Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=3)[C@H:9]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:10]2)=[CH:36][CH:37]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)c1ccc(CBr)cc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Yield: 102 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (228 mg), 1-[4-(bromomethyl)phenyl]ethanone (107 mg) and potassium carbonate (42 mg) in acetonitrile (2 ml) was refluxed for 4.5 hours. After cooling, the mixture was evaporated in vacuo. Ethyl acetate and water were added to the residue and the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and methanol as an eluent to give (2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.30 g). To a solution of this piperazine (0.30 g) in ethyl acetate was added 4N hydrogen chloride in ethyl acetate solution (0.13 ml) and the whole was evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and ether to give (2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (283.5 mg) as a powder.
Reaction SMILES: [OH:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])(=O)=O.[CH3:31][OH:32]>C(O)(=O)C.C(Cl)Cl>[OH:32][C:31]1[C:22](=[O:24])[C:23]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[OH:1])[C:7](=[O:25])[C:8]=1[C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[C:17]([Cl:29])[C:12]=1[C:11]([O:10][CH3:9])=[O:21]
Reactant: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Reactant: CO
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)c(C)cc(OC)c1C1=C(O)C(=O)c2c(O)cccc2C1=O

Procedure:
8-Hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione (400 mg) as prepared in Example 1 was dissolved in a 20:100:1 mixture (20 ml) of acetic acid, methylene chloride and methanol, followed by addition of sulfuryl chloride (2 ml). The mixture was refluxed for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give methyl 2-(3,5-dihydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methyl-6-chlorobenzoate.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[F:15][C:16]([F:26])([F:25])[CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19]>>[F:26][C:16]([F:15])([F:25])[CH2:17][S:18]([CH2:21][C:22]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:23])(=[O:20])=[O:19]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
When the t-butyl ester of 7-ADCA is acylated with trifluoroethylsulfonylacetic acid by the procedure of Example 8, 7-trifluoroethylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4](Cl)[N:3]=1.[C:20]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]3[NH:32][CH:33]=[N:34][C:30]=3[CH:29]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC1C=CC=CC=1)C1C=CC=CC=1.N1C2C=CC=CC=2NC=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([N:34]2[C:30]3[CH:29]=[C:28]([O:27][CH2:26][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:36]=[CH:35][C:31]=3[N:32]=[CH:33]2)[N:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reactant: c1ccc(COc2ccc3[nH]cnc3c2)cc1
Agent: c1ccc2[nH]cnc2c1
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1cnc2c(-n3cnc4ccc(OCc5ccccc5)cc43)nc(Cl)nc21
Temperature: 120 °C
Yield: 48.8 %

Procedure:
860 mg of product obtained in stage 1 above are mixed with 605 mg of 5-(phenylmethoxy)-1H-benzimidazole (benzyl ether in the 5-position of benzimidazole) and 15 ml of butanol. The mixture is heated at 120° C. for 24 hours. Partial drying, washing with H2O and then drying under vacuum at 50° C. are carried out. 667 mg of 2-chloro-6-[6-(phenylmethoxy)-1H-benzimidazol-1-yl]-9-[[2-(trimethylsilyl)ethoxy]methyl]-9H-purine are obtained, in the form of beige-colored crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([N:29]([CH3:42])[C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([N:29]([CH3:42])[C:27](=[O:28])[O:26][C:23]([CH3:22])([CH3:25])[CH3:24])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 77.3 %

Procedure:
Preparation of example 151 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (57 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (14 mg, 0.047 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (18 mg, 0.047 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (55 mg, 0.099 mmol) as a yellow powder in 78% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[S:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2ccc(NC(=S)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Yield: 42 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190 mg, 0.6 mmol) obtained in Example 1, (3), phenyl isothiocyanate (243 mg, 1.8 mmol), and tetrahydrofuran (76 mL) were mixed, and the mixture was refluxed by heating for 24 hours. After the mixture was left to cool to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform=1/50) to obtain the title compound (114 mg, yield 42%) as slightly yellow crystals.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])[CH:10]=O.[CH2:24]1[CH2:31][CH:30]([NH2:32])[C:28](=[O:29])[NH:27][CH2:26][CH2:25]1>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])[CH2:10][NH:32][CH:30]1[CH2:31][CH2:24][CH2:25][CH2:26][NH:27][C:28]1=[O:29]
Reactant: NC1CCCCNC1=O
Reactant: COc1cc(C=O)ccc1OCCc1scnc1C
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1scnc1C
Reaction time: 2 h

Procedure:
Acetic acid (9.4 mmol) was added to 3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzaldehyde (6) (2.3 mmol) and DL-α-amino-ε-caprolactam (2.3 mmol) in minimal amount of methanol and stirred for 2 h. MeOH (0.2 M) was added followed by NaH3BCN (2.3 mmol), and the reaction was stirred for 19 h. The product (7) was obtained by purification upon reverse phase HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](O)([CH3:14])[CH3:13].S(=O)(=O)(O)O>CCCCCC>[CH:12]([O:1][C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5])([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
201 g mixture of 2,5-dihydroxy benzoic acid and isopropanol was added to 1201 g of 80% sulfuric acid and stirred for 8 hours at 75° C. The solution was allowed to cool, and was added with 2 liters of ice water and 140 ml of hexane and was stirred in an ice bath. Resultant crystal deposit was filtrated, and the residue was washed with hexane. Then, it was dispersed in a mixture liquid consisting of methanol and water in a ratio of 6:4, and filtration was conducted. The substance was dried for 48 hours at 60° C., and 65.4 g of isopropyl-salicylic acid intermediate was obtained.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C.[NH4+:23]>C1(C)C=CC=CC=1>[NH2:18][C:17]1[N:23]=[C:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]=1[C:15]#[N:16]
Reactant: O=C1CCCC1
Reactant: [NH4+]
Reactant: N#CC(C#N)=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)nc2c(c1-c1ccccc1)CCC2

Procedure:
In 12 ml of toluene, 500 mg (5.94 mmol) of cyclopentanone, 916 mg (5.94 mmol) of benzylidenemalononitrile and 1.00 g (13.1 mmol) of ammonium acetate were heated under reflux for 2 h. The mixture was washed with 10 ml of a saturated aqueous sodium bicarbonate solution and then with 10 ml of water, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. 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: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[C:29]([CH3:36])=[N:28]1>ClCCl>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[S:32]([C:30]3[C:29]([CH3:36])=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1S(=O)(=O)N(C)CCN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine hydrochloride salt (0.5 g, 1.29 mmol) in dichloromethane (10 ml) and cool in an ice-bath. Add triethylamine (0.90 ml, 6.44 mmol) and then 1,3-dimethylpyrazole-4-sulfonyl chloride (250 mg, 1.29 mmol). Remove the ice-bath and allow to warm to ambient temperature and allow to stir for 2 hr. Wash the organic phase with aqueous sodium bicarbonate, brine and water. Dry over sodium sulfate and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the title preparation (535 mg, 100% yield) as a white foam. MS ES: m/z=414 [M+H]+.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]1[O:20][C:19](=[O:21])[CH2:18][CH2:17]1.C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:2]([CH:18]1[CH2:17][CH:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)[O:20][C:19]1=[O:21])[CH2:1][CH3:3]
Reactant: O=C1CCC(Cc2ccccn2)O1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCBr
Product: CCCC1CC(Cc2ccccn2)OC1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 5-(pyridin-2-yl-methyl)dihydrofuran-2(3H)-one and the mixture is stirred for 1.5 hours at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 hours at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted with 3 times dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 3-propyl-5-(pyridin-2-ylmethyl)dihydrofuran-2(3H)-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([NH:12]CC3C=CC=CC=3)[CH2:9]2)C=CC=CC=1.[ClH:31].O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[ClH:31].[CH3:23][CH:22]([NH:21][CH2:20][C:10]1([NH2:12])[CH2:11][NH:8][CH2:9]1)[CH3:24]
Reactant: CC(C)NCC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)NCC1(N)CNC1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of the 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 0.88 mmol) in methanol was added a solution of hydrogen chloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and the resulting mixture was concentrated to give a white solid which was taken back into methanol. To this solution were added palladium hydroxide (20% on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psi in a Parr apparatus for 3 h. The reaction mixture was filtered and concentrated to give a solid, which was washed with ether and dried in vacuo to give 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride as a white solid (0.18 g, 81% yield). MS (EI) for C7H17N3: 144 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[OH:20].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH3:21])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Reaction time: 17 h
Yield: 94.4 %

Procedure:
1.60 g (0.0057 mole) of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) [prepared as described in step (B3) above] were dissolved in 20 ml of dimethylformamide, and 1.20 g (0.0085 mole) of potassium carbonate and 2.40 g (0.017 mole) of methyl iodide were added to the resulting solution. The mixture was then stirred at 60°-65° C. for 17 hours. At the end of this time, the solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the methylene chloride extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 1.60 g of ethyl 6,7-difluoro-8-methoxy-1-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =methyl) as a pale brown powder.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClCl.[OH-].[Na+].[SH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)(Cl)Cl.C(O)C>[C:1]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[N:3][OH:4])[CH3:2]
Reactant: CC=NO
Reactant: CCOC(=O)CS
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CSC(C)=NO
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of 30 g (0.5 m) of acetaldoxime in 100 ml of chloroform cooled at 0° was added, with stirring over a period of 30 minutes, a solution of 35 grams (0.5 mol) of chlorine in 300 ml of chloroform. The reaction mixture was stirred at 0° C. for 30 minutes at which time about one half of the chloroform was removed by evaporation, in vacuo. This residual solution was then added with stirring to a solution consisting of 20 grams (0.5 mol) of sodium hydroxide and 60 grams (0.5 mol) of ethyl mercaptoacetate in 300 ml. of ethanol at 10° C. over a period of 10 minutes. The solvent was removed in vacuo, the residue was dissolved in chloroform and the resulting solution was washed with water. After drying, the chloroform solution was evaporated to give a solid residue which was recrystallized from hexane to provide 20 g (23 percent yield) of S-(ethoxycarbonylmethylene) acetothiohydroximate, m.p. 90°-92° C., lit. 90°-91° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[CH2:15][C:14](=[O:16])[C:13](=[C:17](N4CCOCC4)[CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][C:23]5[O:26][CH2:27][O:28][C:22]=5[CH:21]=4)[C:12](=[O:35])[CH2:11]3)=[CH:4][C:3]=2[O:2]1.[OH2:36].[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[CH2:11][C:12](=[O:35])[CH:13]([C:17](=[O:36])[CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]5[O:26][CH2:27][O:28][C:22]=5[CH:21]=4)[C:14](=[O:16])[CH2:15]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C1CC(c2ccc3c(c2)OCO3)CC(=O)C1=C(C=Cc1ccc2c(c1)OCO2)N1CCOCC1
Reactant: O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccc3c(c2)OCO3)CC1=O

Procedure:
Similarly, 1.0 g of the above-mentioned enamine type adduct compound, that is, 5-(3,4-methylenedioxyphenyl)-2-[3-(3,4-methylenedioxyphenyl)-1-morpholinoallylidene]-cyclohexane-1,3-dione, was dissolved in 80 ml of acetic acid, and 0.5 g of a 5% palladium-carbon catalyst and 30 ml of deionized water were added to the solution and catalytic reduction was carried out with hydrogen under atmospheric pressure for 4 hours to obtain 0.38 g (the yield being 44%) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl[C:24]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(F)cc2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate (from Example 83) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 1,4,α-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:32][C:33]([NH2:35])=[O:34].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:32][C:33]([NH2:35])=[O:34])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(O)cc12
Reactant: NC(=O)CI
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(OCC(N)=O)cc12
Yield: 77.8 %

Procedure:
A solution of tert-butyl(4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.42 g, 1 mmol), 2-iodoacetamide (0.27 g, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.22 mL, 1.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.37 g, 78.7%) as crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[N:13][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15]2)=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:14]2[N:13]=[C:12]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:11]3[C:16](=[CH:17][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[N:15]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(Br)cc3n2)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(N4CCOCC4)cc3n2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 102.1 %

Procedure:
Under a nitrogen atmosphere, 2.26 g (2.47 mmol) of tris(dibenzylideneacetone)dipalladium-(0) and 4.42 g (12.35 mmol) of 2-(dicyclohexylphosphino)biphenyl were dissolved in 1.5 l of toluene, and 215.2 ml (2.47 mol) of morpholine and 269.0 g (0.5 mol) of 7-bromo-2,4-bis(4-methoxybenzyloxy)quinazoline [dissolved in 5 l of toluene] were added successively. 66.47 g (0.7 mol) of sodium tert-butoxide were subsequently added in portions, and the mixture was stirred at 90° C. for 12 h. Conventional work-up gave 249.0 g of 2,4-bis(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=488 as oil [crude product; was reacted further directly].
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC1C=CC(N2CCNCC2)=CC=1.[CH:29]1([CH2:32][CH2:33][NH:34][C:35]([C:37]2[N:38]=[N:39][C:40](Cl)=[CH:41][CH:42]=2)=[O:36])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][CH2:33][NH:34][C:35]([C:37]2[N:38]=[N:39][C:40]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[S:9][N:8]=4)[CH2:2][CH2:3]3)=[CH:41][CH:42]=2)=[O:36])[CH2:31][CH2:30]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nsc4ccccc34)CC2)nn1
Yield: 25 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 3-piperazin-1-ylbenzo[d]isothiazole to replace 1-(4-fluorophenyl)-piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 25% yield (0.0307 g). 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.94 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 4.05 (m, 4H), 3.73 (m, 4H), 3.51 (m, 2H), 1.50 (m, 2H), 0.73 (m, 1H), 0.45 (m, 2H), 0.06 (m, 2H). MS (ES+) m/z 409 (M+1).