Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.S(O)(O)(=O)=O.[NH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1.C(N(CC)CC)C.[BH4-].[Na+]>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1
Reactant: Nc1ncc[nH]1
Reactant: O=Cc1cccc(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cccc(CNc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of 3-chlorobenzaldehyde (0.16 ml, 1.4 mmol) in dichloromethane (10 ml) were added sequentially 2-aminoimidazole sulfate (0.19 g, 0.7 mmol), tetraisopropyl orthotitanate (0.51 ml, 1.7 mmol) and triethylamine (0.19 ml, 1.4 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was taken up in ethanol (5 ml) and then sodium borohydride (54 mg, 1.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then quenched by the addition of water. After stirring for a further 15 minutes at room temperature, the reaction mixture was filtered and the filter cake washed with ethanol. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (eluant:methanol/dichloromethane 0:100 to 10:90) to yield the title compound as an off-white solid (87 mg, 30%); MS (ISP): 208.7 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.S(=O)(=O)(O)O>CC(=O)CC.O>[C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Temperature: -6 °C

Procedure:
L-aspartic acid, 133.1 parts, was slurried with 375 parts by volume of water and 81.5 parts 98.2% sodium hydroxide were added with cooling and stirring, the temperature being kept below 35° C. After all solid had dissolved, 50 parts by volume of 2-butanone were added and the mixture was cooled to -6° C. Diketene, 88 parts, was then added gradually over a period of 30-40 minutes with good stirring, with the temperature being maintained at from about -6° to -4° C. The mixture was then stirred for an additional 30-45 minutes without cooling. The pH of the reaction mixture initially was about pH 11.5 but fell to about pH 9 or less at the end of the reaction period. To the reaction mixture was then added 61 parts by volume of concentrated sulfuric acid with constant stirring but without cooling. The resulting mixture having a pH from about 1.9-2.0 was then warmed further to 40°-45° C. Additional 2-butanone, 250 parts by volume, was added and the liquid layers were well mixed. The organic layer was then separated and the aqueous layer was extracted at 40°-45° C. three times with 125 parts by volume portions of 2-butanone to which 12.5 parts by volume of water had been added. The aqueous layer was given a final extraction with 125 parts by volume of 2-butanone and the combined organic extracts were shaken with a little sodium sulfate to remove suspended water droplets. The extract was filtered and 2-butanone was distilled at 25-30 mm pressure to leave a residual solution of N-acetoacetyl-L-aspartic acid in water. The temperature of the solution was increased to 80°-90° C. in order to distill much of the water resulting in the formation of a thick syrup. The warm syrup was immediately mixed with 250 parts by volume of acetone and the mixture was stirred well. N-acetoacetyl-L-aspartic acid soon crystallized and the resulting slurry was cooled to about 10° C. The solid was collected on a funnel, rinsed with acetone, and then dried at 65° C. Acetone and some water were removed from the filtrate by distillation and the residual syrup was stirred with 70 parts by volume of acetone to afford a second crop of N-acetoacetyl-L-aspartic acid. A small third crop was obtained by reworking the filtrate from the second crop. The yield of crystalline N-acetoacetyl-L-aspartic acid in three crops averaged 193.3 parts.
Reaction SMILES: COC[O:4][C:5]1[C:6]([O:12][CH2:13][CH2:14][OH:15])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][O:12][C:6]1[CH:7]=[C:8]([CH3:11])[N:9]=[CH:10][C:5]=1[OH:4]
Reactant: COCOc1cnc(C)cc1OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(OCCO)c(O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 168.1 %

Procedure:
2-(5-(Methoxymethoxy)-2-methylpyridin-4-yloxy)ethanol (900 mg, 4.22 mmol) was dissolved in ethyl acetate (10 mL). The resultant mixture was added with 4N hydrochloric acid-ethyl acetate solution (10 mL) and stirred at room temperature for 5 hours. After completion of the reaction, 4N aqueous solution of sodium hydroxide was used under ice-cold conditions, and the reaction solution was adjusted to pH=8. The reaction solution was concentrated in vacuo. The obtained residue was washed with chloroform/methanol and dried. 4-(2-Hydroxyethoxy)-6-methylpyridin-3-ol (1.2 g) was obtained as a white solid, as crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Fe]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Fe]
Solvent: CO
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (10.05 g, 31.6 mmol) was dissolved in methanol (200 ml). Iron powder (8.81 g, 157.8 mmol) and ferrous sulfate 7 hydrate (40.5 g, 145.6 mmol) were added and the mixture was stirred at 40° C. for 17 h. Since the starting material remained, the insoluble matter was removed by filtration. Iron powder (8.81 g, 157.8 mmol) and ferrous sulfate 7 hydrate (40.5 g, 145.6 mmol) were added and the mixture was stirred at 40° C. for 7 h. The insoluble material was removed by filtration, and methanol was removed by concentration under reduced pressure. Ethyl acetate (300 ml), water (100 ml) and 10% aqueous sodium carbonate solution were added for pH adjustment to 9 and extraction. Ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (5.01 g, yield 55.0%).
Reaction SMILES: Br[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24][CH3:25])=[O:23])[CH2:4][C@@H:3]1[OH:26].O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br-].[Li+].C(=O)([O-])[O-].[Ca+2]>C1C=CC=CC=1.CC(N(C)C)=O>[OH:26][C@@H:3]1[CH:2]=[CH:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24][CH3:25])=[O:23])[CH2:4]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 2β-bromo-3α-hydroxy-17β-methoxycarbonyl-5α-androstan-11-one. (3.48g.,), dihydropyran (8 ml.) and p-toluenesulphonic acid (60 mg.) in benzene (150 ml.) was stirred at room temperature for 15 minutes before being washed with aqueous 10% sodium bicarbonate and water. The benzene solution was dried and evaporated to give a gum which was dissolved in dimethylacetamide (120 ml.). After the addition of anhydrous lithium bromide (14.4g.) and calcium carbonate (11.2g.) the mixture was heated (100°) for 6 hr. Cooling, dilution with chloroform and filtration gave a solution which was washed with water, dried, filtered and evaporated. The residue was dissolved in methanol (200 ml.) containing aqueous 2N hydrochloric acid (1 ml.) After 4 hr. the methanol was removed by evaporation and chloroform added. This solution, after being washed with aqueous 10% sodium bicarbonate and water, was dried, filtered and evaporated to an oil. The addition of ether resulted in crystallisation of the title compound (1.125g.); m.p. 172°-175°; [α]D + 40°, (c 0.7).
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1([Cl:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[N:18]=[C:19]=[S:20]>>[Cl:11][C:12]1([Cl:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[N:18]=[C:19]1[N:7]([CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][S:20]1
Reactant: S=C=NC1C=CC=CC1(Cl)Cl
Reactant: ClCC[NH2+]CC1CCC1
Agent: [Cl-]
Product: ClC1(Cl)C=CC=CC1N=C1SCCN1CC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,2-dichlorophenyl isothiocyanate to give 2-(2,2-dichlorophenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[O:24]1[CH2:12][C@H:11]1[C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=1
Reactant: CC(=O)Nc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@@H]2CO2)cn1
Reaction time: 0.67 h

Procedure:
A solution of (R)-toluene-4-sulfonic acid 2-(6-acetylamino-pyridin-3-yl)-2-hydroxy-ethyl ester (prepared as described in Preparation Four, 200 g, 0.57 mol) in THF (2.4 L) was cooled to −15° C. and potassium t-butoxide (542 ml, 0.542 mol, 1M in THF) was added slowly at −15° C. to −10° C. over a two hour period. Stirring was continued at −15° C. for an additional 40 minutes. The reaction mixture was filtered with the aid of Celite®. The filtration was done through cloth precoated with Celite®. The filter cake was washed with tetrahydrofuran. The filtrate was concentrated under vacuum to afford 300 ml of an oil. The oil was diluted with 1.2 liters of hexanes which resulted in the formation of a solid. The suspension was stirred at room temperature for one hour to granulate the solid. The suspension was filtered and the filtrate was washed with hexanes to afford 80.0 g (78.8%) of the title product as a solid. mp 96-98° C. 1H NMR (CDCl3): δ=8.70 (br, 1H); 8.21 (m, 2H); 7.57 (d of d, 1H); 3.86 (m, 1H); 3.17 (m, 1H); 2.83 (m, 1H); 2.19 (s, 3H). MS (CI): m/z=179 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:29]1
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CCC(CC)CC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 31 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as an off-white solid (50 mg, 31%); ES+-HRMS m/e calcd for C25H31N5O4F2 [M+H+] 504.2417 found 504.2417. 1H-NMR (400 MHz, CDCl3-d) δ ppm 0.86 (t, J=7.5 Hz, 3H) 0.87 (t, J=7.5 Hz, 3H) 1.08-1.14 (m, 1H) 1.15 (s, 3H) 1.16 (s, 3H) 1.21-1.50 (m, 4H) 2.01-2.19 (m, 1H) 2.19-2.37 (m, 1H) 3.93 (s, 2H) 5.67 (dd, J=9.6, 5.8 Hz, 1H) 6.01 (d, J=3.0 Hz, 1H) 6.72 (d, J=2.3 Hz, 1H) 7.08 (t, J=8.0 Hz, 2H) 7.27-7.33 (m, 2H) 8.01 (d, J=3.0 Hz, 1H) 8.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[C@H:9]2[CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[O:7])=[C:4](I)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.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>[F:1][C:2]1[C:28]([F:29])=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[C@H:9]2[CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[O:7])=[C:4]([C:36]2[N:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:3]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 2-(((2S,3R)-1-(4,5-difluoro-2-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.738 g, 1.409 mmol), 2-(tributylstannyl)pyrimidine (0.52, 1.409 mmol), CsF (0.43 g, 2.818 mmol), CuI (0.027 g, 0.14 mmol) and Pd(PPh3)4 (0.16 g, 0.14 mmol) in DMF (15 mL) was degassed and heated at 100° C. for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a white solid. MS (ESI) 477 (M+H).
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=2)[C:20]=1[CH:21]=[CH:22][C:23](Cl)=[O:24])#[N:15].O>O1CCCC1>[C:1]1([CH2:7][S:8]([NH:11][C:23](=[O:24])[CH:22]=[CH:21][C:20]2[N:19]([C:26]3[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=3)[N:18]=[CH:17][C:16]=2[C:14]#[N:15])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)NS(=O)(=O)Cc1ccccc1
Reaction time: 1.25 h
Yield: 26.2 %

Procedure:
To a stirred solution of 0.31 gram (0.002 mole) of phenylmethanesulfonamide in 15 mL of tetrahydrofuran was added 0.05 gram (0.002 mole) of sodium hydride which was washed into the reaction vessel with 10 mL of tetrahydrofuran. The reaction mixture was warmed to reflux temperature, and a solution of 0.32 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 5 mL of tetrahydrofuran was added dropwise during a 20 minute period. Upon completion of the addition, heating of the reaction mixture at reflux was continued for 75 minutes. After this time, the reaction mixture was cooled, and 1 mL of water was added. The mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 35 mL of water, and the solution was acidified with aqueous 4N hydrochloric acid. The resultant solid was collected by filtration, and the filter cake was washed with water. The filter cake was then stirred with hot water. The hot water was decanted away from a semi-solid material. The semi-solid was stirred with fresh cold water which caused the semi-solid to totally solidify. The solid was collected by filtration and was then dissolved in 1:1 toluene/ethyl acetate. The solution was passed through a column of silica gel. The eluate was concentrated under reduced pressure, yielding 0.13 gram of N-phenylmethanesulfonyl-3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CO)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added acetoxyacetyl chloride (48.9 μL, 0.455 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.0 mL), sodium carbonate (100 mg, 0.943 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with 5% aqueous ammonium chloride solution (10 mL), 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (63.0 mg, 56%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C(=O)O)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Temperature: 40 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (4.6 g) in dry methylenechloride (26 ml) was added two drops of dry DMF. Thionylchloride (3 ml) was added and reaction mixture was stirred at 40° C. for 4 h. Solvent was evaporated under vacuum. Precipitate was dissolved to methylenechloride. Solution was cooled to 0-3° C. This solution and aluminium chloride (2.5g) were mixed slowly over 4 hours keeping temperature under 4° C. After mixing reaction mixture was stirred at room temperature for 2 h. Reaction was quenched by pouring to dilute ice cold hydrochloric acid. Layers were separated and water solution was extracted with methylenechloride. Combined organic layers were washed with water, dried and evaporated. Crude product was triturated to give 2.9 g of 6-Methoxy-2-phenylindan-1-one. 1H-NMR (400 MHz, d6-DMSO): 7.56 (d, 1H), 7.35-7.23 (m, 4H), 7.18-7.13 (m, 3H), 4.02 (dd, 1H, J 3.9, 8.0 Hz), 3.82 (s, 3H), 3.61 (dd, 1H, J 8.0, 17.2 Hz), 3.11 (dd, 1H, J 3.9, 17.2 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(OC(O)C)C>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Cl)c3)c2cc1OC
Yield: 54.2 %

Procedure:
A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.51 g of 3-chloroaniline, 0.16 ml of pyridine, and 6 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 6 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexanes to give 0.37 g of 4-[(3-chlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 214-217° C.
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:21]([O:23][C@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[C:25]=1[OH:26])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>C(Cl)(Cl)Cl>[C:37]([O:26][C:25]1[C@@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[O:23][C:21](=[O:22])[C:20]=1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC1=C(OC(=O)c2ccccc2)[C@@H]([C@@H](O)CO)OC1=O
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 2-O-octadecyl-L-ascorbic acid (0.8 g, 2 mmole) in chloroform (20 ml) was added pyridine (1 ml), followed by adding dropwise benzoyl chloride (0.28 g, 2 mmole) at room temperature. The reaction mixture was stirred for one hour, to which was added 2N hydrochloric acid to acidify it. The organic layer was washed with water and dried (over magnesium sulfate). The solvent was evaporated off, and the product was recrystallized from isopropyl ether-ethyl acetate to give 3-O-benzoyl-2-O-octadecyl-L-ascorbic acid (0.6 g, 49%), m.p. 68°-69° C. C3H48O7 (Found: C,69.94; H,8.98%. Anal. Calcd: C,69.89; H,9.08)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[C:9]([C:13](OC)=[O:14])=[CH:10][O:11][CH:12]=2)[C:6](=[O:17])[N:5]([CH3:18])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.C(OCC)(=O)C>C(Cl)Cl.CC(C)=O>[OH:14][CH2:13][C:9]1[C:8]([N:7]2[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:18])[C:6]2=[O:17])=[CH:12][O:11][CH:10]=1
Reactant: COC(=O)c1cocc1-n1c(OC)nn(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1cocc1CO
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A solution of the title compound of Step E (4.6 g) in methylene chloride (40 mL) under nitrogen was cooled to -78° C. while stirring. A solution of diisobutylaluminum hydride (55.0 mL, 1 M in CH2Cl2) in methylene chloride was then added, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was monitored by TLC (5% methanol/ethyl acetate). After cooling back down to -78° C., the reaction was diluted with acetone (45 mL), quenched with glacial acetic acid (20 mL) and then allowed to warm to room temperature. The resulting mixture was further diluted with water (200 mL) and extracted successively with methylene chloride and ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to yield 3.62 g of the title compound of Step F as an orange solid melting at 132.5-133.5° C. 1H NMR (CDC3): δ 7.53 (s,2H), 4.38 (s,3H), 3.99 (s,3H), 3.44 (s,3H).