Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([O:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1)[CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH2:40]([O:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:49]([CH3:62])=[N:48]1)[CH3:41]
Reactant: CCOc1cccc(Cn2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cccc(Cn2nc(C)c(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (125 mg, 0.189 mmol) was coupled with 1-(3-ethoxybenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 46) (81.13 mg, 0.227 mmol) in sodium carbonate (60.1 mg, 0.567 mmol), Pd(PPh3)2Cl2 (6.6 mg, 0.0095 mmol), toluene/ethanol/water (3/5/1 ml) to give 140 mg of titled compound. MS: m/z=761.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:4]([O:13][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:14])[CH2:3][CH2:11][CH3:7]
Reactant: COc1cccc2cc(C(=O)O)[nH]c12
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)c1cc2cccc(OC)c2[nH]1
Yield: 105.7 %

Procedure:
A suspension of 6.0 g of 7-methoxyindole-2carboxylic acid in 100 ml of toluene is combined with 4.3 ml of thionyl chloride; the mixture is heated under stirring for 3 hours to 90° C., then concentrated under vacuum. The residue is combined with 50 ml of n-butanol and heated for one hour under reflux Then the mixture is evaporated to dryness under vacuum, the oily residue is boiled with 60 ml of petroleum ether, the clear solution is decanted from the dark residue, and cooling of the solution yields 4.1 g of 7-methoxyindole-2-carboxylic acid n-butyl ester, mp 66°-69° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].S(=O)(=O)(O)[OH:21].N([O-])=O.[Na+].NC(N)=O>O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To N-(2-fluoro-5-aminophenyl)-3,4,5,6-tetrahydrophthalimide (VIII) (2.6 g), acetic acid (26 g) and conc. sulfuric acid (2.5 g) were added, and the resultant mixture was kept at a temperature below 10° C. A solution of sodium nitrite (1.0 g) in water (10 g) was added dropwise thereto at a temperature of 5° to 10° C. The resulting mixture was stirred for 15 minutes, followed by decomposition of excess of sodium nitrite with urea (0.3 g). A solution of cupric nitrate (38.6 g) in water (100 g) was added dropwise thereto at room temperature. After addition of cuprous oxide (1.5 g), the resultant mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography using a mixture of n-hexane and ethyl acetate as an eluent to give 0.7 g of N-(2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI). M.P., 164.6° C. M.P., 164.6° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1([NH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:11]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:10]=2)=[O:8])[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH3:31][N:6]([C:3]1([C:2]([F:1])([F:26])[F:27])[CH2:4][CH2:5]1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:11]([O:21][CH2:22][CH:23]2[CH2:24][CH2:25]2)[N:10]=1)=[O:8]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide (20 mg, 51.1 μmol) and sodium hydride (3.3 mg, 76.7 μmol) in DMF (0.2 mL) was stirred for 15 min. at ambient temperature. Iodomethane (14.5 mg, 6.38 μL, 102 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice water/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude brown oil was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 4:1, elution with EtOAc) to give the title compound (13 mg, 63%) as colorless oil; MS (EI): m/e=406.4 [MH]+.
Reaction SMILES: C[Mg]Br.ClC1N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N=C2N(CC3C(C)=C(OC)C(C)=CN=3)N=C(CC=O)C=12.CC1C=CC(S([O:53][CH:54]([C:92]#N)[CH2:55][C:56]2[C:64]3[C:59](=[N:60][C:61]([N:66]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[N:62][C:63]=3[Cl:65])[N:58]([CH2:81][C:82]3[C:87]([CH3:88])=[C:86]([O:89][CH3:90])[C:85]([CH3:91])=[CH:84][N:83]=3)[N:57]=2)(=O)=O)=CC=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Cl:65][C:63]1[N:62]=[C:61]([N:66]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:68])[N:60]=[C:59]2[N:58]([CH2:81][C:82]3[C:87]([CH3:88])=[C:86]([O:89][CH3:90])[C:85]([CH3:91])=[CH:84][N:83]=3)[N:57]=[C:56]([CH2:55][CH:54]([OH:53])[CH3:92])[C:64]=12
Reactant: COc1c(C)cnc(Cn2nc(CC(C#N)OS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: COc1c(C)cnc(Cn2nc(CC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2nc(CC(C)O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A 3 N solution of methylmagnesium bromide in diethyl ether (0.15 mL) was added dropwise to a mixture of di-tert-butyl {4-chloro-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of Step 1) of Example 3 (120 mg) and dehydrated tetrahydrofuran (1 mL) under cooling in a dry ice-acetone bath, and then the mixture was stirred for one hour. A saturated ammonium chloride solution (1 mL) was added dropwise to the reaction mixture, and then the dry ice-acetone bath was removed. The reaction mixture was separated with ethyl acetate (30 mL) and water (30 mL). Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (ethyl acetate-hexane) to obtain the title compound (52 mg, 42%) as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([F:2])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]1[C:31]([O:32][CH3:33])=[O:34]
Reactant: COC(=O)C1CCNC(Cc2cc(F)c(F)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Methyl 2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylate hydrochloride (3.957 g, 12.22 mmol) and DIPEA (4.68 mL, 26.89 mmol) were dissolved in DCM (20 mL) and methyl carbonochloridate (1.059 mL, 13.45 mmol) was added. The reaction was stirred at room temperature for 18 h, diluted with DCM (200 mL), washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried through a phase separator and evaporated in vacuo to yield dimethyl 2-(3,4,5-trifluorobenzyl)piperidine-1,4-dicarboxylate (4.01 g, 95%) as a brown oil. MS m/z 346 (M+H)+
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[N:16]1([CH2:1][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-formylpiperidine-1-carboxylate (110 mg, 0.51 mmol) and piperidine (53 mg, 0.62 mmol) was added NaBH(OAc)3 (153 mg, 0.73 mmol) and AcOH (37.2 mg, 35 μL, 0.62 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:30]=[CH:31][CH:32]=[C:3]([C:2]([F:34])([F:33])[F:1])[CH:4]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)cc(OC)c1OC
Yield: 3.3 %

Procedure:
In a similar manner as described for Example 1, 3-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 14) (0.12 g, 0.25 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 5-methyl-7-[3-(trifluoromethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0038 g) as a yellow solid. 1H NMR (CD3OD): δ9.08 (s, 1H), 8.72 (d, J=7.7 Hz, 1H), 8.59 (s, 1H), 7.76-7.65 (m, 2H), 7.00 (s, 2H), 6.99 (s, 1H), 3.76 (s, 3H), 3.74 (s, 6H), 2.60 (s, 3H). MS m/z 460 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([F:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 5.7 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (3-fluoro-4-hydroxyphenyl)boronic acid (24 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 4 mg (9% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: COC1C=CC(N2C3C(=CC=CC=3)C(=O)C=C2C2C=CC=CC=2)=CC=1.C([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[C:43](=O)[CH:42]=[C:41]2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:36][CH:35]=1)C1C=CC=CC=1>>[OH:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH:41]2[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc2c(c1)c(=O)cc(-c1ccccc1)n2-c1ccc(OCc2ccccc2)cc1
Agent: COc1ccc(-n2c(-c3ccccc3)cc(=O)c3ccccc32)cc1
Product: COc1ccc2c(c1)CCC(c1ccccc1)N2c1ccc(O)cc1

Procedure:
Following a procedure similar to that described in Example 7, Procedure 2, but substituting for 1-(4-methoxyphenyl)-2-phenyl-4(1H)-quinolone an equivalent amount of 1-(4-benzyloxyphenyl)-2-phenyl-6-methoxy-4(1H)-quinolone there can be obtained 1-(4-hydroxyphenyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[C:41]#[CH:42]>CC(C)=O>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:42][C:41]#[CH:40])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)NC)n3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (30 mg, 0.0619 mmol) was placed in acetone (3 mL) and cesium carbonate (60.4 mg, 0.186 mmol, 3.0 eq) was added followed by propargyl bromide (80% in toluene) (7.28 μL, 0.0681 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent. Further purification by prep-HPLC using a gradient of 10-90% acetonitrile/water to obtain 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a thin yellow film (6.9 mg, 21%). LCMS (m/e) 523 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.10 (s, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.09 (s, 1H), 7.95 (dd, 1H, J=1.6 and 8.0 Hz), 7.60-7.53 (m, 1H), 7.30-7.20 (m, 3H), 7.01 (d, 1H, J=7.9 Hz), 6.99 (bs, 1H), 4.76-4.67 (m, 1H), 3.36 (d, 2H, J=2.4 Hz), 3.05-3.00 (m, 1H), 2.95-2.84 (m, 3H), 2.63 (d, 3H, J=5.3 Hz), 2.51-2.43 (m, 2H), 2.21-2.15 (m, 2H), 2.14 (t, 1H, J=2.3 Hz), 1.70-1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[C:4]([CH:21]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>COC(=O)OC>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][CH2:12][CH2:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:21][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(CC(C)C)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCC1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
To a solution of methyl 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoate (10.0 g) in dimethylcarbonate (250 ml) was added a methanol solution of 28% sodium methoxide (6.8 g) and the mixture was heated at 50° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to 0° C., neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (8.6 g). A suspension of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.0 g), 4-(2-butoxyethoxy)phenylboric acid (4.8 g) and potassium carbonate (5.6 g) in toluene (60 ml), ethanol (6.0 ml) and water (6.0 ml) was stirred for 30 minutes under an argon atmosphere. After addition of tetrakis(triphenyl)phosphine palladium (0.9 g), the mixture was heated at 105° C. for 3 hours under an argon atmosphere. The mixture was cooled, followed by addition of water, and extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.43 g). The oil was redissolved in THF (50 ml) and methanol (50 ml). To the solution was added aqueous 2N sodium hydroxide solution (23 ml), and the resulting mixture was heated at 90° C. for 3.5 days. The mixture was cooled to 0° C., followed by addition of water, and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diisopropylether-ethyl acetate to obtain yellow crystals of 8-[4-(2-butoxyethoxy)phenyl-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (1.04 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].[BH4-].[Na+]>C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(OCCCC2OCCO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(OCCCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To an ice-cooled solution of 3-(3-(1,3-dioxolan-2-yl)propoxy)benzaldehyde (prepared as in Example 10; Step 1) (3.08 g, 13.1 mmol) in ethanol (66 mL), was added sodium borohydride (1.98 g, 52.4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 16 hours. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride and extracted twice with DCM. The combined organic phases were poured through a hydrophobic column, and the solvent was evaporated at reduced pressure to afford the title compound as a colourless oil (2.96 g, 95%).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=O)=O)=[CH:22][CH:21]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)C>[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:17])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[C:26]=2[C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Cc1ccc(CC(=O)Cc2ccc(C)cc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2=C(c3ccc(C)cc3)C(c3ccc(C)cc3)=C(c3ccc(C)cc3)C2=O)cc1
Reaction time: 0.42 h

Procedure:
23.13 g (0.11 mol) of 1,3-bis(p-tolyl)-2-propanone and 26.2 g (0.11 mol) of 4,4′-dimethylbenzil were dissolved in 75 ml of hot ethanol (abs.). 53 ml of a methanolic benzyltrimethylammonium hydroxide solution (0.11 mol Triton B, 35% Fluka) were slowly added dropwise at 80° C. with stirring (caution: the reaction batch froths vigorously) and refluxing was effected for 25 minutes. The crude product was filtered off after three hours, then washed with cold ethanol and recrystallized from toluene (violet red, yield: 46.2 g (95%); m.p.: 244-245° C., literature: 250.4-251.4° C. [15]; elemental analysis for C33H38O: found: C, 89.8%, H, 6.6%. calculated: C, 89.96%, H, 6.41%, MS-El [m/z (rel. intensity): M+440 (100), 412 (47), 206 (98), 191 (16), 189 (10)). The IR spectrum of 1,2,3,4-tetra(p-tolyl)cyclopenta-1,3-dien-5-one is shown in FIG. 10.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
A mixture composed of 18.0 g of 6-hydroxy-2-methylbenzoxazole synthesized in Synthesis Example 1, 36.6 g of 1-bromohexadecane, 24.0 g of potassium carbonate and 120 ml of N,N-dimethylformamide was stirred at 90° C. for 4.5 hours. Solids were removed from the reacting solution by filtration, and the filtrate was poured into 500 ml of methanol. The crystals formed were separated by filtration to obtain 45.0 g of 6-hexadecyloxy-2-methylbenzoxazole.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: Cc1c(O)cccc1O
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1c(O)ccc(C(=O)Cc2ccc(O)cc2)c1O
Temperature: 110 °C

Procedure:
2-Methylresorcinol (4.00 g, 1 equivalent) and 4-Hydroxyphenylacetic acid (5.00 g, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled BF3.OEt2 (20 ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (110° C.). A yellow solid formed at 20 minutes indicating that the reaction had gone to completion. The reaction was left on heat for a further 10 minutes and then cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF3.OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was 1-(2,4-Dihydroxy-3-methyl-phenyl)-2-(4-hydroxy-phenyl)-ethanone in >95% purity. The solid was dried on a freeze dryer for 24 hours (8.93 g, 99%).