Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].ClC1C([N+]([O-])=O)=C2C(C(=O)NC=N2)=CC=1.S(Cl)(Cl)=O.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39]>C(O)(C)C.CCCCCC.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([F:43])=[C:36]([Cl:35])[CH:37]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Agent: O=c1[nH]cnc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1Cl
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture (about 3:1, 52.0 g; described in Leonard et al., J. Org. Chem. 1975, 40, 356-363) of 7-chloro-6-nitro-3H-quinazolin-4-one and 7-chloro-8-nitro-3H-quinazolin-4-one and DMF (0.7 mL) were added to thionyl chloride (200 mL) and the mixture was heated under reflux for 4 hrs. The reaction mixture was concentrated to dryness and toluene (150 mL) was added. The mixture was concentrated further. This step was repeated twice and dichloromethane (280 mL) was added to the residue. The mixture was stirred at room temperature. To this suspension was added dropwise a solution (760 mL) of 3-chloro-4-fluoroaniline (36.9 g, 253.6 mmol) in isopropanol. Dichloromethane (300 mL) was added and the mixture was stirred, at 20° C. for 20 min. Hexane (600 mL) was added under ice-cooling, and stirring was continued at 20° C. The precipitate was collected by filtration, washed with hexane (200 mL×2) and dried under reduced pressure. The obtained solid was added to methanol (1 L)-water (120 mL), and triethylamine (30 mL) was added with stirring under ice-cooling. After stirring at room temperature for 1 hr, the precipitate was collected by filtration and washed with water (700 mL×2). The crudely purified substance (65 g) was suspension-washed with acetonitrile (1.2 L) with heating, and collected by filtration to give the objective (7-chloro-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (54.6 g, 67%). 2) Nitrogen was passed through a solution (70 mL) of (7-chloro-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (14.2 g. 40.1 mmol), 1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (4a) (10.0 g, 60.1 mmol), copper iodide (I) (380 mg), and tetrakis(triphenylphosphine)palladium (1.39 g) in DMF at 50° C. for 15 mm and triethylamine (13.9 mL, 100.0 mmol) was added and the mixture was stirred at an oil bath temperature of 140° C. for 50 mm. The reaction mixture was allowed to cool and concentrated. Aqueous sodium hydrogen carbonate (300 mL) was added, and the product was extracted with ethyl acetate (200 mL×2), dried and concentrated. The residue was subjected to silica gel column chromatography (chloroform-methanol; ethyl acetate-methanol) to give the objective nitro compound of (3-chloro-4-fluorophenyl)-{7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-nitro-4-quinazolinyl}amine (3a) (7.25 g, 37%).
Reaction SMILES: [C:1]([N:4](C)[NH:5][C:6](=[O:24])[CH:7](OCC1C=CC=CC=1)[C:8]([NH:10][N:11](C(O)=O)[CH3:12])=[O:9])(O)=O>[Pd].CO>[CH3:12][NH:11][NH:10][C:8](=[O:9])[CH2:7][C:6]([NH:5][NH:4][CH3:1])=[O:24]
Reactant: CN(NC(=O)C(OCc1ccccc1)C(=O)NN(C)C(=O)O)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CNNC(=O)CC(=O)NNC
Reaction time: 8 h

Procedure:
A flask was charged with crude N′1,N′3-dicarboxybenzyloxy-N′1,N′3-dimethylmalono-hydrazide from the step below, methanol, 10% palladium on carbon, put under an atmosphere of hydrogen, and stirred overnight. The suspension was filtered through celite and evaporated to dryness to give N′1,N′3-dimethylmalonohydrazide (2.4 g; 15 mmol)
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH3:4].[CH2:13](Br)[CH3:14]>C1(C)C=CC=CC=1>[CH2:3]([N:5]([CH2:13][CH3:14])[C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCNc1cccc(C)n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc(C)n1
Temperature: 93 °C
Reaction time: 1 h

Procedure:
To a 3000 ml dry toluene were added 185 g of 60% sodium hydride. A solution of 632 g of 6-ethylamino-2-picoline and 500 ml of toluene was dropwise added at 90° C. over about 2 hours to the resulting dispersion and stirred at 93° C. for additional one hour. Ethyl bromide of 554 g were dropwise added at 90° C. over about 2 hours to the resulting mixture and stirred for additional one hour. The reation mixture was added to 3000 ml of ice water. The organic phase was extracted and the extract was washed two times with water, concentrated and dried. The product obtained above was evaporated under reduced pressure (7 mmHg). Thus, 630 g of 6-diethylamino-2-picoline (bp7 103-108) were obtained.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][C:4]#[N:5].S(C)C>C1COCC1>[NH2:5][CH2:4][CH2:3][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:1])[CH3:6]
Reactant: CC(O)(CC#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: CC(O)(CCN)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.1 %

Procedure:
To a solution of 3-hydroxy-3-phenylbutanenitrile (1 g, 6.2 mmol) in THF (10 mL) was added dropwise BH3.Me2S (32 mL, 62 mmol) under a N2 atmosphere. The mixture was stirred at rt overnight. The reaction was quenched with MeOH (10 mL). The mixture was concentrated to give crude 4-amino-2-phenylbutan-2-ol (1.2 g, crude), which was used in the next step without further purification.
Reaction SMILES: CC([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=CC.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.P([O-])([O-])([O-])=O>CC(C)=O>[CH3:23][C@:22]12[CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH:11]=[C:12]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:14](=[O:24])[CH2:13]4)[C@@H:8]1[CH2:7][CH:6]=[CH:5]2
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC=C3CC(=O)CC[C@]3(C)[C@H]1CC2
Reaction time: 0.08 h
Yield: 104.8 %

Procedure:
This synthesis is depicted in FIG. 179. To a solution of alcohol 8 (545 mg, 2.0 mmol) in acetone (100 ml) at 0° C. under N2 was added rapidly Jones reagent (i, 1.5 ml, ca. 4 mmol). After 5 min., the mixture was poured into a dilute phosphate buffer (pH 7.2, 1200 ml) and extracted with ether. The extracts were washed with sat. aq. NaCl solution, dried (Na2SO4) and evaporated to give mainly Androsta-5,16-dien-3-one as an oil (567 mg). The crude product was dissolved in THF (7 ml) and reduced with lithium tris (1,2-dimethylpropyl) hydridoborate (c) at 0.55° as described for the preparation of 2. The crude product (530 mg) was chromatographed on silica gel (100 g) with CH2Cl2 /ethyl acetate 4:1 to give 280 mg (51) of pure a-alcohol 7 (eluted first) and 13 mg of 5 starting alcohol 8. A small sample of 7 was recrystallized from acetone/water at RT. M.p. 1380, [8 ]D -77.5° (c-1.2. -IR. (CDCl3): 3580m, 3430m, 1665w, 1590w, -1H-NMR. (360 MHz): 0.80 (s, 3 H); 1.06 (s, 3 H); 4.02 (m, w,8, 1 H); 5.44 (m, 1 H); 5.72 (m, 1 H); 5.86 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].Cl[CH:26]([F:28])[F:27].Cl>CO>[F:27][CH:26]([F:28])[O:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:19])[CH3:20])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: FC(F)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC(F)F)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 5 °C

Procedure:
Into a solution containing 1.25 g methyl 5-hydroxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinate and 1.40 g sodium methoxide in 50 mL absolute methanol at 50° C. is passed through a dispersion tube, chlorodifluoromethane for one hour. The mixture is cooled to 5° C. and the pH adjusted to 5 with 2N methanolic HCl. The solution is filtered and the filtrate concentrated in vacuo. The residue is extracted with 2×100 mL ether, the extracts combined, dried and concentrated. The residue is chromatographed on silica gel using ether as the eluant to give the product, analytically pure methyl 5-difluoromethoxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate as a white crystalline solid, mp 104°-105° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:47][NH2:48].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:48][OH:47])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)ON
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(methoxycarbonyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 43) (200 mg, 0.49 mmol) and N-methylmorpholine (59 μl, 0.54 mmol) in anhydrous dichloromethane (7 ml) was cooled to 0° C., treated with isobutyl chloroformate (70 μl, 0.54 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (175 μl, 1.47 mmol) was added and the mixture was for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with aqueous citric acid solution (10% w/v, 10 ml) and stirred for 2 hours. This mixture was then diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLC to afford the title compound as a foam (150 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:4]([OH:6])=[O:5].[C:14](#N)[CH3:15]>>[CH:8]1([CH2:7][C@@H:3]([N:2]2[CH2:15][C:14]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:5])[C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Reactant: CC#N
Agent: Cl
Product: O=C(O)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of (R)-(+)-α-aminocyclohexanepropionic acid hydrochloride (2.69 g; 15.7 mmol) and phthalic dicarboxaldehyde (2.50 g; 14.6 mmol) in acetonitrile (60 mL) was refluxed for 42 h under nitrogen. The mixture was allowed to cool to room temperature and further cooled to 0° C. The solid was filtered off and washed once with cold acetonitrile to give 2.65 g (63%) of (R)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C17H21NO3 (M+) 287.1521, found 287.1523.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].C[C:15](C)([O-:17])C.[K+].C(OCC)=O.O>C(OCC)C.O1CCCC1>[CH:15]([CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8]1=[O:13])=[O:17]
Reactant: CC(C)(C)[O-]
Reactant: COc1cccc2c1CCCC2=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC=O
Product: COc1cccc2c1CCC(C=O)C2=O
Reaction time: 0.25 h

Procedure:
To a solution of 5-methoxy-1-tetralone (10 g) in diethyl ether (100 ml) at 0° C. was added 1M potassium t-butoxide in tetrahydrofuran (68 ml) with stirring. After 15 minutes, ethyl formate (25 g) was added in one portion, and the reaction mixture allowed to rise to room temperature over a period of 45 minutes. The mixture was poured into water (500 ml), extracted with diethyl ether, the ether extract dried over magnesium sulfate, and solvent removed under reduced pressure to give 2-formyl-5-methoxy-1-tetralone (10.2 g), m.p. 67°-68° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
1-[2-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 313) (1.10 g) was suspended in a mixed solution composed of methanesulfonic acid (0.8 ml) and trifluoroacetic acid (10 ml), and the mixture was stirred at 70° C. for one hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate powder and was then extracted with chloroform. Next, the chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (700 mg, yield 83%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.[O:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]4([OH:40])[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: O=C1CCOCC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4(O)CCOCC4)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.53 mmol) and THF (10 mL) is added 1.56 M n-Bu-Li (1.03 mL, 1.61 mmol). After 30 minutes tetrahydro-pyran-4-one (0.21 mL, 2.29 mmol) is added over 5 minutes. The solution is stirred at −78° C. for 2 hours, warmed to ambient temperature, diluted with EtOAc (50 mL), washed with sat. NH4Cl (50 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-100% EtOAc/hexane gradient) furnish the title compound (0.38 g, 0.92 mmol, 60%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 1.91-2.00 (m, 2H), 2.11 (s, 3H), 2.20-2.30 (m, 2H), 2.46 (s, 3H), 2.51 (s, 3H), 3.30-3.39 (m, 1H), 3.83-3.98 (m, 5H), 6.66 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C23H31N3O2S (M+H)+: 414.3; found: 414.2.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Br:24])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:11].[C:25]([O-])(O)=O.[Na+]>CO>[Br:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Br:24])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:25])=[O:19])=[O:11]
Reactant: O=C(O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Added conc. H2SO4 (0.2 mL) to a solution of N-(3,4-dibromobenzoyl)-6-aminohexanoic acid (1.73 g, 4.4 mmol) in methanol (50 mL). Heated under reflux for 2 hours until reaction complete (as determined by TLC). Allowed solution to cool to room temperature and neutralized by adding NaHCO3 solution. Removed solvent in vacuo and extracted residue with ether (2×50 mL). Washed extract with brine (2×30 mL) and dried over anhydrous MgSO4. Filtered extract and dried filtrate under high vacuum to afford a white solid. Obtained 1.72 g (96% yield) of methyl N-(3,4-dibromobenzoyl)-6-aminohexanoate. 1H NMR (300 MHz, DMSO-d6): δ8.59 (triplet, J=5.7 Hz, 1H), 8.16 (doublet, J=1.8 Hz, 1H), 7.84 (doublet, J=8.1 Hz, 1H), 7.73 (doublet of doublets, J=8.1, 1.8 Hz, 1H), 3.55 (singlet, 3H), 3.21 (doublet of triplets, J=6.0, 6.6 Hz, 2H), 2.28 (triplet J=7.3 Hz, 2H), 1.51 (multiplet, 4H), 1.28 (multiplet, 2H). 13C NMR (300 MHz, DMSO-d6): δ173.55, 164.05, 135.67, 133.96, 132.31, 128.20, 127.09, 124.13, 51.19, 39.20, 33.21, 28.56, 25.89, 24.15.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>CCCCCC>[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Yield: 79.7 %

Procedure:
In a similar manner to that described in Refernce example 29(a), a reaction was carried out using 4-isopropylphenoxyacetic acid (14.1 g), oxalyl chloride (15.8 ml), (R)-4-benzyloxazolidine-2-one (11.7 g) and a solution of n-butyl lithium in hexane (1.61N, 45.0 ml) and the reaction mixture was treated to afford the desired compound (18.6 g) as colorless crystals.
Reaction SMILES: [N+](C1C=CC(OC(=O)[C:12](C)=[CH:13][C:14]2[CH:19]=[C:18](OC)[C:17](OC)=[CH:16][C:15]=2N)=CC=1)([O-])=O.C[N:28](C)C=O>>[C:14]1([CH2:13][CH2:12][NH2:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Product: NCCc1ccccc1

Procedure:
Into 30 ml of dimethylformamide, 0.72 g (2.0 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid p-nitrophenyl ester obtained above and 0.48 g (4.0 mmol) of 2-phenylethylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) were dissolved; and the mixture was reacted at room temperature for one night. The solvent was eliminated under a reduced pressure, and the residue was dissolved in ethyl acetate. After the resulting solution was washed and was dried with magnesium sulfate anhydride, the solvent was eliminated under a reduced pressure, whereby a crude product was obtained. This product was refined by an aminopropyl-modified type silica gel column chromatography (n-hexane/ethyl acetate=1/1), whereby 0.68 g of the aimed compound was obtained (yield: quantitative).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[CH3:20].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:20])=[C:4]2[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(CCc2ccccc2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(CCc1ccccc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1,2-dimethyl-3-(2-phenyl-ethyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(NC1C=C(C2C=CC(C=C)=CC=2)NN=1)=O.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[C:35]([NH:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH:50]=[CH2:51])=[CH:45][CH:44]=2)[NH:40][N:39]=1)=[O:36]>>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[C:35]([NH:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH3:51])=[CH:45][CH:44]=2)[NH:40][N:39]=1)=[O:36]
Reactant: C=CCc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Agent: C=Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Product: CCCc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1

Procedure:
The title compound was prepared in the same manner as that described in Example 38 except that 3-(2-indanyl)carbonylamino-5-(4-vinylphenyl)pyrazole used in Example 38 was replaced with 3-(2-indanyl)carbonylamino-5-{4-(2-propenyl)phenyl}pyrazole.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:8][N:7]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:8][N+:7]=1[O-:27])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCCOc1ccc(COC(C)=O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(COC(C)=O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.74 g of the crude product from example 25A is dissolved in 3.4 ml of dry dichloromethane, and 0.74 g (3.21 mmol) of meta-chloroperbenzoic acid is added a little at a time. The reaction mixture is stirred at RT for 8 h, and 2 ml of saturated aqueous sodium bicarbonate solution are then added. With stirring, more sodium bicarbonate powder (about 0.4 g) is added until the evolution of gas has ceased. The aqueous phase is extracted twice with in each case 5 ml of dichloromethane, and the combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product that remains is used directly for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(OCC)(=O)C>C(O)C.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cn2ncc3c([N+](=O)[O-])cccc32)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc3c(N)cccc32)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A suspension of 1-(4-methoxybenzyl)-4-nitro-1H-indazole (9 g, 31.77 mmol) and platinum(IV) oxide (0.433 g, 1.91 mmol) in ethanol (150 mL)/ethyl acetate (10 mL) was hydrogenated under 40 psi at 25° C. for 2 hours. The resulting mixture was filtered and the filtrate was concentrated to dryness to afford 1-(4-methoxybenzyl)-1H-indazol-4-amine (8.03 g, 100%) as a yellow-orange solid. Mass spectrum: MH+ 254.
Reaction SMILES: COC1C=CC([NH:9][C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:13]=[C:12]([C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)=CC=1.[Cl:28]N1C(C)(C)C(=O)N(Cl)C1=O.S(=O)(=O)(O)O.C(Cl)Cl>C(#N)C.O>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:13]=[C:12]([C:24]([O:26][CH3:27])=[O:25])[C:11]=1[Cl:28]
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl

Procedure:
In a typical reaction accomplishing both chlorination and deprotection, methyl 4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate is reacted with about two equivalents of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence of a 1 M (molar) solution of sulfuric acid in a mixture of acetonitrile/water. The mixture is heated at reflux until the reaction is complete. The mixture is added to methylene chloride and the organic layer is separated, washed with brine and dried. The solvent is evaporated to provide crude methyl 4-amino-5-fluoro-3-chloro-6-(4-chlorophenyl)picolinate.