Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 96% yield: MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 2-amino-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 6 & 7, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 74% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11](O)=[O:12])=[N:6][CH:7]=1.Cl.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@H:37]([NH2:39])[CH3:38])=[N+:34]([O-:36])[CH:35]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@H:37]([NH:39][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:38])=[N+:34]([O-:36])[CH:35]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Reactant: C[C@@H](N)c1ccc(F)c[n+]1[O-]
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)c[n+]3[O-])cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid (50.0 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) were added (1R)-1-(5-fluoro-1-oxidopyridin-2-yl)ethanamine hydrochloride salt (33.4 mg, 0.17 mmol), EDC (33.3 mg, 0.17 mmol), HOAT (7.9 mg, 0.06 mmol) and triethylamine (0.11 mL, 0.81 mmol). The reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was heated to 50° C. After 20 min, the mixture was cooled to ambient temperature and the solid in the reaction was filtered off. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→65% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (46 mg). HRMS 498.1954 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J=4.8 Hz, 1H); 8.48 (s, 1H); 8.46-8.35 (m, 3H); 8.15-8.08 (m, 2H); 7.73-7.65 (m, 2H); 7.54 (t, J=8.9 Hz, 2H); 7.34 (t, J=7.8 Hz, 1H); 7.20 (dd, J=7.7, 4.8 Hz, 1H); 7.06 (ddd, J=8.8, 6.6, 2.4 Hz, 1H); 5.86 (dd, J=10.9, 6.9 Hz, 1H); 5.58-5.48 (m, 1H); 3.92-3.74 (m, 2H); 2.35 (s, 3H); 1.70 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:26]([OH:29])(=[S:28])[CH3:27].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:28][C:26](=[O:29])[CH3:27])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(C#N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cnc(C#N)c1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(4-cyanoimidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (13.4 g) was reacted with thioacetic acid (5.46 ml) and potassium t-butoxide (8.17 g) in substantially the same manner as Preparation 4-12) to give (2R,4S)-1-allyloxycarbonyl-4-acetylthio-2-[2-(4-cyanoimidazol-1-yl)ethyl]pyrrolidine (12.5 g) as a yellow paste.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CS(C)=O.[C]=O.[C:59]([O:62][CH2:63][CH3:64])(=[O:61])C>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C(N(CC)CC)C.ClCCCl>[CH2:63]([O:62][C:59]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH2:5][N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:13][C:12]2([CH3:15])[CH3:14])=[O:61])[CH3:64]
Reactant: CC1(C)CN(C2CC2)Cc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CN(C1CC1)C2

Procedure:
Following general procedure K and using 2-cyclopropyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline (Intermediate 22, 1.6 g, 4.6 mmol), palladium acetate (0.127 g, 0.56 mmol), 1,3-bis(diphenylphosphino)propane (0.160 g, 0.39 mmol), dimethylsulfoxide (2 mL), 1,2-dichloroethane (5 mL), triethyl amine (2 mL) , ethanol (5 mL) and an atmosphere of carbon monoxide followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent the title compound was obtained as an oil (1 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16](Cl)=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[Li][C:26]#[N:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16]([C:26]#[N:27])=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Reactant: [Li]C#N
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Temperature: 120 °C
Yield: 45.1 %

Procedure:
The product of Example 2, 1-(4-chloro-2-fluoro5-propargyloxyphenyl)-5-chloro-4-cyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (V) (0.25 g, 0.68 mmol), was stirred in 10 mL dimethylformamide (DMF). To this mixture was added LiCN (2 mL of 0.5M in DMF, 1 mmol) and the resulting mixture was heated to 120° C. for 15 minutes. The mixture was cooled poured onto water, extracted with ethyl acetate, dried, concentrated and eluted through silica gel (50:50 ethyl acetate:hexane) to give 0.11 g of 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4,5-dicyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (VI) (m.p. 76° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:20]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CF)[C@H]2CS1
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (19.40 g, 0.048 mol, 1.0 equiv.) was dissolved in methanol (97 mL), under nitrogen. 1,8-diazabicyclo[5.4.0]undec-7-ene (8.92 mL, 0.060 mol, 1.25 equiv.) was added, and the solution was heated to 55-60° C. After 8 h, the reaction mixture was concentrated under reduced pressure, and the residue purified by silica gel flash column chromatography (5% to 100% EtOAc in heptane) to afford the title compound (9.01 g). 1H NMR (500 MHz, DMSO) δ ppm 7.38-7.28 (m, 1H), 7.26-7.14 (m, 2H), 6.12 (s, 2H), 4.66-4.41 (m, 2H), 4.37-4.27 (m, 2H), 4.29 (d, J=8.2 Hz, 1H), 3.74 (dd, J=8.2, 2.6 Hz, 1H), 3.30 (s, 1H), 3.06-2.90 (m, 2H), 2.79-2.71 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 150.84 (dd, J=244.8, 14.0 Hz), 149.71, 148.07 (dd, JCF=247.8, 13.4 Hz), 133.08 (d, JCF=7.7 Hz), 125.24, 124.55 (dd, JCF=7.2, 4.3 Hz), 116.58 (d, JCF=17.2 Hz), 83.91 (d, JCF=170.0 Hz), 79.12 (d, JCF 18.2 Hz), 77.96 (d, JCF=4.9 Hz), 66.22, 36.41 (d, JCF=3.3 Hz), 23.40.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>>[C:2]1([C:16]2[C:17]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Solvent: CCN(CC)CC
Product: c1ccc(-c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of bromobenzene (1 mmol), of 1-naphthylboronic acid (1.2 mmol), of PdBr2 (2.5 mol %), and of triethylamine (2 mmol) in N,N′-butylmethylimidazolium methyl H-phosphonate of (1 g) is brought to 100° C. under stirring for 24 hrs. Extraction with hexane (3×5 mL) gives a white and sublimable solid (Mp 112-113° C.), (m=0.2 g; yield=98%).
Reaction SMILES: Cl[N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=O.N>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:4]1[C:12](=[C:11]3[C:6]([N:5]=1)=[CH:7][CH:8]=[CH:9][CH2:10]3)[CH:3]=[N:2]2
Reactant: ClN(c1ccccc1)c1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: C1=CCC2=c3cnc4ccccc4c3=NC2=C1
Temperature: 80 °C
Yield: 37.9 %

Procedure:
A mixture of 4-(chlorophenylquinolin-3-yl-amine (400 mg), CF3COOH (8 ml), Pd(OAc)2 (300 mg) was refluxed for 6 hr at 80° C. The reaction mixture was allowed to cool to room temperature, poured in ice cold water (15 ml), neutralized with aqueous ammonia and extracted with EtOAc (3×50 mL), washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to yield the pure solid product (130 mg). Mp: 146-148° C. 1H-NMR: (DMSO-d6): δ 9.52 (s, 1H), 8.96 (d, 1H, J=8.1 Hz), 8.86 (d, 1H, J=1.5 Hz), 8.24 (d, 1H, J=8.1 Hz), 7.88-7.78 (m, 3H), 7.70-7.66 (dd, 1H, J=6.6, 2.1 Hz).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@@:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)([OH:8])[CH2:3]1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]#[C:9][C@@:4]2([OH:8])[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:23]([C:20]3[CH:21]=[CH:22][O:18][CH:19]=3)=[O:24])[CH2:3]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccoc1
Reactant: N[C@@H]1CCC[C@](O)(C#Cc2cccc(Cl)c2)C1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCC[C@](O)(C#Cc2cccc(Cl)c2)C1)c1ccoc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
(+)-(1R,3R)-3-Amino-1-(3-chloro-phenylethynyl)-cyclohexanol (115 mg, 0.46 mmol) was dissolved in DMF (5 ml) and treated with furan-3-carboxylic acid ((63 mg, 0.55 mmol) and EDC (108 mg, 0.55 mmol). After stirring for 1.5 h at room temperature, Et3N (0.55 mmol) was added and stirring continued for 18 h. A second batch of EDC (108 mg, 0.55 mmol) was added and stirring continued for 6 h. EtOAc was added and the mixture washed with aqueous sodium bicarbonate and brine. Drying of the organic phase with Na2SO4, filtration and evaporation afforded a crude product (263 mg) which was purified by chromatography on silica gel to afford the title compound as a white solid (105 mg, 66%). MS (LC/MS): 344.2 [M+H]; [α]D=+95.6° (c=0.5, MeOH).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17].[OH-].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:12][OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(-c2ccco2)[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
2.75 g of 2-furan-2-yl-6-methylpyridine 1-oxide (15.7 mmol) are dissolved in 27 ml of tetrahydrofuran. 6.65 ml of trifluoroacetic anhydride (47.1 mmol) are added to the solution cooled to 0° C. under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then 25 ml of a 4N aqueous solution of sodium hydroxide are added. The tetrahydrofuran is evaporated off, the residue is taken up in a saturated aqueous solution of sodium chloride and then the mixture is extracted with chloroform. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/ethyl acetate; 90:10). 2.03 g of a yellow oil are recovered.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1.CO.[OH-].[K+].Cl>O1CCCC1>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution the crude 4-benzyloxy-3-nitro-benzoic acid methyl ester from the previous step in tetrahydrofurane (150 mL) and MeOH (600 mL) was treated with KOH 3N (152 mL) and stirred at room temperature for 18 hours. The mixture was acidified with HCl 3N. The precipitate thus formed was filtered, washing with MeOH/water 1:1 and dried under vacuum. 4-Benzyloxy-3-nitro-benzoic acid (42 g, 95% over two steps) was obtained as a white solid, which was used crude in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl>O1CCCC1>[CH:9]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:21][O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:10]
Reactant: COCCl
Reactant: COc1cc(C=O)ccc1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C=O)cc1OC
Yield: 96 %

Procedure:
A mixed solution of 15.2 g of 2-methoxy-4-formylphenol, 26 ml of diisopropyl ethylamine, 9 ml of methoxymethyl chloride and 100 ml of tetrahydrofuran (THF) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 18.9 g of (4-formyl-2-methoxyphenoxy)methoxymethane (yield: 96%, melting point: 34°-37° C.).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([N:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:7])=[C:4]([CH:17]=[O:18])[CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C.C(OCC)(=O)C>CN(C=O)C.O>[CH3:19][O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][N:6]([CH3:7])[C:5]1[CH:15]=[CH:16][C:2]([Br:1])=[CH:3][C:4]=1[CH:17]=[O:18]
Reactant: CN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(C)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid (3.0 g) in DMF(8 ml), potassium carbonate (1.6 g) and a solution of methyl iodide/DMF (1.6 g/2 ml) were added at room temperature, and the resulting mixture was stirred for 2 hours. Ethyl acetate and water were added to the mixture, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to give yellow oil of 5-(4-bromo-2-formyl -N-methylanilino)pentanoic acid methylester (3.0 g, yield 97%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:14](=[O:24])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37](C(O)=O)=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:6]([N:8]4[CH2:11][CH:10]([N:12]5[CH2:17][CH2:16][N:15]([C:18]6[N:19]=[CH:20][CH:21]=[CH:22][N:23]=6)[C:14](=[O:24])[CH2:13]5)[CH2:9]4)=[O:5])=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Reactant: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Product: O=C(c1ccc2c(ccn2-c2ccc(F)cc2)c1)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1

Procedure:
Cpd 4 was prepared according to the procedures described in Example 2, Step D, using intermediates 3c and 1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid 3h as starting materials. MS 471 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([OH:15])[CH:7]=1.[CH2:17](I)[CH3:18].[Cl-].[NH4+]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:17][CH3:18])[CH:7]=1
Reactant: CCI
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a suspension of sodium hydride (60% mineral oil: 1.20 g) in dimethylformamide (50 mL) was added 3-hydroxy-4-nitrobenzoic acid methyl ester (4.93 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After addition of ethyl iodide (4.4 g), the solution was stirred at 60° C. overnight, cooled down to room temperature, poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine, dried over sodium sulfate and concentrated to give a solid, which was washed with ethyl acetate-hexane to afford 3-ethoxy-4-nitrobenzoic acid methyl ester (3.30 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:7]=1.Br[CH:22]([CH3:35])[C:23]([O:25][CH:26]1[CH:30]([O:31][C:32](=[O:34])[CH3:33])[CH2:29][O:28][CH2:27]1)=[O:24].C(=O)([O-])O.[Na+].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[C:32]([O:31][CH:30]1[CH2:29][O:28][CH2:27][CH:26]1[O:25][C:23]([CH:22]([NH:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:7]=1)[CH3:35])=[O:24])(=[O:34])[CH3:33]
Reactant: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: CC(=O)OC1COCC1OC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A mixture of 8.84 g of N-(5-amino-4-chloro-2-fluorophenyl)-3,4,5,6-tetrahydrophthalimide, 12.6 g of 4-acetoxytetrahydrofuran-3-yl 2-bromopropionate, 3.02 g of sodium hydrogencarbonate and 3 ml of xylene was heated under stirring at 150° to 160 ° C. for 4 hours. Adding ethyl acetate to the reaction mixture while it remained warm, the resulting mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (development solvent: ethyl acetate/hexane=1/2), to obtain 4.88 g of a compound described in Table 1 (No. 10) (33%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].CCOCC.[OH-].[Na+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: N#Cc1cccc(CCCO)c1
Yield: 96.9 %

Procedure:
Into an oven-dried 500 ml flask with 2-neck adapter and stirring bar, 12.9 g of 3-(3-cyanophenyl)propanoic acid (the product of step (a)) was placed. The system was flushed with argon gas; then 84 ml tetrahydrofuran was added. The resulting mixture was stirred until the acid was dissolved. After cooling for about ten minutes with an ice bath, 88 ml borane-tetrahydrofuran was added in two 44 ml portions over a 20 minute period. The reaction mixture was stirred for 20 minutes in an ice bath and then quenched by the addition of about 17 ml water dropwise. The mixture was stripped to give an oil with white crystals. Ether (200 ml) and a solution of 8.8 g (0.22 mole) sodium hydroxide in 150 ml water were added. The organic phase was separated. The aqueous layer was extracted with an additional 35 ml ether. The combined ether extracts were dried over sodium sulfate, filtered, and stripped. The resulting oil was distilled in a Kugelrohr apparatus, the fraction bpt. 95°-110° C. was collected to give 11.5 g of the above-identified product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1.[H-].[Na+]>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccn2)ccc1[N+](=O)[O-]
Yield: 13.1 %

Procedure:
By using 0.76 g of 2-hydroxypyridine, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 0.36 g of the title compound were obtained.