Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([C:17](OC)=[O:18])[CH2:16][CH2:15]2)=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][O:33][CH2:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1.C1COCC1.[BH4-].[Li+]>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([CH2:17][OH:18])[CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][O:33][CH2:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1
Reactant: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(C(=O)OC)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(CO)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Methyl 1-[5-(2,4-difluorophenyl)-4-[2-[[(1S)-2-ethoxy-1-methyl-ethyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]cyclopropanecarboxylate (0.9 g, 1.99 mmol) is dissolved in dry diethyl ether (20 mL) and dry THF (7 mL) under a nitrogen atmosphere and cooled to 0° C. Lithium borohydride (87 mg, 3.99 mmol) is added portionwise and the mixture stirred at 0° C. for 1 h. The remaining reactants are quenched by adding 1 N HCl until pH=1 to the mixture at RT dropwise for 30 min. The mixture is washed with ethyl acetate, the aqueous layer basified (until pH=8) with NaOH, and extracted with dichloromethane. The combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The residue is purified by normal phase chromatography (120 g silica-gel cartridge) using a gradient of hexane-ethanol to afford the title compound (0.56 g, 60%). LC-ES/MS m/z 470.2 (M+1); [α]D22−18.00°, (c=0.50, MeOH); [α]D22−18.0°, (c=0.50, CHCl3).
Reaction SMILES: C1(C(NC2C(C(N)=[O:15])=CN=C(SC)N=2)(C)C)CC1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:30]1([C:33]([NH:36][C:37]2[C:42]([C:43]([NH2:45])=[O:44])=[CH:41][N:40]=[C:39]([S:46]([CH3:48])=[O:47])[N:38]=2)([CH3:35])[CH3:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([C:33]([NH:36][C:37]2[C:42]([C:43]([NH2:45])=[O:44])=[CH:41][N:40]=[C:39]([S:46]([CH3:48])(=[O:15])=[O:47])[N:38]=2)([CH3:35])[CH3:34])[CH2:32][CH2:31]1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Reactant: CSc1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(Nc1nc(S(C)(=O)=O)ncc1C(N)=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylthio)pyrimidine-5-carboxamide (390 mg, 1.46 mmol) in THF (6 mL) was added mCPBA (447 mg, 2.2 mmol) portion-wise. The reaction mixture was stirred for 0.5 h at 0° C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (2.5%-10% DCM in methanol) to give a mixture of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxamide and 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (382 mg, 1.32 mmol, 90% yield). MS (ESI) m/z 299.1 [M+H]+ and 283.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH2:8])[CH2:3][NH:4][C:5]([NH2:7])=[O:6].[C:9]([CH2:11][C:12](O)=[O:13])#[N:10]>C(OC(=O)C)(=O)C.CCOCC>[NH2:10][C:9]1[N:4]([CH2:3][C:2]([CH3:1])=[CH2:8])[C:5](=[O:6])[NH:7][C:12](=[O:13])[CH:11]=1
Reactant: N#CCC(=O)O
Reactant: C=C(C)CNC(N)=O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: C=C(C)Cn1c(N)cc(=O)[nH]c1=O
Temperature: 70 °C

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.9 l), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp 152-153° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)O1>>[N:62]1[CH:63]=[CH:64][C:59]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:46][CH2:47][O:48][CH2:49][CH2:50]5)[N:18]=[C:19]([C:20]5[CH:25]=[N:24][C:23]([NH2:26])=[N:22][CH:21]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])=[CH:6][CH:7]=2)=[CH:60][CH:61]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(I)cc3)cn2)cc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3C(=O)Nc2ccc(-c3ccncc3)cc2)cn1

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-iodo-phenyl)-amide (25 mg) obtained in Step A in Example 1-D-65 and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (13 mg) instead of pyridin-3-boronic acid, in the same manner as Step B in Example 1-D-65, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid-4-pyridin-4-yl-phenyl)-amide was obtained. Further, in the same manner as Step B in Example 1-D-65 according to the above Deprotection method 3, the PMB groups were removed, to obtain the desired compound (D-66) as a colorless solid (8.9 mg, 40%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1c[nH]nn1
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCn3ccnn3)cc2)cc1
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 41.6 %

Procedure:
Benzyl 4-(3-iodopropyl)phenyl ether (2.47 g), 1H-1,2,3-triazole (629 mg), and potassium carbonate (1.26 g) were suspended in DMF (17.5 ml), followed by stirring at 70° C. for 18.5 hours. The reaction mixture was returned to room temperature and extracted with ethyl acetate, after which it was washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to yield 1-[3-(4-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (856 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][C:5]=1[F:20]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:19]=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[F:20]
Reactant: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1F

Procedure:
A solution of the crude 2-fluoroterephthalic acid 4-benzyl ester 1-methyl ester (8, 0.14 mol) in EtOH (210 mL) and EtOAc (210 mL) is treated with 10% Pd/C (4.0 g) under hydrogen atmosphere at room temperature for 5 h. After filtration of the catalyst, the filtrate is evaporated in vacuo. Crystals are collected and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 1-methyl ester (9) as white solid.
Reaction SMILES: C(O)(=O)[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:10]1([CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(Nc2ccncc2)c2ccccc2)cc1
Temperature: 220 °C
Yield: 10.4 %

Procedure:
A mixture of 11.4 grams (0.05 mole) of benzilic acid and 4.7 grams (0.05 mole) of 4-aminopyridine was heated at 220° C. for 3.5 hours. After cooling the mixture was dissolved in toluene and washed with 10% sodium carbonate solution and with 2 N hydrochloric acid. The acidic extracts were basified with 5 N sodium hydroxide and the resulting oil extracted into toluene. After drying over magnesium sulphate, the toluene was removed and the yellow oil was recrystallised from light petroleum (b.p. 80°-100° C.) giving 1.35 grams (10% yield) of the title compound, m.p. 152° to 154° C.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(O)CCC>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(OCCCCCC)cc4)cn3)cc2C1
Temperature: 0 °C
Yield: 76 %

Procedure:
0.25 g (0.62 mM) of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan, 0.07 g of 85% -potassium hydroxide, 0.2 ml of hexyl iodide and 5 ml of n-butanol were placed in a 20 ml-round bottomed flask, followed by heat-refluxing for 3.5 hours under stirring. After the reaction, the reaction mixture was poured into ice water. The resultant insoluble matter was recovered by filtration and dissolved in toluene, followed by washing with 3%-sodium thiosulfate aqueous solution. The water layer was subjected to extraction with toluene and the resultant toluene layer was added to the organic layer, followed by washing with saturated common salt aqueous solution, drying with anhydrous sodium sulfate and distilling-off of the solvent. The resultant crude product was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.23 g of 2-octyl-5-[5-(4-hexyloxyphenyl)pyrimidine-2-yl]indan (Yield: 76.0%). ##STR139##
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=2[C:22]=1[CH3:23]>C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[CH2:17][C:18]1[O:19][C:20]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=2[C:22]=1[CH3:23]
Reactant: Cc1c(CCl)oc2ccc([N+](=O)[O-])cc12
Reactant: CNCCc1ccc(NS(C)(=O)=O)cc1
Solvent: CCO
Product: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc([N+](=O)[O-])cc12

Procedure:
N-Methyl-4-methanesulphonamidophenethylamine (1.66 g, 7.3 mmole) and 2-chloromethyl-3-methyl-5-nitrobenzofuran (see Preparation 7B - 0.82 g, 3.6 mmole) were heated at reflux temperature in ethanol (20 ml) for 3 hours. The solvent was then evaporated and the residue was purified by column chromatography on silica eluting with methylene chloride/hexane (4:1) followed by methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated, and the residue was recrystallised from ethanol to give the title compound, yield 1.52 g, m.p. 124°-124.5°.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C:28](O)=[O:29])=[O:22])([CH3:19])([CH3:18])[CH3:17].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:28](=[O:29])[CH:27]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:33])[CH2:26][CH2:25][CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CC(C)(C)OC(=O)NCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In anhydrous pyridine (30 ml), 2-amino-terephthalic acid dimethyl ester (manufactured by Merck Ltd.) (1.46 g) and 5-t-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-valeric acid (manufactured by Watanabe Chemical Industries, Ltd.) (3.18 g) were dissolved. The whole was cooled to −15° C. and added with phosphorus oxychloride (0.718 ml), followed by stirring at room temperature for 1 hour. After completion of the reaction, the whole was poured in ice-cold water and subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution and dried with magnesium sulfate. After the solvent was distilled off, the resultant was subjected to azeotropic distillation with toluene. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (3.33 g) as a white crystal.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCCc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 2-(4-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (151 mg, yield: 95%).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=1)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([S:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)[S:24][C:20]=2[CH:19]=1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOc1ccc2nc(S)sc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc2nc(SC3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
To the mixture of tert-butyl 4-hydroxy-1-piperidinecarboxylate (2 g, 10 mmol), 6-ethoxy-1,3-benzothiazol-2-thiol (2.54 g, 12 mmol), triphenylphosphine (3.9 g, 15 mmol) and THF (60 ml) was dropwise added a solution of 40% diethyl azodicarboxylate in toluene (5.23 g, 15 mmol) under ice cooling over a period of 10minutes. The mixture was stirred at room tmperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (50 ml). The organic layer was washed with aqueous solution of 0.5N-sodium hydroxide (30 ml),and saturated aqueous solution of sodium chloride (30 ml), successively, dried-over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 50 g, ethyl acetate/hexane=1/20 to 1/5), and the desired fraction was concentrated under reduced pressure. To the concentrate was added hexane (10 ml) and the precipitates were collected by filtration to give the titled compound (2.6 g, 6.5 mmol) as white powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:6][CH:5]([CH2:7][OH:8])[CH2:4]1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:6][CH:5]([CH2:7][O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4]1
Reactant: COC1(OC)CC(CO)C1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1(OC)CC(COCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a stirring solution of crude (3,3-dimethoxy-cyclobutyl)-methanol (11.9 g, 81.5 mmol) in 100 mL of tetrahydrofuran at room temperature was added a solution of potassium t-butoxide (163 mL, 1M tetrahydrofuran). The reaction was allowed to stir for 30 minutes and then benzyl bromide (10.2 mL, 85.6 mmol) was added. After 30 minutes TLC analysis indicated complete consumption of starting material. The reaction was quenched with water and diluted with methylene chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage Column 75 medium, eluting with a gradient of hexanes through 5% EtOAc/hexanes. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (13.2 g, 69% yield), as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.CN([CH:25]=[O:26])C>>[Br:16][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]([CH:25]=[O:26])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2
Reactant: CN(C)C=O
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: [Li]CCCC
Product: O=Cc1c2ccccc2c(Br)c2ccccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
This material was made from 9,10-dibromoanthracene (Eastman, 20 g, 60 mmol) by the procedure of R. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961) with some modifications. In this procedure, the reaction mixture was cooled to -78° before the n-BuLi (Aldrich) was added. The resulting mixture was warmed to RT over 1 h and then refluxed until the crystalline starting material disappeared. The mixture was then cooled to -78° again before the DMF was added (in one portion). The flask was warmed to RT and then quenched with 1M HBr (200 mL). The two-phase system was then extracted with CH2Cl2 (3×500 mL). The extracts were combined, dried (MgSO4), filtered, and the solvent removed to give the crude material. This was purified by preparative HPLC using PhCH3 as the eluting solvent to give 13.06 g (76%) of 10-bromo-9-anthracenecarbaldehyde mp 215°-216.5°, (lit. mp 218°, P. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961)), (C, H, Br).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[O:17][C:16]([C:18]2[C:23]([C:24]#[N:25])=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:21]=[C:20]3[NH:33][N:34]=[CH:35][C:19]=23)=[CH:15][CH:14]=1.O.NN>C(O)C>[NH2:3][CH2:12][C:13]1[O:17][C:16]([C:18]2[C:23]([C:24]#[N:25])=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:21]=[C:20]3[NH:33][N:34]=[CH:35][C:19]=23)=[CH:15][CH:14]=1
Reactant: N#Cc1c(-c2ccc(O)cc2)nc2[nH]ncc2c1-c1ccc(CN2C(=O)c3ccccc3C2=O)o1
Agent: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccc(O)cc2)nc2[nH]ncc2c1-c1ccc(CN)o1
Yield: 21.5 %

Procedure:
To a suspension of 0.39 g (0.80 mmol) of 4-(5-((1,3-dioxoisoindoline-2-yl)methyl)furan-2-yl)-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained following the sequences of procedures B7 and D1, in 8 ml of ethanol, are added 368 μL (0.38 g, 7.6 mmol) of hydrazine hydrate. The mixture is refluxed for 3 h. The precipitate obtained is filtered and dissolved in water. The mixture is brought to pH=7-8 with 30% sodium hydroxide and extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by silica chromatography (eluent 7N NH4OH in methanol in dichloromethane: 10:90) to yield 0.057 g (22%) of 4-(5-(aminomethyl)furan-2-yl)-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a yellow solid.