Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[OH-].[Na+].O>[C:14]1([S:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]3[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=3[CH:3]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)c1csc2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 88.5 %

Procedure:
To a solution of 8.63 g (44.4 mol) of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) (J. Chem. Soc (C), 1899-1905 (1967), M.Martin-Smith et al.) in 160 ml of 80% aqueous tetrahydrofuran and 44 ml of 1N sodium hydroxide was added 87 ml of 0.56N sodium hydroxide and 6.2 ml (48.4 mmol) of benzenesulfonylchloride simultaneously with keeping at pH 11-12 with stirring under ice-cooling. After the reaction completion, the mixture was diluted with water, alkalized and washed with toluene. The aqueous layer was weakly acidified with conc. hydrochloric acid under stirring. The precipitated crystals were filtered, washed with water, and dried to give 14.33 g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2).
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.C1(=O)O[C:27](=[O:28])[CH2:26]C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27](=[O:28])[CH3:26])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (830 mg), succinic anhydride (270 mg) and toluene (30ml) were refluxed together for 30 minutes. After adding 50 ml of acetic anhydride and 82 mg of sodium acetate to the reaction solution, the mixture was stirred at 80° C. for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The second eluted substance was N1-cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide, of which 440 mg was obtained as a colorless powder.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Br[CH:9]([CH3:13])[C:10](Br)=[O:11]>>[CH2:6]([CH:2]1[C:3](=[O:5])[O:4][CH:9]([CH3:13])[C:10](=[O:11])[O:1]1)[CH3:7]
Reactant: CCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Product: CCC1OC(=O)C(C)OC1=O
Yield: 53 %

Procedure:
3-ethyl-6-methyl-2,5-dioxane-1,4-dione was synthesized from 2-hydroxybutyric acid and 2-bromopropionyl bromide. It was purified by distillation (45° C./50 mtorr) to give a colorless oil. Yield: 53% 1H NMR (CDCl3) δ5.03 (q), 4.99 (q, 1H for signal at 5.03 and 4.99 ppm), 4.86 (dd), 4.83 (dd, 1H for signal at 4.86 and 4.83), 1.90-2.20 (m, 2H), 1.69 (d), 1.66 (d, 3H for signals at 1.69 and 1.66 ppm). 1.15 (t). 1.14 (t, 3H for signals at 1.15 and 1.14 ppm). 13C NMR (CDCl3) δ167.6, 166.8, 166.3, 165.6, 77.7, 76.6, 72.5, 72.2, 25.3, 23.3, 17.5, 15.7, 9.1, 8.7, MS (m/q) 159.4 (M+1). The product is approximately a 3:1 mixture of the R,R/S,S and R,S diastereomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])CCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C.Cl>C1COCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:19]([OH:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOCc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB1OCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: COCCOc1ccc(OCC2CO2)cc1
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Solvent: CC(C)O
Product: COCCOc1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 10.2 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene and 11.0 g of 5-[2-(benzylamino)propoxy]salicylamide in 200 ml of isopropanol is refluxed for 24 hours. By concentration of the solution by evaporation, crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is obtained as an oil which is used in its crude state for debenzylation.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:11])[C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH:6][C:5]([N:4]([CH3:11])[CH3:3])=[N:7][N+:8]([O-:10])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(C)C(=N)N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
To a suspension of 0.44 g of 60% sodium hydride (in mineral oil) in 10 ml of DMF was added 1.32 g of N,N- dimethyl-N'-nitroguanidine during 20 minutes at room temperature. After stirring for 10 minutes, 1.62 g of 2-chloro-5-(chloromethyl)pyridine was added to the mixture in 5 minutes, and stirred for 2 hours at room temperature and for 4 hours in an oil bath of 60° C. After filtering insoluble materials off, the filtrate was concentrated. The resulting residue was purified by a column chromatography [developing solvent: dichloromethane-ethyl acetate (5:1-3:1)] to obtain 0.82 g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH2:28][NH:29][C:30](=[N:38][C:39]#[N:40])OC5C=CC=CC=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.CC(O)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C1COCC1>[C:39]([NH:38][C:30]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[N:29][CH2:28][C:27]#[C:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]2)#[N:40]
Reactant: C1COCCN1
Reactant: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#CNC(=NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)N1CCOCC1
Temperature: 80 °C
Yield: 20.1 %

Procedure:
Material from step F (9 mg, 0.016 mmol) is placed in a reaction vial and dissolved in 2 ml of a 1:1 THF:i-PrOH mixture. Morpholine (0.08 mmol) is added at r.t, and the sealed vial is heated in an oil bath at 80° C. Reaction progress at 80° C. is followed by LC/MS, and the reaction is stopped after reaching 90% conversion (3 hours). Chromatography of the crude on silica (MeOH/EtOAc) affords pure desired product (1.8 mg, 20%). MS ESI (+) m/z 560 (M+1) detected; 1H NMR (400 MHz, deuterated acetone containing 10% deuterated methanol) δ 8.58 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.84-7.76 (m, 4H), 7.65 (d, 1H), 7.37 (q, 1H), 7.12 (d, 1H), 7.04 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.FC1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C(O)(=O)C>O1CCCC1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 2 h
Yield: 57.4 %

Procedure:
64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran, and, while the mixed solution was stirred and cooled on ice, a solution obtained by dissolving 258 g of diethyl malonate in 400 ml of tetrahydrofuran was dropped to the mixed solution through 1 hour and 40 minutes so that the reaction temperature was kept below 20° C. Then, while the reaction solution was stirred and cooled on ice, 200 ml of tetrahydrofuran solution dissolving 142 g of 2,3,4-trifluoronitrobenzene was dropped to the reaction solution through 2 hours so that the reaction temperature was kept below 10° C. After reacting at room temperature for 2 hours, 100 ml of acetic acid was added to the reaction solution and tetrahydrofuran was removed by distillation. To the residue, 1 1 of chloroform, 1.5 1 of water and 100 ml of concentrated hydrochloric acid were added, and the solution was separated. The organic layer was separated from the solution, and the solvent was removed by distillation. To the residue, 250 ml of 4 N hydrochloric acid and 200 ml of acetic acid were added, and the solution was heated under reflux for 11 hours. After removing 150 ml of content solution by distillation, 50 ml of acetic acid and 50 ml of water were added to the solution, and the solution was heated under reflux for 31 hours. After the solution was air-cooled, the precipitated crystal was filtered off, washed with diisopropyl ether and was dissolved in 400 ml of methanol. After treating with active carbon, the solvent was removed by distillation. The precipitated crystal was dispersed in diisopropyl ether and was filtered off to obtain 100 g of the subject compound (1) in a 56% yield.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.C[O-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN1C(=O)N(C)CCC1>[C:25]([N:7]1[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[C:5]1=[O:6])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCOC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCOC(=O)n1c(=O)c(C)cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 267 mg AZT in 1 ml DMPU was treated with 500 ul of sodium methoxide solution (4.4M NaOMe, in MeOH) and 250 ul of ethyl bromoacetate and stirred 30 minutes at room temperature. Another 500 ul NaOMe solution and 250 ul ethyl bromoacetate were added and the mixture was heated 1 hourat 60° C. in a water bath. The resulting suspension was diluted with15 ml deionized water and extracted with EtOAc. The organic phase was washed, first with 5% NaHCO3 then saturated NaCl solution, concentrated under reduced pressure and chromatographed by preparative TLCon silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc (95+5+0.5). Three bands were visualized with UV (254 nm) and were eluted separately with MeOH. Fraction A (Rf =0.19) was identified as AZT by TLC and UV spectrum by comparison with an authentic AZT reference. It was also immunologically active in an AZT assay by FPIA. Fractions P (Rf =0.37) and C (Rf =0.57) had similar UV spectra, resembling that of 3-methylthymidine. Fraction B was immunologically active (approximately 110% "cross-reactivity" relative to AZT in an AZT assay by FPIA). FractionC was immunologically inactive. Fraction B was therefore evaporated to dryness and saved.
Reaction SMILES: [CH:1]([SiH:4]([CH:10]([CH3:12])[CH3:11])[CH2:5][C:6]([CH3:9])(C)C)([CH3:3])[CH3:2].BrCCC[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:17][CH2:9][CH2:6][CH2:5][SiH:4]([CH:1]([CH3:2])[CH3:3])[CH:10]([CH3:11])[CH3:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OCCCBr
Reactant: CC(C)[SiH](CC(C)(C)C)C(C)C
Product: CC(C)[SiH](CCCOC(C)(C)C)C(C)C

Procedure:
The procedure of synthesizing Compound 51a was repeated, except that 1-bromo-3-(tert-butoxy)propane (5.40 g, 27.7 mmol) was employed, whereby the Compound 59a was obtained as a brown liquid (3.10 g, 49%).
Reaction SMILES: [B-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:35]=[N:36][N:37]=[C:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:35]=[N:36][N:37]=[C:12]3[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Agent: [B-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)Nc1nnnn1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Sodium hydroborate (0.001 mol) was added portionwise at room temperature to a mixture of intermediate 8 (0.001 mol) in methanol (5 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The organic layer was washed with water, separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried in a vacuo. The residue (0.35 g, 70%) was crystallized from ethanol. The precipitate was filtered off and dried in a vacuo, yielding 0.105 g (21%) of 5-(3-chlorophenyl)-α-(4-fluorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)- tetrazolo[1,5-α]quinazoline-7-methanol (intermediate 9), mp. 230° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCCCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and piperidine following the procedure outlined in Example 15 (modifications: 40° C., 18 h). 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.39 (s, 3H), 7.88 (d, 1H), 7.01 (d, 1H), 4.51 (s, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 2.25 (br, 4H), 2.17 (t, 2H), 2.13 (s, 6H), 1.74 (m, 2H), 1.49-1.23 (m, 12H); MS (ESI): 479.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Se](=O)=[O:14].O1CCOCC1>O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:14])[CH:8]=[CH:7]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2cccc(O)c2n1

Procedure:
8-hydroxy-2-methylquinoline (2 g, 12.4 mmol.), selenium dioxide (1.74 g, 15.8 mmol), 300 ml of pre-dried 1,4-dioxane, and 1.5 ml of water were mixed and stirred in a 1-L round bottom flask. The resulting solution was then refluxed for 24 h. The reaction was monitored until completion using TLC method. The reaction mixture was then filtered off, and the selenium metal was then washed with dichloromethane, and the combined filtrates were then evaporated off under reduced pressure. The crude product was then purified by sublimation under reduced pressure or by silica gel column chromatography to yield pure yellow needle crystal.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2.C(N(CC)CC)C>C(O)C>[CH:29]12[N:32]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH:25]([CH2:31][CH2:30]1)[CH2:26][O:27][CH2:28]2
Reactant: C1CC2COCC1N2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cccc(-c2nc(N3C4CCC3COC4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 130 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.18 g, 0.49 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (approximately 100 mg, 0.67 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (750 μL, 5.7 mmol) and was then heated in the microwave reactor for 10 minutes at 130° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol. MS (ES+): 400.3 (M+H)+
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:12][C:13]([NH2:15])=[S:14])[CH3:11].[O-]CC.[Na+].[C:20]([CH2:22][C:23](OCC)=[O:24])#[N:21].S(=O)(=O)(O)O>CCO.O>[NH2:21][C:20]1[N:12]([CH:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:11])[C:13](=[S:14])[NH:15][C:23](=[O:24])[CH:22]=1
Reactant: CC(NC(N)=S)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(c1nc2ccccc2[nH]1)n1c(N)cc(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.7 %

Procedure:
To a suspension of N-[1-(1H-benzimidazol-2-yl)ethyl]thiourea (0.33 g, 1.5 mmol, obtained from Example 9(a)) in EtOH (2 mL) was added, dropwise, sodium ethoxide (21% w/w, 1.67 mL, 4.5 mmol) and a solution of ethyl cyanoacetate (0.48 mL, 4.47 mmol) in EtOH (1 mL), while heating the reaction to 80° C. during 1 h 20 minutes. The reaction was kept at 80° C. for an additional 2 h 40 minutes. After cooling to r.t., water (50 mL) and 2M sulphuric acid was added. The formed solid was collected by filtration, washed with H2O and dried to give the title compound (0.21 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(I)cc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: COc1ccc(C#CCSc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)cc1

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-4-methoxy-benzene gave the title compound as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([C:37]2[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C@@H:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:20][C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=3[CH3:22])[CH:19]=[CH:18][CH:17]=2)=[CH:29][CH:28]=1)[C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[CH3:36]
Reactant: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1nccn1C
Reactant: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Cs2CO3 (72 mg, 0.22 mmol) and compound 9.9 (53 mg, 0.21 mmol) were added successively to a solution of (S)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.6) (55 mg, 0.2 mmol) in dry DMF (3 mL). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (60 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was flash chromatographed on silica gel (0-5% MeOH in DCM) to afford (S)-ethyl 3-(4-[3-(4-chloro-2-methylphenyl)benzyloxy]phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.10) as a colorless oil (97 mg). LC-MS ESI (pos.) m/e: 489 (M+H).