Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18]C)=[O:16])=O.[BH4-].[K+]>CO.O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[C:15](=[O:16])[O:17][CH2:18][CH:3]1[CH2:12][CH2:11]2
Reactant: CCOC(=O)N1c2ccc(OC)cc2CCC1C=O
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC1COC(=O)N21
Reaction time: 1 h

Procedure:
To a solution of 10.9 g (41.4 mmol) of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate in 100 ml of methanol, cooled to 0° C., are added portionwise 2.2 g (41.4 mmol) of potassium borohydride. The medium is stirred for 1 h and then hydrolyzed, diluted with water and extracted with diethyl ether. The organic phase is then washed with water and dried over sodium sulphate, and the solvent is evaporated off under reduced pressure. The oil obtained is redissolved in 90 ml of toluene, the solution is heated to reflux in order to remove traces of water, and a catalytic amount of 10% sodium methoxide in methanol is then added at 90° C. The mixture is again heated to reflux in order to remove the ethanol formed, followed by evaporation of the solvent. The residue is taken up in ethyl acetate and washed with water, then the organic phase is dried over sodium sulphate and concentrated under reduced pressure. After chromatography on a column of silica with a 4/1 mixture of heptane and ethyl acetate, 5.0 g of product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Cl)[CH2:12]Cl>C(O)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCl
Reactant: Nc1cccnc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1ncccc1N
Yield: 130.5 %

Procedure:
3-Amino-2-picolinic acid (4.14 g) was suspended in ethanol (100 ml) at room temperature with stirring. DMAP (3.7 g) was added and the reaction was stirred for 1 hour at room temperature. A further equivalent of DMAP (3.7 g) was added and the suspension disappeared, and then EDC (5.80 g) was added and the reaction was stirred at room temperature for 17 hours. The ethanol was evaporated to give a dark oil, water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulphate. Evaporation of the solvent gave ethyl 3-amino-2-picolinate as a solid (6.5 g), mixed in a 2:1 ratio with DMAP.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)[CH:12]=[CH:11][N+:10]=2[O-])=[CH:5][CH:4]=1.C(O)(C)C>[Pd].C1CCCCC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)cc[n+]2[O-])cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CC(C)O
Product: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)ccn2)cc1
Temperature: 85 °C

Procedure:
A mixture of 7-({2-[(4-methoxybenzyl)amino]-1-oxidopyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (21.1 g, 0.0502 mol), cyclohexene (100 mL, 0.9 mol) and Pd (10% on Carbon, 4.5 g) in isopropyl alcohol (400 mL, 5 mol) was heated at 85° C. overnight. Additional catalyst (2.5 g) and cyclohexene (30 mL) were added. The mixture was heated at 90° C. overnight and then filtered. The filtrate was concentrated to give 7-({2-[(4-methoxybenzyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid which was used in the next step without purification. LCMS ES+ 405.7
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=2)[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.CC(C)(C)CC=O.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:24]1[CH:23]=[C:22]([N:15]([CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CCC(C)(C)C)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CC(C)(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)Nc1cccc(N(CCC(C)(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, 3,3-dimethylbutyraldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C@@H:1]1[CH2:2][C@H:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=Cc1ccccn1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccn1

Procedure:
A solution of 2-vinylpyridine (2 g, 19.02 mmol) in toluene (40 mL) was treated with ethyl diazoacetate (1.973 ml, 19.02 mmol) and stirred at reflux overnight. The mixture was concentrated in vacuo and the residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to elute peak 1 (A-1-trans) (1.6 g, 44%), then the solvent gradient was increased to 100% EtOAc to elute peak 2 (A-2-cis). (914 mg, 25%), both as yellow oils. Enantiomers of A-1-trans can be resolved by chiral preparative supercritical fluid chromatography (SFC) (3.0 cm i.d.×25 cm ChiralTech IC, 7% EtOH/CO2, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d.×25 cm ChiralTech IC, 7% EtOH/CO2, 2.4 mL/min) ent1=3.6 min, ent2=4.1 min to give the title compound. 1H NMR δ (500 MHz, CDCl3): 8.44 (m, 1H), 7.56 (td, J=7.6, 1.7 Hz, 1H), 7.22 (dd, J=7.8, 1.0 Hz, 1H), 7.08 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 2.58 (ddd, J=10.0, 6.1, 3.9 Hz, 1H), 2.25 (ddd, J=9.5, 5.6, 3.9 Hz, 1H), 1.61, (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LRMS (ES) calculated M+H for C11H13NO2S: 192.2. Found: 192.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:14][CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-3-hydroxypyridine (1.90 g, 10.92 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.52 g of an 80% dispersion in mineral oil, 17.47 mmol) in DMF (14 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added dropwise over 5 min 1-choro-3-iodopropane (2.68 g, 13.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water (30 mL) was carefully added, followed by saturated NaCl solution (20 mL). The resulting mixture was extracted with ether (5×25 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (4.07 g). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[N:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[NH:10][N:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nn(S(=O)(=O)c2ccc(C)cc2)c2nccc(-c3ccsc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(F)ccc1-c1n[nH]c2nccc(-c3ccsc3)c12
Temperature: 60 °C

Procedure:
To a stirred solution of 3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine 27 (50 mg 0.102 mmol) in methanol (10 mL) and water (5 mL) was added potassium carbonate (0.204 mmol) and the RM was heated to 60° C. overnight. After completion of the SM the solvents was completely distilled off, diluted with water and extracted with chloroform twice. The organic layer was dried over sodium sulphate. The crude product was passed through 100-200 mesh silica gel eluting the pre compound at 28-30% ethyl acetate in hexane as eluent to get the pale yellow colored solid of compound 3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 28. 1H NMR (CDCl3) δ: 8.56(d,1H), 7.44(m,1H), 7.23(m,1H), 7.16(m,1H), 7.02(m,1H), 6.95(m,1H), 6.73(m,1H), 6.34(m,1H) and MS m/z=325.8.
Reaction SMILES: O1CCCC1.[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])[CH2:7][CH2:8][CH3:9].CCCCCC.[Br:23]Br>C(OCC)(=O)C.O>[C:11]1([C:6](=[O:10])[CH:7]([Br:23])[CH2:8][CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: CCCC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(Br)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (20 mL) of 9.917 g (67.0 mmol) of butyrophenone, a hexane solution (10 mL) of 11.78 g (1.1 equivalents) of bromine was gradually added at 5° C. The temperature was elevated to 15° C., and the solution was stirred for 1 hour. To the solution, 20 mL of water and 40 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a saturated sodium hydrogen carbonate solution three times, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. 1-Phenyl-2-bromo-1-butanone was obtained as a light peach-colored oily substance (23.94 g, crude yield: 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CC(CCC1C=CC=CC=1)CO.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: CC(CO)CCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a mixture of 302 mg (purity: 100%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 826 mg (5.48 mmol) of 2-cyclopropyl-6-methylphenol were added 2-methyl-4-phenylbutanol (2.76 g) and 330 mg (5.60 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 332 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 66%) and 3.6 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[C:22]([O:29]C)[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:20]2[NH:21][C:22](=[O:29])[C:23]([N:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N(C)C
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(dimethylamino)-6-methoxypyridin-2-yl]ethenyl}pyrrolidin-2-one (41 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) and crystallized from chloroform-ethyl acetate to give the title compound as a light yellow powder (11 mg, 26% (two steps)).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].COC1C=C(O)C=CC=1O.[CH2:17]([NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH2:17]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:18][CH3:19]
Reactant: C=CC(=O)OC
Reactant: CCCNCCC
Agent: COc1cc(O)ccc1O
Solvent: CO
Product: CCCN(CCC)CCC(=O)OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Methanol (128 g; 4 moles) was added to 344 g (4 moles) of methyl acrylate containing 500 ppm of methoxyhydroquinone and 404 g (4 moles) of dipropylamine were added dropwise thereinto while placed in a water bath and stirred for a period of 30 minutes. After completion of the addition, the temperature of the liquid was raised to 70° C. and the reaction was carried out for three hours. After completion of the reaction, methanol was removed by distillation to give 746 grams of methyl beta-dipropylaminopropionate with a purity of 99%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(C1C=NC(N2CCC(OC3SC4C=C(C5CCNCC=5)C=CC=4N=3)CC2)=NC=1)CC>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)cn1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)cn1

Procedure:
Compound 50C was prepared from Compound 50B and TFA in a similar manner to the procedure described for Compound 1E in Example 1. LCMS (m/z)=408 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[CH:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]2[CH3:27])[CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]2[CH3:27])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1C(=O)c2c(c(OC)c(F)c(F)c2[N+](=O)[O-])N(C2CC2)C1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(C)n(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 15.9 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydro-8-methoxy-2-methyl-5-nitro-4-oxoquinoline-3-carboxylate (1.42 g, 3.69 mmol) and manganese dioxide (16.1 g, 185 mmol) in CH2Cl2 (80 mL) was stirred at room temperature for 36 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 5:1→1:1) to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-5-nitro-4-oxoquinoline-3-carboxylate (225 mg, 16%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:37](Cl)(=[O:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:37](=[O:39])[CH3:38])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCOCC4)c23)ccc1OCc1ccccn1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCOCC1
Yield: 68 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(tetrahydro-2H-pyran-4-ylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 68% yield; NMR spectrum (DMSO-d6) 1.49-1.71 (m, 2H), 1.75-1.98 (m, 2H), 2.11 (s, 3H), 3.36-3.45 (m, 2H), 3.78-3.96 (m, 5H), 4.26-4.46 (m, 2H), 5.31 (s, 2H), 7.22 (d, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.35-7.40 (m, 1H), 7.56-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 7.99-8.03 (m, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.98 (s, 1H); Mass spectrum MH+ 548.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:19][NH2:20]>ClCCl.CO>[CH3:19][NH:20][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Reaction time: 0.03 h

Procedure:
To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL), and the reaction mixture was stirred for 2 minutes after precipitation was complete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL), and the solution was extracted with dichloromethane (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCBr
Reactant: Nc1ccccc1Cc1ccccc1
Product: O=C(CCCBr)Nc1ccccc1Cc1ccccc1

Procedure:
2-benzylaniline and 4-bromobutyryl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([O:13]C)=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.O[Li].O>C1COCC1.CO.O.O>[Br:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: COC(=O)C1CCCc2nc(Br)sc21
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCc2nc(Br)sc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (150 mg, 0.54 mmol) and LiOH.H2O (34 mg, 0.81 mmol) in THF/MeOH/H2O (5 mL, 3:1:1) was stirred at RT for 90 min. The mixture was diluted with H2O and extracted with DCM. The aq. layer was acidified to pH=3 and extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:7]=1.[C:21]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:20])[O:19][CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:8]2=[O:18]
Reactant: COc1ccccc1CC(=O)c1cc(Cl)c(O)cc1O
Reactant: Cc1cc(C)c(Cl)c(C)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
BF3—OEt2 complex (7 ml, 56 mmol) was gradually added to a solution of 1-(5-chloro-2,4-dihydroxy-phenyl)-2-(2-methoxy-phenyl)-ethanone (4.1 gm, 14 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (1.5 ml, 42 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 6-chloro-7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (2.5 gm, 60%) as white solid.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].[NH2:25]/[C:26](/[CH3:35])=[CH:27]\[C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29]>CC(O)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH:17]2[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:1]([CH3:2])[NH:25][C:26]([CH3:35])=[C:27]2[C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
193 mg (0.568 mmol) of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propene-1-yl)acrylamide and 87.6 mg (0.568 mmol) of 2-cyanoethyl 3-aminocrotonate were heated at 70° C. under stirring in 2.8 ml of 2-propanol overnight. 2-Propanol was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[S:16][CH3:17])[C:11]#[N:12].O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[S:16][CH3:17])[CH2:11][NH2:12]
Reactant: CSc1ccc(C#N)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(CN)cc1C
Temperature: 25 °C

Procedure:
A solution of lithium aluminium hydride (1.0 M in THF, 18.4 mL, 18.4 mmol) is cooled in an ice bath and treated slowly with a solution of 3-methyl-4-methylsulfanyl-benzonitrile (preparation 66a, 1.0 g, 6.1 mmol) in THF (10 mL) while the temperature is kept below 5° C. The mixture is allowed to warm to room temperature and stirred over night. The mixture is cooled again at 0° C., and water (2 mL) and aqueous sodium hydroxide (4 M, 2 mL) is added. The mixture is filtered and the filtrate is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure. Yield: 923 mg (90% of theory); ESI mass spectrum: [M+H−NH3]+=151; r.t. HPLC: 0.61 min (X011_S03).
Reaction SMILES: [Br-].[Na+].[C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:16]O>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OO
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 72.3 %

Procedure:
The procedure of Example I was repeated, but this time cobalt (II) acetate tetrahydrate (0.008 moles), sodium bromide (0.04 moles), diphenylmethane (0.055 moles) and hydrogen peroxide (35%, 0.28 moles) were used. The final reaction mixture, analysed by HPLC, revealed that 91.5% of the diphenylmethane had been consumed, yielding products including benzophenone (72.3% yield).