Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH:23]=O)[CH:22]=1)=[O:17].C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH2:23][NH:7][C:4]2[CH:3]=[CH:2][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)[CH:22]=1)=[O:17]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(C=O)c(C)o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of biphenyl-4-ylamine (150 mg, 0.883 mmoles) and 4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135 mg, 0.803 mmoles) in methanol (2.0 ml) was stirred over molecular sieves (type 3 Å) for 1 hour. Sodium cyanoborohydride (55 mg, 0.883 mmoles) was added and the mixture stirred for 18 hour at room temperature. The mixture was concentrated and partitioned between ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was re-extracted with ethyl acetate (2×25 ml) and the combined extracts were washed with brine (50 ml) and dried (MgSO4). After removal of the solvent, the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(75 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18].C([O-])(=O)C.[Na+]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 3,4-dimethoxy-aniline (153 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 295 mg (100%) of off white solids. 1H NMR (CDCl3): 7.85-7.70 (m, 4H), 7.51-7.46 (m, 1H), 7.38 (brs, 1H), 7.16 (dd, J=2.1 Hz, J=8.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 3.95 (s, 3H)), 3.91 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:18]([O:25][CH2:26][C:27](Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:12]1([N:11]2[C:10]3[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[C:27]2[CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(COCc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.8 %

Procedure:
A 4-neck flask equipped with a reflux condenser was charged with 3-amino-4-phenylaminobenzoic acid (see Synthesis Example 1-2) (3.09 g, 13.54 mmol) and anhydrous toluene (45 mL) and this was refluxed. To this was added dropwise benzyloxyacetyl chloride (5 g, 27.08 mmol) in toluene solution (approx. 3 mL) over approx. 10 minutes. This was stirred under these conditions for 15 hours. This was allowed to cool to room temperature, and was extracted with dilute aqueous sodium hydroxide solution (10%, 100 mL). This was washed with toluene, and after separating the dark orange aqueous layer, this was cooled (5 to 10° C.), and concentrated hydrochloric acid (12 M) was added to the liquid to give pH 4. The precipitated crystals were filtered off, washed with distilled water, and dried under reduced pressure with heating to yield the title compound (4.21 g, 86.8% yield) as a light purple powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:25])[CH3:24]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1sc(-c2ccc(F)cc2)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
A vigorously stirred mixture of 2-amino-5-(4-fluorophenyl)- 3-thiophenecarboxamide (0.01 mole) and pyridine (20 ml) at 0° was treated dropwise with acetyl chloride (0.011 mole). The resulting solution was stirred a further 30 minutes at 0° and then poured on to cold water. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from ethanol yielded 2-acetamido-5-(4-fluorophenyl)- 3-thiophenecarboxamide (90°/o, m.p. 230°-3°).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CS(C)=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][CH:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[OH:2])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(C(O)Cc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 10° C. solution of 4-formyl benzonitrile (65.6 gm, 0.500 mol), 4-methyl-3-nitro benzonitrile (81.1 gm, 0.500 mol) and 750 mL of dry dimethylsulfoxide (DMSO), was added sodium methylate (4.01 gm, 75 mmol) in one portion. After 4 hrs, the reaction was added dropwise to 6 L of ice water and then allowed to stir for 1 hr. The product was collected via vacuum filtration and washed with water (3×1 L) and then dried over night in a vacuum oven at 40° C. to give 2-(4-cyano-2-nitro-phenyl)-1-(4-cyano-phenyl)-ethanol.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloro-5-fluoronicotinic acid (500 mg, 2.381 mmol) and 4-fluoroaniline (265 mg, 2.381 mmol) in THF (30 mL) was treated with 1 M lithium bis(trimethylsilyl)amide in THF (7.14 mL, 7.14 mmol) slowly and stirred at rt. Solvent was removed on rotary evaporator. The residue acidified with 1 N HCl, extracted into ethyl acetate, and concentrated to give a dark solid. LCMS: (M+H)+=285.12.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11]C.B(F)(F)F.O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[OH:11]
Reactant: COc1c(F)c(CC(=O)O)cc2ccsc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)Cc1cc2ccsc2c(O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
In 17.4 mL of methylene chloride is suspended 1.74 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetic acid, to which is added 13.8 mL of 1 mol/L solution of boron trifluoride in methylene chloride. The mixture is stirred at ambient temperature for 3 hours. The reaction mixture is introduced into a mixture of methylene chloride and water and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.42 g of 2-(6-fluoro-7-hydroxybenzo[b]thiophen-5-yl)-acetic acid is obtained as a gray-colored crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 g of the acid of Step A in 3.5 l of methanol and add slowly 25 ml of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature and add 100 g of sodium bicarbonate in portions. Stir for an additional hour and strip to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]OC[CH2:41]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH:25]([CH2:41][CH2:40][CH3:44])[C:26]([O:28][CH3:29])=[O:27]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.260 g; 0.62 mmol), LHMDS 1N in THF (0.7 mL; 0.7 mmol), 1-iodopropane (0.127 mL; 1.3 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.233 g (83%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=O)[CH2:5]Br.[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CC1C=CC=CC=1C>[C:14]1([C:13]2[O:20][CH:5]=[C:4]([C:3]3[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=3[F:12])[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CBr)c1c(F)cccc1F
Solvent: O
Solvent: Cc1ccccc1C
Product: Fc1cccc(F)c1-c1coc(-c2ccccc2)n1
Yield: 121.8 %

Procedure:
5.7 g 2,6-difluorophenacyl bromide and 3.63 g benzamide were suspended in 20 ml o-xylene, and the suspension was subjected to reflux under heating for 1.5 hours. After completing the reaction, the suspension reacted was added with water, then extracted with ethyl acetate and further washed with saturated saline solution. The organic layer obtained was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. Out of 7.6 g residue obtained, 1.0 g thereof was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.6 g.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C(=O)O)ccc2C)cc1
Yield: 25.3 %

Procedure:
3-Iodo-4-methylbenzoic acid (8.7 g, 33.3 mmol), (4-methoxycarbonylphenyl)boronic acid (6.0 g, 33.3 mmol), caesium carbonate (1 0.8 g, 33.3 mmol) and tetrakis(triphenylphosphine)palladium (1.92 g, 1.∂mmol) in DME (120 ml) were heated at 90° C. for 6 h. The cooled reaction mixture was filtered and the residue washed with DME. The combined filtrate and washings were absorbed onto silica and chromatographed on a silica flash column eluting with DCM/ethanol/ammonia (40:8:1 then 30:8:1). The product fractions were reduced to dryness under vacuum to give 4′-(methoxycarbonyl)-6-methyl-1,1′-biphenyl-3-carboxylic acid (2.28 g, 25%). LCMS: retention time 3.22 min, [M−H]−269.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].Cl[CH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:24]1[C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]=[CH:35][C:23]=1[CH2:22][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: ClCc1ccc2oc3ccccc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (75 mg, 303 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.15 mL, 0.30 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (70 mg, 323 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave, after evaporation and drying, 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (11 mg, 8% yield). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.20 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol hydrochloride 7 as a pale brown solid (11 mg, 8% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][S:27][CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][S:27][CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:32][CH:33]=1)[CH3:22]
Reactant: CCOC(=O)CCSCc1csc(N)n1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)n1

Procedure:
3-[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-4-ylmethylsulfanyl]-propionic acid ethyl ester was prepared from 3-isopropoxy-5-phenoxy-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:44][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reactant: Nc1c(Cl)cc(C#Cc2ccccn2)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)CC1=O
Yield: 81.4 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (137 mg, 0.37 mmol), 5-chloro-7-(pyridin-2-ylethynyl)-1,3-benzodioxol-4-amine (113 mg, 0.41 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.8 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (181 mg, 80%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.21 (quintet, 2H), 2.31 (s, 3H), 2.63 (t, 2H), 3.09 (s, 2H), 3.38 (t, 2H), 3.61 (t, 2H), 3.97 (s, 3H), 4.20 (t, 2H), 6.08 (s, 2H), 7.18 (d, 2H), 7.25 (m, 3H), 7.54 (d, 1H), 7.70 (t, 1H), 8.62 (m, 2H); Mass Spectrum: M+H+ 601/603.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=[CH:10][C:11]([OH:13])=O)=[O:8])[CH:2]=1.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=[CH:10][C:11]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:13])=[O:8])[CH:2]=1
Reactant: O=C(O)C=CC(=O)c1cccnc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1cccnc1

Procedure:
As for Example 27, 3-(3-pyridylcarbonyl)acrylic acid (0.01 mole) is reacted with N,N'-carbonyldiimidazole (0.011 mole) in tetrahydrofuran and to the mixture is added 0.011 mole of L-proline. The mixture is refluxed for 16 hours and the solvent removed under reduced pressure. The mixture is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo to yield 1-[3-(3-pyridylcarbonyl)acryloyl]-L-proline. The preceding compound is dissolved in carbon tetrachloride and 0.03 mole of thioacetic acid is added. The mixture is heated 3 hours and the solvent is removed in vacuo to give the product of the Example as a glass.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[OH:5].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:26])[CH3:25]>O.C(OCC)(=O)C>[OH:5][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(C(O)CN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2cccc(C(O)CNC(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step E (20 mmol) is dissolved in a mixture of water/ethyl acetate (25 ml/75 ml) cooled to 0° C. Potassium carbonate (60 mmol) is added, and then acetyl chloride (26 mmol) is added dropwise to the reaction mixture. The mixture is stirred vigorously for 30 minutes at ambient temperature. The two phases are separated and the organic phase is washed with 0.1M aqueous hydrochloric acid solution and then with water. After drying over magnesium sulphate, the organic phase is evaporated under reduced pressure. The residue obtained is recrystallised from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]1[C:35]([O:37][CH3:38])=[O:36].C(N(CC)C(C)C)(C)C.[F:48][C:49]([F:60])([F:59])[CH2:50]OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][CH2:50][C:49]([F:60])([F:59])[F:48])[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]1[C:35]([O:37][CH3:38])=[O:36]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2[N+](=O)[O-])N1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2NCC(F)(F)F)N1
Temperature: 130 °C

Procedure:
To a stirred solution of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (example 10, 1.56 g/2.92 mmol) and N,N-diisopropylethylamine (3.78 g/29.2 mmol) in toluene (50 ml) was added trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (6.78 g/29.2 mmol) at room temperature. The reaction mixture was refluxed at 130° C. for 1 day. The reaction was quenched with water and the separated organic layer was washed with sat.NaHCO3 and brine, dried over MgSO4, filtered and concentrated to afford a crude mixture. This crude was purified by column chromatography on silica gel (Hexane:EtC,Ac=2:1) to afford a pale yellow oil (1.34 g/75%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:29])[O:24][CH2:25][CH2:26][O:27][CH3:28].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][O:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Yield: 22.5 %

Procedure:
Analogously to Example 5, 2.0 g (12.4 mmol) of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine, 3.6 g (13.9 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate, 0.18 g of sodium iodide and 1.3 g of sodium carbonate are reacted in 30 ml of acetone. 1.07 g (22.5%) of the title compound of m.p. 107°-108° C. are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:21]=[C:20]4[C:19](=[CH:15][CH:14]=3)[N:18]([CH2:22][C:23]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: COc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 124 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 4-methoxybenzylamine to give the title compound (0.011 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 61 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 61% of theory; Rf value: 0.62 (silica gel; dichloromethane/methanol=19:1).