Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:33]=[CH:32][C:17]3[N:18]([CH3:31])[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=4)=[N:20][C:16]=3[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].C(#N)C.[C:43]1([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[C:43]1([CH2:49][S:50]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:33]=[CH:32][C:17]4[N:18]([CH3:31])[C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=5)=[N:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:6])(=[O:52])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(C(=O)NCCN)c4)ccc3n2C)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(C(=O)NCCNS(=O)(=O)Cc5ccccc5)c4)ccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture containing 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzo-imidazol-5-yloxy]-pyridine-2-carboxylic acid (2-amino-ethyl)-amide (1 eq) (prepared using previously described example 3), K2CO3 (5 eq), (0.2 M in a 5:1 mixture of acetonitrile and water) were added α-toluenesulfonyl chloride (1 eq) via syringe. The resulting heterogeneous mixture was allowed to stir for 1 hour at room temperature. The mixture was then diluted with water and extracted with dichloromethane. The organics were washed with water and a saturated solution of sodium chloride, dried with sodium sulfate and concentrated in vacuo to viscous oil. Purification by chromatography yielded 4-[2-(3-Isopropyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (2-phenylmethanesulfonylamino-ethyl)-amide. MS: MH+599
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[O:33][CH:34]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:33][CH:34]=2)[N:3]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.18 mmol) of the compound from Example 38A and 46 mg (0.20 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole together with 46 mg (0.55 mmol) of sodium bicarbonate were suspended in 1.9 ml of dry DMF. The reaction mixture was stirred at RT for 20 h. The mixture was then freed from the solvent on a rotary evaporator, and the residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:16]([O-])=O)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].Cl.[H][H]>C(O)C.CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:16])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1c(N)cc(C(=O)O)cc1OC(C)=O
Yield: 103.4 %

Procedure:
3-Acetoxy-4-methoxy-5-nitro-benzoic acid (4.50 g, 17.6 mmol) (R. T. Borchardt et al., J. Med. Chem. 25 (1982), 312-323; F. Tiemann et al., Ber. dt. Chem. Ges. 9 (1876), 937) was dissolved in ethanol (180 ml) and 0.5 M hydrogen chloride in methanol (4 ml) and hydrogenated in an H-Cube™ hydrogenation reactor with 100 bar hydrogen at 40° C. over a 10% palladium on charcoal cartridge. The mixture was evaporated to dryness to give 4.1 g of the title compound.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].ClC1C=CC([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2C2C=CC(Cl)=CC=2)(=[O:27])=[O:26])=CC=1>CN(C=O)C>[C:20]1([S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1-c1ccc(Cl)cc1)c1ccccc1-c1ccc(Cl)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of benzimidazole (11.8 g, 0.10 mol) in DMF (500 ml) is added, at room temperature under nitrogen, sodium hydride (60% in mineral oil, 4.4 g, 0.11 mol), and the mixture is stirred for 10 min. The mixture is admixed with 4-chlorophenyl phenylsulfone (26.1 g, 0.10 mol) and stirred at 100° C. for 16 h. After again adding sodium hydride (60% in mineral oil, 2.0 g, 0.05 mol) at room temperature, the mixture is stirred at 130° C. for 16 h. After cooling to room temperature, the mixture is added to ice-water. Precipitated product is filtered off and washed with water. Yield: 91%.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1>[Pd].C(O)(C)C>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Yield: 77.8 %

Procedure:
Hydrochloric acid (2.08 g) and 10% palladium on carbon (0.88 g, 50% wet) was added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (8 g) in 30% aqueous iso-propanol (Iso-propanol:Water::64 mL:28 mL). The reaction mixture was flushed with nitrogen twice and hydrogenated at 35° C. to 40° C. under hydrogen pressure of 0.5-1 Kg/cm2 for about 1 hour. After completion of the reaction, the reaction mass was filtered and washed with 20% aqueous iso-propanol (Iso-propanol:Water::6.4 mL:1.6 mL). Iso-propanol (123.3 mL) was added at about 20° C. to 25° C. in about 1 hour. The reaction mass was cooled to about 10° C. to 15° C. and maintained for about 1 hour, filtered, washed with 10% aqueous iso-propanol solution (10 mL) followed by washing with iso-propanol (10 mL) and dried to obtain valganciclovir hydrochloride (4.8 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]/[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: CCOC(=O)/C=C/CC(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (2.84 g, 12 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (E)-5-methyl-hex-2-enoic acid ethyl ester (1.56 g, 10.0 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. Saturated sodium bicarbonate was added, and the organic portion was separated, washed with brine, and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (trans)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 3 as an oil (1.28 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.IC.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-methoxyphenyl)acetonitrile (1.0 g, 6.79 mmol) and iodomethane (0.42 mL, 6.79 mmol) in THF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 6.8 mL, 6.8 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][CH:32]1[S:34](Cl)(=[O:36])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:31]2[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1CC1COCc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCO2
Yield: 40.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.08 g, 0.0002 mol) in dry pyridine (2 ml) was reacted with 2-benzyloxymethyl-cyclopropanesulfonyl chloride (57 mg, 0.0002 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 51 mg of the product (21% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:7]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(4-chlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (400 mg, 0.86 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (57 mg, 2.59 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 12 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate to give the title compound (250 mg, 0.60 mmol, 69%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[N:26]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[CH3:14][C:12]1[CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:32](=[O:34])[CH3:33])[CH2:27][CH2:28]3)[CH:7]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccnc(F)c2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2cc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)ccn2)CC1
Temperature: 130 °C

Procedure:
A mixture of N-[3-(2-fluoropyridin-4-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.144 mmol), 1-(piperazin-1-yl)ethanone (36.8 mg, 0.287 mmol), and tribasic potassium phosphate (60.9 mg, 0.287 mmol) in DMSO (250 μL) was heated at 130° C. for 48 hours. The reaction mixture was diluted with DMSO (600 μL) and filtered through a plug of CELITE. The residue was purified by mass triggered reverse phase HPLC (21-55% acetonitrile in water+0.1% formic acid) to afford 1-{4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperazin-1-yl}ethanone as a tan solid. MS APCI calc'd for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (600 MHz, DMSO-d6) δ10.20 (s, 1H), 8.80 (d, J=4.8 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.24 (d, J=4.9 Hz, 1H), 7.22 (s, 1H), 6.98 (s, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.62-3.56 (m, 2H), 3.52 (d, J=7.5 Hz, 6H), 2.34 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1.Cl[C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>>[N+:23]([C:15]1[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[S:18][C:14]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1)([O-:25])=[O:24]
Reactant: O=C1COc2cc(O)ccc2N1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc3c(c2)OCC(=O)N3)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from 7-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (826 mg, 5.0 mmol) and methyl 5-chloro-4-nitro-thiophene-2-carboxylate (1.1 g, 5.0 mmol). The title compound was obtained as a white solid (400 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.92 (1H, S), 8.04 (1H, S), 7.22 (1H, M), 7.10 (2H, S), 7.03 (1H, M), 4.66 (2H, S), 3.80 (3H, S). MS m/z: 349.20 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12](OCC)=O)=[CH:7][C:6]=2[C:5]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]=2[N:3]=1.[Li+].[B-](CC)(CC)[CH2:24]C>C1COCC1>[CH2:12]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[C:5]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:4]1=[N:3][C:2]=2[NH2:1])[CH3:24]
Reactant: CC[B-](CC)CC
Reactant: CCOC(=O)c1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cnc2c(N)nc3cc(C)ccc3c2c1

Procedure:
To a stirred solution of ethyl 5-amino-8-methylbenzo[f][1,7]naphthyridine-2-carboxylate (from the previous step) in THF (0.2 M) cooled in an ice-water bath was added 1 N solution of super hydride in THF (10 eq.). Upon completion of the reaction the reaction was quenched with 1 N HCl, and extracted with EtOAc. Combined organic extracts were concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)methanol as a white solid. 1H NMR (CDCl3): δ 8.68 (d, 1H), 8.52 (d, 1H), 8.04 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 4.90 (s, 2H), 2.45 (s, 3H). LRMS [M+H]=240.1
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1ccc(N2N=C3c4cc(F)ccc4CCC3CC2=O)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 1 using 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and 3-dimethylaminopropyl chloride, there is obtained 9-fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCO
Product: COc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 4.8 g (0.025 mole) of 1-(4-methoxyphenyl)piperazine, 5.0 g (0.025 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 6.4 g (72%) of tan towder., m.p. 95°-97° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCN(C)CC2)ccc1N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.549 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)benzamide (0.270 g) and glacial acetic acid (0.047 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.102 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.67 (m, 2H), 1.91 (m, 2H), 2.11 (s, 3H), 2.24 (s, 3H), 2.44 (m, 2H), 2.64 (t, 2H), 2.84 (m, 1H), 3.52 (t, 2H), 3.60 (t, 2H), 7.22 (d, 1H), 7.36 (m, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.78 (d, 1H), 7.87 (m, 1H), 7.96 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[O:27][CH3:28])#[N:2].Cl.[C:30](=[NH:33])([NH2:32])[CH3:31].C[O-].[Na+]>CO>[CH3:28][O:27][C:10]1[CH:11]=[C:12]([CH2:15][C:16]2[C:17](=[O:18])[NH:32][C:30]([CH3:31])=[N:33][C:22]=2[CH2:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:9]=1[C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)c(OC)c1
Yield: 52 %

Procedure:
To a suspension of 60% sodium hydride (1.80 g) in tetrahydrofuran (50 mL) was added dropwise a solution of ethyl butyrylacetate (9.50 g) in tetrahydrofuran (30 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-methoxybiphenyl-2-carbonitrile (8.79 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (3.25 g) and 28% sodium methoxide (9.91 g) in methanol (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.63 g, 52%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C(c1ccc(F)cc1)C1CCN(c2ccncc2)CC1
Temperature: 145 °C
Yield: 41.5 %

Procedure:
A stirred mixture of 4-(4-fluorobenzoyl)piperidine, hydrochloride salt (3.90 g), 4-chloropyridine, hydrochloride salt (2.85 g) and triethylamine (4.90 ml) in xylene (75 ml) was heated at 145° C. for 27 hours. The solvent was evaporated and the residue partitioned between methylene chloride (150 ml) and water (100 ml), the pH being adjusted to ˜10 with 0.880 ammonia. The aqueous phase was extracted with a further methylene chloride (50 ml). The combined organic phases were washed with water, dried (Mg SO4) and evaporated. The residue was purified by column chromatography using a 19:1 mixture of methylene chloride and methanol as eluent to give 4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine (1.89 g);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:21]=1
Reactant: Fc1cccc(-c2cccs2)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: Fc1cccc(-c2ccc(Cc3cc(Br)ccc3F)s2)c1

Procedure:
2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH2:19][CH2:20][CH2:21]O)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH2:19][CH2:20][CH2:21][Cl:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(Cl)Cl
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1
Product: OC1(c2ccc(Cl)c(Cl)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Reaction of 3-(3,4-dichlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(3,4-dichlorophenyl-2-(3-chloropropylamino)-3H-indol-3-ol.