Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.N1CCCCC1.CS([C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1)(=O)=O.Cl>O.N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[C:18]1[CH:25]=[CH:24][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccccc1
Temperature: 25 °C
Yield: 154 %

Procedure:
Combine 312 g (2.99 mole) of malonic acid, 506 mL of pyridine, 30 mL of piperidine and 300 g (1.49 mole) of p-methylsulfonyl-benzaldehyde and heat the mixture to 95°-100° C. for 4 h. Cool the mixture to room temperature and slowly pour into 3 L of a mixture of HCl, water and ice. Collect the resulting precipitate by filtration and dry the solid to give 340 g (83% yield) of the E-cinnamic acid derivative, m.p.=294°-296° C. 1H NMR (DMSO-d6, ppm): 7.96 (s, 4H); 7.78 (d, J=16 Hz, 1H); 6.71 (d, J=16 Hz, 1H); 3.5 (hr. s, 1H); 3.25 (s, 3H). ##STR15##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:39][C:40]([F:42])=[CH2:41]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][C:40]([F:42])=[CH2:39])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(F)CCl
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(F)CN1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1
Reaction time: 20 h
Yield: 46.9 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090 mmol) in THF (1 mL) was added under an atmosphere of nitrogen potassium bis(trimethylsilyl)amide (0.885 M in THF, 132 μL, 0.116 mmol). After stirring for 15 min at ambient temperature 3-chloro-2-fluoroprop-1-ene (13 mg, 0.13 mmol) was added and the reaction mixture was stirred for 20 h at this temperature. It was diluted with ethyl acetate (10 mL) and washed with an aqueous solution of sodium carbonate (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, ethyl acetate:(ethyl acetate:triethylamine=95:5):methanol=100:0:0 to 0:90:10) afforded the title compound (26 mg, 47%) as a light brown foam. MS m/e: 616.4 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[O:14]=[C:15]1[C@@H:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][CH2:17][O:16]1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]([C@@H:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:17][OH:16])=[O:14]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOC1=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (7.11 g) in anhydrous DCM (40 ml) under N2 at 0° C. was treated dropwise with trimethylaluminium (2N in heptane; 15 ml). The mixture was allowed to stir for 30 min before a solution of tert-butyl (3S)-2-oxotetrahydrofuran-3-ylcarbamate (5.03 g), in anhydrous DCM (35 ml), was added dropwise. The reaction was allowed to warm up to ambient temperature and stirred for 18 h, before quenching with 10% aqueous citric acid acid (10 ml) Saturated aqueous potassium sodium tartrate (100 ml) was then added with stirring followed by separation of the organic and aqueous layers. The organic layer was dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:2) to afford an off-white solid which was an inseparable mixture (c. 1:2) of the starting material and the title compound (5.55 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[OH-].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
Dimethyl sulfoxide (50 g) was added to about 60% toluene solution of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine (20 g) which had been obtained separately, and potassium iodide (5.32 g) and a solid of 85% potassium hydroxide (14.1 g) were added thereto. After the slurry solution was heated to 70° C., benzyl chloride (17.58 g) was dropped for 5 hours. Subsequently, after the solution was stirred for 16 hours, a conversion rate (*) reached 98%. After the reaction finished, the solution was cooled to 20° C., and toluene and 30% aqueous solution of sodium thiosulfate were added and an aqueous layer was removed, followed by washing an organic layer with water. The resultant organic layer was concentrated under reduced pressure, thereby obtaining toluene solution of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine (yield: 98%). (*) Conversion rate (%)=(amount of production of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine g))/[(amount of production of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine g))+(residual amount of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine(g))]
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>OP(O)(O)=O>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:17][C:18](=[O:19])[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=P(O)(O)O
Product: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Temperature: 85 °C

Procedure:
A mixture of resorcinol (20 g), ethyl benzoylacetate (23.8 mL) and O-phosphoric acid (130 mL) was heated at 85° C. (care!) for 1 hr. The solution was cooled, poured onto H2O, extracted 3×EtOAc/THF, washed twice with H2O, and then twice with brine. The organic phase was dried and evaporated. Trituration with Et2O followed by filtration afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[CH:9]=O)[C:2]#[C:3][CH3:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[C:2]#[C:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC#CCOc1cc(C=O)ccc1OC(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC#CCOc1cc(/C=C/C(=O)O)ccc1OC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 2.2 mmol) and malonic acid (0.34 g, 3.3 mmol) in a mixture of piperidine (0.2 mL) and pyridine (5.0 mL) was heated to 120° C. and stirred for 16 h. The mixture was cooled to rt and acidified with 1 M HCl. The crude product was collected by filtration and recrystallised from acetonitrile to give (E)-3-(3-(but-2-ynyloxy)-4-difluoromethoxyphenyl)-2-propenoic acid (0.38 g, 61%) as a colourless crystalline solid; mp 206-208° C.; δH (500 MHz, DMSO-d6) 1.84 (t, J=2.2 Hz, 3H, C≡CH3), 4.87 (q, J=2.2 Hz, 2H, OCH2), 6.55 (d, J=16.0 Hz, 1H, CH═CHCO2H), 7.13 (t, J=72.0 Hz, 1H, CHF2), 7.19 (d, J5,6=8.0 Hz, 1H, H5), 7.30 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.52 (d, J2,6=2.0 Hz, 1H, H2), 7.54 (d, J=16.0 Hz, 1H, CH═CHCO2H), 12.41 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 3.1, 56.8, 74.1, 84.1, 113.6, 116.4 (t, J=256 Hz), 119.7, 120.6, 122.0, 132.4, 141.2, 142.9, 148.6, 167.4; νmax 1011, 1113, 1267, 1516, 1629, 1686, 2578, 2924 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9](OC2C=CC(F)=CC=2F)[C:8]([C:20]([C:22]2[CH:27]=[C:26]([S:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Cl:30])=O)=[CH:7][N:6]=1.[NH2:36][NH2:37]>O1CCOCC1.CCO>[Cl:30][C:23]1[CH:24]=[CH:25][C:26]([S:28][CH3:29])=[CH:27][C:22]=1[C:20]1[C:8]2[C:9](=[N:10][C:5]([O:4][C:3]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:2]=3[F:1])=[N:6][CH:7]=2)[NH:37][N:36]=1
Reactant: NN
Reactant: CSc1ccc(Cl)c(C(=O)c2cnc(Oc3ccc(F)cc3F)nc2Oc2ccc(F)cc2F)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CSc1ccc(Cl)c(-c2n[nH]c3nc(Oc4ccc(F)cc4F)ncc23)c1
Temperature: 25 °C
Yield: 7.7 %

Procedure:
To a solution of [2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-(2-chloro-5-methylsulfanyl-phenyl)-methanone (3.0 g, 5.76 mmol) in 10 mL of dioxane/EtOH (10:1) was added hydrazine (0.19 mL, 5.76 mmol) The resulting mixture was heated to reflux for 24 hours, then cooled to room temperature. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, washed twice with 1N aqueous HCl and once with wtisaturated brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 5-20%) to give 180 mg of 3-(2-chloro-5-methylsulfanyl-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine, MS (M+H)=405.
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[F:16].NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42](C3C=CC(F)=CC=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:12]3[CH:13]=[CH:14][C:15]([F:16])=[C:10]([F:9])[CH:11]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2ccc(F)c(F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3,4-difluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3,4-difluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.035 g), and the mixture was stirred at room temperature overnight. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.043 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1Br.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>C1C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:16][CH:15]=[CH2:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=CCc1ccc(OC)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To an ambient temperature solution of 2-Bromo-5-methoxy-benzoic acid methyl ester (750 mg, 3.02 mmol) in benzene (2 mL) are added allyltri-n-butyl tin (1.16 mL, 3.73 mmol) and tetrakis(triphenylphosphine)palladium (0) (174 mg, 0.157 mmol, 5 mol %). The reaction mixture is heated in a sealed tube to 100° C. After 3 h, the reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 10% EtOAc/Hex) to yield the title compound (451 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.00 (dd, 1H, J=8.6, 2.9 Hz), 6.04-5.93 (m, 1H), 5.03-4.94 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70-3.65 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CCNC2=O
Temperature: 150 °C

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.56 g, 9.45 mmol) was deposited in a sealed vessel with 25 mL 33% dimethylamine in ethanol. This was heated at 150° C. for 7 hours. The resulting solution was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with ethyl acetate) to yield 6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (787 mg, 4.14 mmol). MS (ESI) 191.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl.[OH-].[Na+]>CCO>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: Cc1ccc(NN)cc1I
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1I
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A solution of the above phenylhydrazine (5.08 g, 22 mmol) and 4,4-dimethyl-3-oxopentanenitrile (3.06 g, 1.1 equiv.) in EtOH (100 mL) containing conc. HCl (3 mL) was refluxed for 17 h, then cooled to room temperature. The pH was adjusted to 14 with 40% aqueous sodium hydroxide solution. The aqueous mixture was extracted with EtOAc, (3×50 mL), dried (MgSO4), and concentrated to give 5-tert-butyl-2-(3-iodo-4-methyl-phenyl)-2H-pyrazol-3-ylamine (6.3 g, 86%). This material was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1/[CH:12]=[CH:13]/[C:14](/[CH3:44])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:43])=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[C:23](\[CH3:42])/[CH:24]=[CH:25]/[CH:26]=[C:27](\[CH3:41])/[CH:28]=[CH:29]/[C:30]1[C:36]([CH3:38])([CH3:37])[CH2:35][C@H:34]([OH:39])[C:32](=[O:33])[C:31]=1[CH3:40]>CCCCCCC>[CH3:40][C:31]1[C:32](=[O:33])[C@H:34]([OH:39])[CH2:35][C:36]([CH3:37])([CH3:38])[C:30]=1/[CH:29]=[CH:28]/[C:27](/[CH3:41])=[CH:26]/[CH:25]=[CH:24]/[C:23](/[CH3:42])=[CH:22]/[CH:21]=[CH:20]/[CH:19]=[C:18](\[CH3:43])/[CH:17]=[CH:16]/[CH:15]=[C:14](\[CH3:44])/[CH:13]=[CH:12]/[C:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][C@H:6]([OH:9])[C:7](=[O:8])[C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Solvent: CCCCCCC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@@H](O)C1=O
Yield: 92.5 %

Procedure:
A total of 40 preparative injections were processed using 84 L of mobile phase. Thirty-six (36) L of effluent were collected among the five fractions. The preparative system was flushed with 100 mL of methylene chloride approximately every 6–8 injections or whenever the chromatographic separation deteriorated due to effects from mixing with mobile phase in the pump heads during the injection process. Purified materials were recovered by removing the solvents in a rotary evaporator protected from light to afford 25.4 g of 3R, 3′R ester, 47.8 g of meso-(3R, 3′S) ester, and 24.9 g of 3S, 3′S ester. The purified astaxanthin dicamphanate esters were saponified to afford 8.5 g (79.8% purity by HPLC) of 3R, 3′R-astaxanthin, 18.2 g (90.1% purity by HPLC) of meso-astaxanthin, and 9.4 g (82.0% purity by HPLC) of 3S, 3′S-astaxanthin. The major impurities of the saponification reaction were the 13- and 9-cis isomers of astaxanthin, identified by HPLC. The cis-isomers were thermally isomerized to all-trans by refluxing in heptane to afford 8.5 g (87.3% purity by HPLC) of 3R, 3′R-astaxanthin, 18.2 g (92.5% purity by HPLC) of meso-astaxanthin, and 9.4 g (86.8% purity by HPLC) of 3S, 3′S-astaxanthin.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1ccc2[nH]c(C)cc(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nc(C)cc(Cl)c2c1
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of 2,6-dimethyl-1H-quinolin-4-one (17.3 g, 100 mmol) and phosphorus oxychloride (30 mL) was heated at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was poured onto ice. The resulting solution was carefully alkalinized to pH 8–9 with 0.5 N NaOH and saturated Na2CO3. The solution was extracted with CH2Cl2 (200 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in n-hexane) to give 4-chloro-2,6-dimethyl-quinoline (12.4 g, 65% yield).
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butylthio-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([OH:10])=[O:9].C1(C)C=CC=CC=1>CO>[CH3:1][O:9][C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyldiazomethane (2 M solution in hexane, 1.5 ml) was added dropwise to a mixed solution of tert-butyl 2-carboxymethylpyrrolidine-1-carboxylate (CAS No. 194154-91-1, 500 mg) in methanol (1 ml)-toluene (1 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for three hours. The reaction solution was concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 506 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.BrC1C=C(C=CC=1)N>>[C:21]1([NH:20][C:14]([C:12]2[S:13][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[C:10]([NH2:17])[CH:11]=2)=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Reactant: Nc1ccccc1
Solvent: Nc1cccc(Br)c1
Product: Nc1cc(C(=O)Nc2ccccc2)sc1Sc1ccc(O)cc1

Procedure:
The product from Example 351C was reacted with aniline according to the procedure of Example 351D substituting aniline for 3-bromoaniline followed by reduction of the nitro group according to the procedure from Example 351E to provide the title product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[CH:22]=[C:23]([CH3:37])[C:24]([C:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH:28]=2)=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>[O:31]1[C:30]2([CH2:35][CH2:36][C:27]([C:24]3[N:25]=[CH:26][C:21]([NH:19][C:17]([C:3]4[CH:4]=[N:5][N:6]([C:7]5[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=5)[C:2]=4[CH3:1])=[O:18])=[CH:22][C:23]=3[CH3:37])=[CH:28][CH2:29]2)[O:34][CH2:33][CH2:32]1
Reactant: Cc1cc(Br)cnc1C1=CCC2(CC1)OCCO2
Reactant: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCC2(CC1)OCCO2
Temperature: 110 °C
Yield: 85.9 %

Procedure:
A suspension of 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (538 mg), 5-bromo-2-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)-3-methylpyridine (620 mg) described in Reference Example 105, tris(dibenzylideneacetone)dipalladium (0) (18 mg), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropylbiphenyl (48 mg), trisodium phosphate (509 mg) and tert-butanol (10 ml) was stirred at 110° C. After the reaction, the reaction solution was left stand, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (chloroform/methanol) to give N-[6-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)-5-methylpyridin-3-yl]-5-methyl-1-[4-(trifluoromethyl)-phenyl]-1H-pyrazole-4-carboxamide (856 mg) as a pale yellow solid.