Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Yield: 72.3 %

Procedure:
A mixture of 5-aminoindole (1.32 g, 10.0 mmol), acetonylacetone (4.0 mL, 34 mmol, 3.4 eq) and toluene (25 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 24 hours. The reaction was cooled and then poured through a silica gel (approximately 200 g) filter followed by 10% ether in hexanes to afford the title compound (1.52 g, 72%) as an off-white, crystalline solid: Rf =0.75 in diethyl ether; 13C NMR (CDCl3) δ 135.0, 131.4, 129.5, 128.1, 125.6, 122.4, 120.3, 111.3, 105.0, 103.0, 13.2. Anal. calcd for C14H14N2 ; C, 79.97; H, 6.71; N, 13.32. Found: C, 79.72; H, 6.75; N, 13.13.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][O:45][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1
Yield: 58.9 %

Procedure:
To a solution of triphenylphosphine (1.24 g, 4.74 mmol) in 20 mL of tetrahydrofuran at room temperature was added diethyl azodicarboxylate (0.746 mL, 4.74 mmol) dropwise with stirring. After stirring at room temperature for 30 minutes, (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (350 mg, 3.16 mmol) and 3-hydroxypyridine (450 mg, 4.74 mmol) were added to the reaction mixture. The resultant solution was then stirred at room temperature overnight. After all of the starting material was consumed, the organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography. Elution with chloroform:methanol (10: 1) provided 518 mg of the title compound along with substantial amount of reduced DEAD reagent. MS (DCI/NH3) m/e 279 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)cc3F)cc1CC2
Yield: 87 %

Procedure:
In accordance with general method AA, 0.50 g (1.8 mmol) of 2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34), 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of K—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 8+2). Yield: 87%; melting point: 123-126° C. (decomposition)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:18])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (4 g, 22.6 mmol) was dissolved in DMF (115 ml) and treated with NaH (1 g, 45.2 mmol) and CH3I (2.8 ml, 45.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. EtOAc was added to the mixture and extracted with 5% citric acid (2×10 mL), saturated NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated to yield the desired product.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH:4]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[K+]>>[CH:1](=[N:11][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: NC1CCCCCC1
Reactant: CC=O
Agent: [K+]
Agent: [OH-]
Product: CC=NC1CCCCCC1
Yield: 86 %

Procedure:
90% Acetaldehyde (19.55 g) was added dropwise to cycloheptylamine (45.28 g) with ice bath cooling over about 2 hours. After the completion of the dropwise addition, potassium hydroxide, in solid form, was added and the organic layer was separated by a separatory funnel. This liquid was distilled under reduced pressure to obtain pure N-ethylidenecycloheptylamine (47.92 g). b.p. 100°-104° C./106.4 mbar.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]([C:13]1[C:14](OS(C(F)(F)F)(=O)=O)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:6]([O:10][C:11]([C:13]1[C:14]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of diethyl amine (0.078 ml, 0.75 mmol) in THF (5 ml) was added 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (200 mg, 0.38 mmol) and potassium carbonate (208 mg, 1.51 mmol) at 25° C. The resulting reaction mixture was stirred at 70° C. for 3 h. Volatiles were removed in vacuo and the resulting crude mixture was diluted with water (15 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (3% EtOAc in hexane) to afford 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid tert-butyl ester (110 mg, 64%) as a pale yellow solid. LC-MS (ESI): 453 (M+H)+.
Reaction SMILES: C([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:19])([CH3:18])[CH3:20]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1

Procedure:
A solution of t-Butyl 4-(4-formyl phenoxy)piperidine-1-carboxylate (50.2 grams, 0.164 moles, obtained in above step), malonic acid (50.6 grams, 0.486 moles) and piperidine (12.5 mL) in pyridine (250 mL) was stirred for 8 hours at 110° C. under nitrogen atmosphere.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].C(O[C:12]([C:14]1[N:15]([N:24]=[CH:25]N(C)C)[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=1)=[O:13])C.CC(O)=O>C1COCC1>[CH2:22]([O:21][C:19]([C:16]1[N:15]2[N:24]=[CH:25][C:6]([C:7]#[N:8])=[C:12]([OH:13])[C:14]2=[CH:18][CH:17]=1)=[O:20])[CH3:23]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N=CN(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a solution of n-BuLi (1.6 M in hexanes) (290 μl, 0.465 mmol) in THF (1 ml) was added a solution of CH3CN (19.1 mg, 0.465 mmol) in THF (2 ml) dropwise at 0° C. The mixture was stirred for 20 min, then a solution of 406D (62 mg, 0.221 mmol) in THF (5 ml) was added. After the mixture was stirred for 40 min, the reaction temperature was lowered to −78° C., AcOH (38 μl, 0.663 mmol) was added. The reaction mixture was then stirred at rt overnight. Solvent was removed, 406E (26 mg, 50%) was obtained as a yellowish solid after preparative HPLC purification. LCMS Found: (M+H)+=232.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13]C)[C:7]=1[Cl:15]>ClCCl.O>[Br:5][C:6]1[C:7]([Cl:15])=[C:8]([OH:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: COc1cc(Cl)cc(Br)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Boron tribromide as a 1 M solution in dichloromethane (41 mL, 41 mmol) was added to 1-bromo-2,5-dichloro-3-methoxybenzene (10.5 g, 41 mmol) in dichloromethane (100 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature, and after 21 hours, the mixture was poured into 100 g of ice, diluted with 100 g of water, and the organic layer separated. The aqueous layer was extracted with dichloromethane (200 mL) and the combined organic extracts were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. 1H NMR (CDCl3) δ 7.20 (m, 1H), 7.00 (m, 1H), 5.70 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg), (5-chloropyridin-2-yl)-methanol (152 mg) and tributylphosphine (437 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (536 mg). The mixture was stirred under sonication at 50° C. for 3 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (40 mg) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 30 h
Yield: 85.5 %

Procedure:
1H-indole-2-carboxylic acid (1 g, 6.2 mmol) was dissolved in 20 mL of ethanol. To this thionyl chloride (5.86 g, 49.68 mmol) was added drop wise with stirring at 0° C and stirring was continued for 30 h at room temperature. Excess of SOCl2 was evaporated, water was added to the residue and the suspension was filtered to afford the title compound (1.0 g, yield: 85.5%).
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][C:10]2[C:11](=[O:12])[NH:13][C:17](=[O:18])[C:16]=2[OH:22])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Cc1ccc(OCC(N)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetonylphenoxyacetamide, ethylene ketal (3.2 g) and diethyl oxalate (2.0 g) in dry dimethylformamide at 0° C. was treated with potassium tert-butoxide (3.24 g) in two portions at 15 min. intervals. The solution was then stirred 16 h at ambient temperature, poured into water, and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the combined organic extracts dried (magnesium sulphate), filtered and evaporated and the residue crystallised from acetone/ether to give 4-[4-acetonylphenoxy]-3-hydroxy-1H-pyrrole-2,5-dione, (1.5 g).
Reaction SMILES: [CH2:1]([O:8]C(N1CCC2C(CO)(C2)C1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O.O>[CH2:2]([C:1]([OH:8])=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCC2CC2(CO)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of the compound of Step 3 (580 mg, 2.22 mmol) in acetone (10 ml) was added Jones reagent (2.8 ml) at 0° C. The mixture was stirred at this temperature for 1 hour. After addition of methanol (5 ml), the reaction mixture was warmed to room temperature and diluted with water. The product was extracted into methylene chloride, and the combined organic layers were washed with brine and dried over magnesium sulfate. Removal of solvent in vacuo provided the title compound as a white solid, (570 mg, 2.1 mmol, 93% yield).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20][OH:21])=[C:18]([F:26])[C:17]=1[F:27])[CH:14]=[CH2:15].[C:28]([C:30]([CH3:40])=[CH:31][C@@H:32]1[C@@H:34]([C:35](O)=[O:36])[C:33]1([CH3:39])[CH3:38])#[N:29]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:28]([C:30]([CH3:40])=[CH:31][C@@H:32]1[C@@H:34]([C:35]([O:21][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:13][CH:14]=[CH2:15])=[C:23]([F:24])[C:22]=2[F:25])=[O:36])[C:33]1([CH3:39])[CH3:38])#[N:29]
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C=CCc1c(F)c(F)c(CO)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=CCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 0.23 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.20 g of 4-allyl-2,3,5,6-tetrafluorobenzyl alcohol, 0.16 g of (1R)-trans-3-(2-cyano-1-propeny)-2,2-dimethylcyclopropanecarboxylic acid, 0.05 g of 4-dimethylaminopyridine and 4 ml of anhydrous chloroform, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate two times. Ethyl acetate layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.32 g of 4-allyl-2,3,5,6-tetrafluorobenzyl(1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: [Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.[C:29]([O:34]C)(=[O:33])[C@@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:27]([O:28][C@@H:30]([CH3:32])[C:29]([OH:34])=[O:33])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Reactant: COC(=O)[C@@H](C)O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 of Example 5 (0.42 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[S:18]1[C:22]([C:23]2[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=2)[CH:28]=O)=[CH:21][C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]1=2>C(O)C>[S:18]1[C:22]([C:23]2[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]=[CH:14][C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])[CH:30]=2)=[CH:21][C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3′,4′,5′-Trimethoxyacetophenone (1.62 g, 7.7 mmol) was dissolved in ethanol (50 mL). Sodium hydroxide solution (50%, 4 mL) was added and the mixture was stirred at room temperature for 30 minutes. 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (2.2 g, 7.7 mmol) from Ex-6A was added, and the mixture was stirred at room temperature overnight. The resulting yellow precipitate was filtered out, rinsed with water and dried over an oil pump to give 3.4 g (92%) of the desired 3-[5-(benzo[b]thien-2-yl)-2,4-di-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one product as a solid, m.p. 194-196° C. 1H-NMR (300 MHz, CDCl3): 8.09 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 7.52 (d, 1H), 7.25-7.38 (m, 4H), 6.57 (s, 1H), 3.9-4.1 (m, 15H). Anal. Calculated for C28H26O6S: C, 68.55, H, 5.34, S, 6.53; found C: 68.48, H: 5.43, S: 6.52.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCCC1=O>CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCOCC3)c(F)c21
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A mixture of 289 mg of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 300 mg of morpholine and 5.6 ml of 1-methyl-2-pyrrolidone was heated in a stoppered flask at 65° C. for one hour. Ether was added, the solid collected, dissolved in 200 ml of acetone, filtered and boiled down to about 50 ml. The solid was collected, giving 137 mg of the desired product, mp 281°-283° C.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](F)[C:18]=3[F:20])[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:2][CH3:1])[C:18]=3[F:20])[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(F)c(F)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1ccc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-7,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ethanol (2 ml) was added to the residue, and solids were collected by filtration to obtain the title compound (40 mg) as an orange powder.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].[OH-].[Na+].Br[CH2:54][CH:55]([OH:58])[CH2:56][OH:57]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:54][CH:55]([OH:58])[CH2:56][OH:57])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I
Reactant: OCC(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CC(O)CO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 96 h
Yield: 14 %

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)-phenyl]urea (0.25 g, 0.18 mmol) was dissolved in water (5 ml) followed by 2M aqueous NaOH (2.1 ml) and, after 5 min, bromopropane-2,3-diol (0.196 ml) was added. The solution was stirred for 4 days, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification by preparative HPLC gave 38 mg (14%) of the product as a white solid. MS (ESP, m/e): 1450 (M+).