Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=O>O>[CH2:26]([O:25][C:23]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:27]
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOc1nc2ccc(CN(C)C=O)cc2c(=O)o1

Procedure:
To 6.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)-benzoic acid, there was added 30 mL of pyridine and then 11.1 mL of ethyl chloroformate was dropwise added to the mixture while ice-cooling the same. After the elapse of a night, 20 mL of water was dropwise added to the mixture to separate out a solid material, the solid was then isolated through filtration under reduced pressure and washed with 20 mL of water. Then the solid thus separated was dried under reduced pressure to give 3.97 g of the intended compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH3:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[BH4-].[Na+].C(OC(N1CCC[C@H]1C(O)=O)=O)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C@H:5]2[CH3:16]
Reactant: Cc1nc2ccccc2c2ccc(F)cc12
Agent: CC(C)COC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1Nc2ccccc2-c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 96 h
Yield: 151.9 %

Procedure:
To a stirred suspension of sodium borohydride (9.28 g, 0.245 mole) in anhydrous tetrahydrofuran (372 mL) kept under nitrogen at 0° C. was added dropwise a solution of (S)-N-isobutyloxycarbonylproline (160 g, 0.743 mole; prepared according to S. Atarashi et al., J. Heterocyclic Chem. 28, 329 (1991)) in anhydrous tetrahydrofuran (372 mL). After stimring the reaction mixture overnight at room temperature the solvent was removed to provide a solid foam (168 g). This material was dissolved in dichloromethane (272 mL), the solution was cooled to 0° C. and treated dropwise under nitrogen with a solution of 8-fluoro-6methylphenanthridine (17.3 g, 0.082 mole) in dichloromethane (100 mL). The progress of the reaction was monitored by NMR. After 4 days at room temperature conversion reached 50% . Additional solution of S-hydridotris[1-(2-methylpropyl) 1,2-pyrrolidinedicarboxylato-O2]borate(1-) (freshly prepared from 4.7 g of sodium borohydride and 81.6 g of (S)-N-isobutyloxycarbonylproline as described above) in dichloromethane (150 mL) was added dropwise at 0° C. After 7 days at room temperature the conversion reached 100% . The reaction mixture was cooled to 0° C. and 10% aqueous citric acid was added dropwise (200 mL). The mixture was allowed to reach room temperature (over 80 minutes) and then it was diluted with ethyl acetate (1.2 L). The organic layer was washed with 10% aqueous citric acid, followed by saturated aqueous potassium dihydrogenphosphate (2×200 mL). The organic layer was divided in 3 portions and each portion was washed sequentially with 1:1 (v/v) saturated aqueous sodium bicarbonate/ water (2×400 mL), water (1×400 mL), 1:1 (v/v) saturated aqueous sodium bicarbonate/ water (2×400 mL), water (1×400 mL), and brine (1×400 mL) to remove the (S)-N-isobutyloxycarbonyl proline. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to give 26.57 g of a brown oil which was immediately used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC
Yield: 84.9 %

Procedure:
3-Chloro-4-fluoroaniline (30.08 kg) in 8 L ethanol was heated at 40-50° C until a clear solution was obtained. Said solution was added to a 100 gallon glass-lined unit charged with 196 L ethanol. Diethyl ethoxymethylenemalonate (49.1 kg) was then added over an 80 minute period with stirring. The mixture was brought to reflux for one hour and then cooled to near 0° C. with stirring. Crystallization was initiated with seeding when the temperature had reached 27° C. during the cooling process. Stirring was continued for another hour, the solid product was filtered on a ceramic filter, and the filter cake was washed with 3×16 L cold (1°-5° C.) ethanol. The product was dried at 40° C. in vacuo for 19 hours to give 55.4 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate, m.p. 71.5°-72.5° C. (85% yield). The combined filtrate and washes were concentrated to 54 L and a second crop was isolated and dried as before to give 5.6 kg additional product, m.p. 71.5°-72.5° C. for a combined yield of 93.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][NH:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]([C:14]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)=[O:16])=[CH:12][NH:11][C:10](=[O:18])[NH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)N1
Temperature: 80 °C

Procedure:
The product of Step b above (258 mg, 1.09 mmol, 1 equiv) was combined with 5-aminoindazole (303 mg, 2.28 mmol, 1.2 equiv) and EDC (437 mg, 2.28 mmol, 1.2 equiv) in a round bottom flask. DMF (4.5 mL) was added, followed by DMAP (30 mg) and triethylamine (0.318 mL, 2.28 mmol, 1.2 equiv). The reaction mixture was heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into a separatory funnel containing ethyl acetate and water. The layers were separated, and the organic layer was washed with 1M HCl (2×), satd. NaHCO3 (1×), and satd. NaCl (1×). The organic extracts were dried over Na2SO4, filtered and concentrated to a yellow solid. One-fourth of the residue was further purified by reverse-phase HPLC (0-80% CH3CN/H2O/0.1% TFA over 10 minutes, retention time 6.26 min) to provide 9 mg of the product as a colorless solid. NMR 1H NMR (400 MHz, DMSO-D6) 5 ppm 12.92 (br s, 1H), 9.56 (s, 1H), 9.12 (dd, J=1.6, 5.9 Hz, 1H), 8.04 (t, J=1.3 Hz, 1H), 7.97 (s, 1H), 7.43 (d, J=1.3 Hz, 2H), 7.40 (d, J=5.8 Hz, 1H), 7.34 (m, 2H), 7.17 (t, J=9.1 Hz, 2H), 5.45 (d, J=3.1 Hz, 1H) MS m/z 352 [M+H]+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:17]([O:19][CH3:20])=[O:18].[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:28]=3)[C:5]=2[C:4]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(SC)cc(-c2ccc(C)cc2)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(C)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-p-tolyl-2H-pyran-3-carboxylate (290 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 334 mg (74%) of methyl 8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25]C(OC)=O)=[CH:20][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1.Cl>CO>[F:3][C:4]1[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[CH:20][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
1M Aqueous sodium hydroxide solution (4 ml, 4 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-7-hydroxy-6-methoxyquinazoline (820 mg, 2.2 mmol) in methanol (20 ml) and the mixture stirred for 1 hour at ambient temperature. Concentrated hydrochloric acid (0.8 ml) was added, the volatiles removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (60/40) to give 4-(2-fluoro-5-hydroxy4-methylanilino)-7-hydroxy-6-methoxyquinazoline (313 mg, 45%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].C(=O)([O-])[OH:16].[Na+].O>CS(C)=O>[CH:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:16]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (3.00 g, 11.6 mmol) in dimethyl sulfoxide (16 ml) was added sodium hydrogen carbonate (1.00 g, 13.6 mmol), and the mixture was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (870 mg, 39%) as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH:9]([CH3:12])[CH:8]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:7][C:6]1=[O:19])(=O)[CH2:2][CH3:3].[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].Cl>C(O)C>[CH2:20]([O:23][NH:24][C:1](=[C:5]1[C:10](=[O:11])[CH:9]([CH3:12])[CH:8]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:7][C:6]1=[O:19])[CH2:2][CH3:3])[CH:21]=[CH2:22]
Reactant: C=CCON
Reactant: CCSC(C)CC1CC(=O)C(C(=O)CC)C(=O)C1C
Agent: Cl
Solvent: CCO
Product: C=CCONC(CC)=C1C(=O)CC(CC(C)SCC)C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
Into 10 ml of ethanol, 2.8 g of 2-propionyl-5-(2-ethylthiopropyl)-4-methylcyclohexane-1,3-dione was dissolved and 1 g of allyloxyamine was dropped thereto at 0° C. and the resulting solution was stirred at room temperature for 3 hours. After pouring the reaction solution into ice-cold water and acidifying the mixture with hydrochloric acid, the mixture was extracted with chloroform. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate. The removal of chloroform by distillation under reduced pressure gave 2.9 g of the desired product as yellow oily material. Yield 86%, nD18.5 1.5389.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31]([N:23]([CH2:22][C:18]2[CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=3)[CH:21]=[CH:20][CH:19]=2)[CH3:24])=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)OC
Yield: 47.3 %

Procedure:
In a manner similar to Example 1(g), by reacting 500 mg (1.5 mmol) of methyl (S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate with 680 mg (3.1 mmol) of 4-biphenylcarboxylic acid chloride, 360 mg (47%) of the expected product are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:31]>CN1C(=O)CCC1>[NH2:31][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Reactant: N
Solvent: CN1CCCC1=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To a solution of (5-bromopyridin-3-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 43, 643 mg, 1.32 mmol) in NMP (1 mL) was added Cu2O (18.9 mg, 0.132 mmol) and 880 ammonia (6 mL) and the reaction heated to 80° C. in a Reactivial™ for 18 hours followed by an additional 18 hours at 90° C. The reaction was cooled and partitioned between water (15 mL) and EtOAc (20 mL). The aqueous layer was extracted twice with EtOAc (2×20 mL), the organic layers combined, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50:50 DCM:EtOAc to 80:20 EtOAc:MeOH to afford the title compound as a yellow gum (320 mg, 57%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[C:5](I)=[N:4]1)[CH3:2].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([N:24]2[C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[C:5]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([C:22](=[O:23])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)[CH2:25][CH2:26]3)=[N:4]1)[CH3:2]
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: CCn1nc(I)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C)c2)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
A 25 mL microwave pressure tube was charged 1-ethyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (105 mg, 0.363 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (137 mg, 0.363 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14.83 mg, 0.018 mmol), and sodium bicarbonate (61.0 mg, 0.726 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was sealed and heated at 120° C. for 40 minutes in a microwave reactor. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 50 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved with CH2Cl2/MeOH (4 mL/1 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc (Analogix Si SF15-24g cartridge), to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=413.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 1.41 (t, J=7.20 Hz, 3H), 2.31 (s, 3H), 3.21-3.29 (m, 2H), 3.85 (s, 2H), 4.23 (t, J=8.46 Hz, 2H), 4.32-4.40 (m, 2H), 7.07-7.14 (m, 3H), 7.21-7.28 (m, 1H), 7.44-7.46 (m, 1H), 7.51 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.24 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1.C(O)(C(F)(F)F)=O.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCOc1ccc(Br)cc1C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCOc1ccc(Cc2cc(C)c(O)c(C)c2)cc1C(C)C

Procedure:
Intermediate 2,6-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol was prepared from 3,5-dimethyl-4-hydroxy benzaldehyde and bromo-4-methoxymethoxy-3-iso-propylbenzene according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and transformed into the title compound according to the procedure described for the synthesis of compound 7-17, step b; (0.12 g, 85%); 1H NMR (300 MHz, CD3OD): δ 6.97 (s, 1 H), 6.83 (s, 2 H), 6.77 (d, J=7.5 Hz, 1 H), 6.65 (d, J=7.5 Hz, 1 H), 4.0 (d, J=9.9 Hz, 2 H), 3.75 (s, 2 H), 3.20-3.29 (m, 1 H), 2.28 (s, 6 H), 1.19 (d, J=6.6 Hz, 6 H); LC-MS m/z=363 [C20H25O6P−H]+; (94%) HPLC conditions: ODSAQ AQ-303-5 column; mobile phase=CH3OH: 0.05% TFA/H2O (7:3) flow rate=1.0 mL/min; detection=UV@254 nm retention time in min: 10.92; Anal Calcd for (C20H25O6P+1.2H2O): C, 59.12; H, 7.15. Found: C, 58.96; H, 6.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[C:23]4[CH2:22][C:21]([O:24]CC)=[CH:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 6B for the product of Example 1H.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]([C:13]#[N:14])([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)=[O:6]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1cccc(Br)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-bromobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=485, RT=0.75 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35]O[CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5].N1CCCC1>>[CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCOCC5)nc4)cc3)cc2C1=O
Solvent: C1CCNC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCCC5)nc4)cc3)cc2C1=O
Yield: 67 %

Procedure:
The compound of example 216 was prepared analogous to compound of example 212 by reaction of compound of example 211 with pyrrolidine.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][C:14](=[O:18])[N:15]([CH3:17])[N:16]=1.C1(O)C=CC=CC=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>CO>[OH:1][CH:2]([CH2:19][NH:30][CH:27]([CH3:29])[CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][C:14](=[O:18])[N:15]([CH3:17])[N:16]=1
Reactant: CN1N=C(c2ccccc2OCC2CO2)CCC1=O
Reactant: CC(C)N
Solvent: CO
Solvent: Oc1ccccc1
Product: CC(C)NCC(O)COc1ccccc1C1=NN(C)C(=O)CC1
Yield: 75 %

Procedure:
A mixture of 6-[2-(2,3-epoxypropoxy)phenyl]-2-methyl-4,5-dihydro-3(2H)-pyridazinone (1.05 g, 0.004 mole; prepared from the corresponding phenol by the method of Example 1 (b)(i), methanol (15 ml) and isopropylamine (2.1 ml, 0.024 mole) was heated under reflux for 90 minutes. The solution was evaporated under reduced pressure to give a viscous oil (1.43 g.), which was purified on a silica column by elution with a mixture of chloroform and methanol to give 6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-methyl-4,5-dihydro-3(2H)-pyridazinone (0.97 g, 75%, m.p. 82°-84° C). The hydrochloric crystallised from 2-propanol, had m.p. 170°-171° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[NH:3]1>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[CH:7][CH2:8]2)[NH:3]1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccccc1

Procedure:
2,2-dimethyl-7-methoxy-4-phenyl dihydroquinoline (contaminated with 2,2,4-trimethyl compound) [60 g] was hydrogenated with 10% Pd/C (1.4 g) in ethanol-acetic acid (200 ml). The reaction mixture was filtered through `Mgflo` and the solvent removed under reduced pressure to give the title compound slightly contaminated with the trimethyl isomer (5 g).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 81C. mp 150-152° C.; IR (KBr) cm−1: 3074, 3042, 1701, 1324, 1124, 1099; 400 MHz 1H NMR (DMSO-d6): δ 7.58-7.75 (m, 2H), 6.92-7.20 (m, 4H), 6.80 (t, 1H, J=7.5 Hz), 6.51 (d, 1H, J=8.5 Hz), 5.16 (s, 2H), 4.57 (s, 2H), 3.99 (s, 2H), 2.70 (t, 2H, J=7.5 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.80 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75. found: C, 63.54; H, 4.52.