compound as an yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH2:21])=O)[CH2:14]2)=[CH:9][CH:8]=1.S(Cl)(Cl)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]#[N:21])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N#C[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (0.400 g, 0.001 mol) and thionyl chloride (2.3 ml, 0.032 mol) was refluxed under argon for 3 hours. The mixture was cooled to room temperature, diluted with 5 ml tetrahydrofuran, concentrated under vacuum and purified by column chromatography on silica gel using a 2:3-mixture of ethyl acetate and hexane as the eluent. The product fractions were concentrated to dryness to yield (0.106 g, 28% of theory) of a light brown oil. MS (m/e)=311.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(OC)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.7 %

Procedure:
Under a static N2 atm, a stirred solution of the compound of Example 2 (8.14 g, 32 mol) in 100 ml of methanol was treated dropwise with 7.6 g of 25% sodium methoxide in methanol. After stirring at ambient temperature for 24 hr, the mixture was added to H2O and extracted twice with ether. The ether layer was washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a white solid which was recrystallized from methylcyclohexane to yield 5.5 g of methyl 2-methoxy-5-phenyl-4-thiazolecarboxylate as a white solid, m.p. 86°-88° C., yield 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=O.[O:12]1[CH:16]=[CH:15][CH2:14][C:13]1=[O:17]>>[CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1/[CH:8]=[CH:9]/[CH:14]1[CH2:15][CH2:16][O:12][C:13]1=[O:17]
Reactant: O=C1CC=CO1
Reactant: CC1=CCC(CC=O)C1(C)C
Product: CC1=CCC(/C=C/C2CCOC2=O)C1(C)C
Yield: 42 %

Procedure:
The process of Example 1 was carried out except that the aldehyde was 2-(2,2,3-trimethylcyclopent-3-en-yl) ethaldehyde and the furanone did not contain a 5-methyl group to obtain (E)-3-[2-(2,2,3-trimethylcyclopent-3-en-yl)ethenyl]dihydro-2 (3H)-furanone. 1HNMR (CDCl3) [Redistilled E isomer] δ6.80 (m, 1H), 5.24 (close spaced m, 1H), 4.40 (t, 2H), 2.93 (m, 2H), 2.45-1.77 (m, 6H), 1.62 (close spaced m, 3H), 1.04 (s, 3H), 0.85 (s, 3H). BP 1.38°-156 ° C. at 0.20 mm Hg Yield 42-57%
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][CH:6]=1)(=O)C.C([O-])(O)=O.[Na+]>CO.Cl.CCOC(C)=O>[NH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][CH:6]=1
Reactant: CCCCC12CCC(=O)C=C1c1ccc(NC(C)=O)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC12CCC(=O)C=C1c1ccc(N)cc1C2
Temperature: 80 °C

Procedure:
The crude product from step 3 (7.0 g) was dissolved in MeOH (100 mL) and the solution was diluted with 6N HCl (100 mL). The resulting brown solution was stirred and heated in an oil bath at 80° C. for one hour. After cooling, the mixture was diluted with EtOAc (300 mL), stirred, and neutralized by the careful addition of aqueous 5% NaHCO3 and solid NaHCO3. The layers were separated and the aqueous portion was extracted with EtOAc (100 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange-red solid. The crude product was purified by Biotage flash chromatography on a 75 L silica gel column (7.5×35 cm), eluting with 2:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to an orange solid (4.2 g) which was shown by 1H NMR to contain 7-amino-9a-butyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one along with approximately 10% of the 9a-butyl-4-methyl-8,9,9a,10-tetrahydro-7H-indenol[1,2-g]quinolin-7-one by-product. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2ON=[C:29]([CH3:32])[N:28]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Cl.C(C1[C:38](N[C@H]2CCC[C@@H]2N)=[N:39]C=C(C(F)(F)F)N=1)C.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:39]=[CH:38][CH:32]=[CH:29][N:28]=2)=[N:5][CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide (Example 149) from (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg 1.64 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 328 mg, 1.64 mmol) to afford the title compound.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 93.9 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (5.06 g) and octanoyl chloride (6.67 g), the desired compound (9.39 g) was obtained.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[C:20]=1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:15])[CH2:12]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2M aqueous sodium hydroxide solution (51.7 mL, 103.32 mmol) was added to methyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate (Intermediate #56) (4.5 g, 10.33 mmol) in methanol (100 mL). The mixture was stirred at 70° C. for 1 hour and then cooled to ambient temperature, concentrated under reduced pressure and diluted with water (100 mL). The reaction mixture was adjusted to pH 3 with 2M HCl. The reaction mixture was extracted with EtOAc (500 mL) and washed to sequentially with water (2×100 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a pale yellow solid. The solid was washed with EtOAc (20 mL), collected by filtration and dried under vacuum to give 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (3.89 g, 89%) as a cream crystalline solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(CCCOCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(CCCOCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-(benzyloxy)propyl]benzaldehyde (1.86 g, 7.31 mmol) in ethanol (28 mL), sodium borohydride (83 mg, 2.19 mmol) was slowly added at room temperature. The mixture was stirred for 1 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][C:13]([CH3:18])=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([F:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Reactant: BrCc1cccc(Br)n1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(C)nc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 110 mg (0.352 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 106.1 mg (0.423 mmol) of 2-bromo-6-bromomethyl-pyridine, 16.9 mg (0.423 mmol, 60% dispersion in oil), and 2 mL of N,N dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3-fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C23H17BrFN3O3 [M+H]: 482.04 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.6 min.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[C:60]([O:86][CH3:87])=[CH:61][C:62]3[C:68](=[O:69])[N:67]4[CH:70]=[C:71](/[CH:73]=[CH:74]/[CH3:75])[CH2:72][C@H:66]4[C:65](=[O:76])[N:64]([CH2:77][O:78][CH2:79][CH2:80][Si:81]([CH3:84])([CH3:83])[CH3:82])[C:63]=3[CH:85]=2)=[CH:52][C:12]2[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:14](=[O:43])[C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C>[NH2:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[C:14](=[O:43])[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:12]3[CH:52]=[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]4[C:60]([O:86][CH3:87])=[CH:61][C:62]5[C:68](=[O:69])[N:67]6[CH:70]=[C:71](/[CH:73]=[CH:74]/[CH3:75])[CH2:72][C@H:66]6[C:65](=[O:76])[N:64]([CH2:77][O:78][CH2:79][CH2:80][Si:81]([CH3:84])([CH3:83])[CH3:82])[C:63]=5[CH:85]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)OCC6c7ccccc7-c7ccccc76)C[C@H]4C(=O)N5COCC[Si](C)(C)C)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CN)C[C@H]4C(=O)N5COCC[Si](C)(C)C)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Piperidine (0.40 mL, 4.0 mmol, 12 eq.) was added to a stirred solution of Fmoc amine 14c (0.380 g, 0.334 mmol, 1.0 eq.) in DMF (5.0 mL). After stirring at room temperature for 20 minutes, LCMS analysis indicated consumption of starting material and the reaction mixture was diluted with DCM (300 mL) and washed with water (3×300 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness under reduced pressure to afford the crude product which did not undergo further purification (0.306 g, assumed 100% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]2=[O:25])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24][C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]([OH:31])=[O:30])[CH2:20][C:19]2=[O:25])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1ccc(N2CC(CO)CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CC(COC(=O)c3ccccc3C(=O)O)CC2=O)cc1
Yield: 100.1 %

Procedure:
A 8.3 ml (60 mmol) quantity of triethylamine was added to a solution of 12.35 g (50 mmol) of [1-(4-t-butylphenyl)-2-pyrrolidone-4-yl)methyl alcohol (III) and 7.4 g (50 mmol) of phthalic anhydride in dichloromethane (150 ml), and the mixture was refluxed with heating for 24 hours. The reaction mixture was washed with a dilute hydrochloric acid, dried over magnesium sulfate and concentrated under reduced pressure to give 19.8 g (quantitative yield) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of piperazine (10.8 g) in dry dichloromethane (160 ml) and triethylamine (20 ml) at 0° C. was added slowly a solution of 4-bromobenzenesulphonyl chloride (16 g) in dichloromethane (80 ml) and stirred for 24 hours. The reaction was then quenched by removal of the dichloromethane solvent by evaporation, taken up in water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and then evaporated to give a white crystalline solid which was recrystallised from ethyl acetate/isohexane to afford 1-(4-bromophenylsulphonyl)piperazine (14.1 g) as a solid, m.p. 102-104° C.; microanalysis found: C, 39.5; H, 4.4; N, 9.1%: C10H13BrN2O2S requires: C, 39.4; H, 4.3; N, 9.2%; NMR (CDCl3): 1.52(s,1H), 2.97(dt,8H), 7.61(d,2H), 7.69(d,2H): MS m/z 305 (MH)+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(CO)cc1)n1ccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCC(c1ccc(C=O)cc1)n1ccnc1
Yield: 80.7 %

Procedure:
0.1 g of the substituted benzyl alcohol of example 5 is dissolved in 10 ml of methylene chloride, mixed with 0.15 g of manganese dioxide and refluxed for 6 hours. After cooling, the reaction mixture is filtered on silica gel and concentrated by evaporation in a vacuum. The residue is distilled on a bulb tube, boiling point 200° C./0.03 mbar. 0.08 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde is obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.O.[NH2:24][NH2:25]>CO>[CH3:10][C:8]1[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=[C:4]([C:3]([NH:24][NH2:25])=[O:2])[CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc(C)cc(Oc2cccc(C(F)(F)F)c2)n1
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methyl-6-[3-(trifluoromethyl)phenoxy] picolinic acid methyl ester (0.507 g, 0.00163 mol) was dissolved in 10 ml of methanol, and then mixed with hydrazine monohydrate (0.816 g, 0.00163×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated, and the obtained residues were distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.O>CN(C)C=O>[CH3:37][O:36][C:33]1[N:34]=[CH:35][C:30]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:31][N:32]=1
Reactant: COc1ncc(CCl)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.28 g, 1.0 mmol) in dry N,N-dimethylformamide (6 mL) was added cesium carbonate (2.30 g, 7.1 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 30 min, and 5-(chloromethyl)-2-methoxypyrimidine (0.34 g, 2.1 mmol) in dry N,N-dimethylformamide (3 mL) was added dropwise. The mixture was stirred at ambient temperature for 16 h, and additional cesium carbonate (0.68 g, 2.1 mmol) and 5-(chloromethyl)-2-methoxypyrimidine (0.20 g, 1.3 mmol) were added. The mixture was stirred at ambient temperature for 64 h. Water (60 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:1) to afford 1′-[(2-methoxypyrimidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 73%) as a colorless solid: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ8.57 (s, 2H), 7.30-7.23 (m, 1H), 7.22-7.17 (m, 1H), 7.11-7.04 (m, 1H), 6.86-6.81 (m, 1H), 6.44-6.41 (m, 2H), 4.89 (ABq, 2H), 4.81 (ABq, 2H), 4.59-4.50 (m, 2H), 4.01 (s, 3H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 165.4, 161.9, 161.3, 158.8, 141.1, 132.7, 128.8, 124.3, 123.9, 122.8, 120.1, 119.7, 118.7, 108.5, 93.3, 80.5, 72.4, 57.6, 55.1, 38.8, 29.0; MS (ES+) m/z 402.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=2[CH:24]=1.B([O-])([O-])O[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=3)=[CH:24][C:6]=2[CH:7]=[C:8]([C:21]([OH:23])=[O:22])[CH2:9][CH2:10]1
Reactant: COc1cccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)c1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OC)c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
In toluene (20 ml), ethanol (2 ml) and water (2 ml) were suspended 7-bromo-1-(3-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (300 mg), 4-propoxyethoxyphenyl borate (346 mg) and potassium carbonate (534 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (62 mg), and the mixture was heated at 100° C. for 6 hours under argon atmosphere. After allowing to cool, water was added to the mixture, which was made acidic (pH=4) with 1N hydrochloric acid and extracted with ethyl acetate twice. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) and the resulting solid was recrystallized from hexane-ethyl acetate to give 1-(3-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (118 mg) as yellow crystals.