Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[C:36]1([C@@H:42]2[CH2:44][C@H:43]2[C:45](Cl)=[O:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:45]([C@@H:43]4[CH2:44][C@H:42]4[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:46])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol) in pyridine (100 mL) was added racemic trans-2-phenyl-cyclopropane carbonyl chloride (1.163 g, 0.007 mol) at −5° C. The mixture was stirred at −5° C. for 10 minutes then warmed up to room temperature and stirred for 1.5 hours. The mixture was quenched with an aqueous 1N solution of sodium hydroxide. Organic solvents were removed under reduced pressure. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with a 5% aqueous solution of citric acid (3×100 mL), 1 N aqueous solution of hydrochloride (3×100 mL), water, saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure to give trans benzyl 4-[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.47 g, 0.006 mol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[OH:19][CH2:18][C@H:17]([N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[CH3:20]
Reactant: C[C@@H](N)CO
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A round bottom flask was charged with 6-methyl-5-nitro-1H-isochromen-1-one (260.00 mg, 0.0012673 mol), (2R)-2-aminopropan-1-ol (143 mg, 0.00190 mol), triethylamine (1.6 L, 0.011 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 80° C. overnight. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[OH:22])[C:5]2=[O:23].[CH3:24][C:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[C:5]2=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=c1c2cc(Br)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Br)c3ccccc32)c1=O

Procedure:
To a solution of 6-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (1.00 g, 2.67 mmol) in CH2Cl2 (40 mL) was added DMAP (1.68 g, 13.3 mmol) and then tert-butyl dimethylsilyl trifluoromethane sulfonate (1.84 mL, 8.00 mmol) and the reaction was stirred overnight. The reaction was diluted with saturated, aqueous NaHCO3 and extracted 1× with CH2Cl2. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The oily residue was purified via silica gel chromatography, eluting with 5-55% ethyl acetate in hexanes to provide 1,5-anhydro-3-(6-bromo-4-oxobenzo quinazolin-3(4H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol that gave a mass ion (ES+) of 490.8 for [M+H]+.
Reaction SMILES: C(O)(C)(C)C.[F-].[Cs+].Br[C:9]1[C:10]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:11][N:12]([C:14]2([CH2:35][C:36]#[N:37])[CH2:17][N:16]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[O:26])=[CH:20][C:19]=3[F:34])[CH2:15]2)[CH:13]=1.[CH3:43][C:44]1[C:48](B2OC(C)(C)C(C)(C)O2)=[CH:47][NH:46][N:45]=1>O.C(OCC)(=O)C>[C:36]([CH2:35][C:14]1([N:12]2[CH:13]=[C:9]([C:48]3[C:44]([CH3:43])=[N:45][NH:46][CH:47]=3)[C:10]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:11]2)[CH2:17][N:16]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[O:26])=[CH:20][C:19]=2[F:34])[CH2:15]1)#[N:37]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1-c1c[nH]nc1C
Temperature: 85 °C

Procedure:
To a microwave vial were charged with tert-butyl alcohol (1.2 mL), and water (1.2 mL), cesium fluoride (683 mg, 4.50 mmol), ethyl 4-bromo-1-{3-(cyanomethyl)-1-[2,5-difluoro-4-({[(1S)-2,2,2-trifluoro-1-methylethyl]amino}carbonyl)phenyl]azetidin-3-yl}-1H-pyrazole-3-carboxylate (725 mg, 1.28 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (401 mg, 1.93 mmol), followed by Pd-127 (49 mg, 0.064 mmol) (from Johnson Mathew). The reaction mixture was heated at 85° C. for 48 h. The reaction was cooled to room temperature, diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated. The resulting residue was purified with flash chromatography (eluting with 30-100% ethyl acetate in hexanes) to give the desired product as an oil. LCMS calculated for C25H25F5N7O3 (M+H)+: m/z=566.2. Found: 566.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:22][CH:23](Br)[CH3:24]>CN(C)C=O>[CH2:22]([S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH:23]([S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH3:24]
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)cc1
Reactant: CC(Br)CBr
Solvent: CN(C)C=O
Product: CC(CSc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)Sc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1

Procedure:
A solution of 4,5-bis(4-fluorophenyl)-1H-imidazole-2-thione (10 g, 0.035 mol) and 1,2-dibromopropane (3.5 g, 0.017 mol) in N,N-dimethylformamide (25 ml) was refluxed for two hours, then cooled. The precipitate was collected, treated with hot chloroform and recrystallized from isopropanol to give the title compound as its dihydrobromide salt, m.p. 243°-245°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)c(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(Nc1ccc(Cl)c(-c2cccnc2)c1)Oc1ccccc1
Temperature: -40 °C
Yield: 94.7 %

Procedure:
4-Chloro-3-(pyrid-3-yl)aniline (0.08 g, 0.00039 mole) in isopropyl alcohol (8 ml) was cooled to −40° C. and treated under argon with triethylamine (0.06 ml, 0.00043 mole) followed dropwise by phenyl chloroformate (0051 ml, 0.00041 mole). The reaction mixture was stirred at −40° C. for half an hour and allowed to warm to ambient temperature. The solvent was removed in vacuo and the residue dissolved in dichloromethane, washed with H2O, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.12 g, 95%) as an orange solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=3)=[N:10][CH:11]=2)[CH2:2]1.C=O.O.[C:25]([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH:3]3[CH2:4][N:1]([CH3:25])[CH2:2]3)=[CH:11][N:10]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 251d (1.10 g, 2.95 mmol), 37% solution of formaldehyde in water (111 mg, 3.70 mmol) and methanol (15 mL). A suspension of sodium cyanoborohydride (540 mg, 8.60 mmol) and zinc chloride (600 mg, 4.40 mmol) in methanol (10 mL) was added, and the reaction was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated, and the residue was partitioned between 90:10 methylene chloride/methanol (250 mL) and 10% aqueous potassium carbonate (100 mL). The aqueous layer was extracted with 90:10 methylene chloride/methanol (3×150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, 0% to 50% methanol/methylene chloride) to afford a 80% yield (830 mg) of 251e as an brown solid: mp 100-101° C.; 1H NMR (500 MHz, DMSO-d6) d 8.66 (s, 1H), 8.55 (d, 1H, J=2.5 Hz), 7.86 (d, 1H, J=3.0 Hz), 7.47 (d, 1 h, J=2.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.24 (dd, 1H, J=9.5, 3.5 Hz), 4.76 (m, 1H), 3.77 (t, 2H, J=7.5 Hz), 3.50 (s, 3H), 3.03 (t, 2H, J=7.5 Hz), 2.26 (s, 3H); MS (ESI+) m/z 366.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:4]=1.[C-:30]#[N:31].[Na+].CS(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:5]1[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:7][C:3]([CH2:2][C:30]#[N:31])=[N:4]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
A mixture of the 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole (720 mg, 1.42 mmol), NaCN (250 mg, 5.1 mmol), and DMSO (10 mL) was stirred in a sealed vial at 100° C. for 5 h, diluted with water, and extracted with EtOAc. The combined extracts were washed with water, brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a white solid (350 mg, 54%). 1HNMR (CDCl3): δ 8.03 (d, 1H), 7.84 (m, 1H), 7.72 (m, 1H), 7.58-7.44 (m, 5H), 7.22 (d, 1H), 6.79 (d, 1H), 6.73 (s, 1H), 3.87 (s, 2H), 3.09 (s, 3H). MS(ES): 454 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(CCSc1ccc(F)cc1)NO
Reactant: OO
Solvent: CC(=O)O
Product: O=C(CCS(=O)c1ccc(F)cc1)NO
Reaction time: 3 h

Procedure:
9.85 g (0.046 mol) of 3-(p-fluorophenylthio)-propiohydroxamic acid dissolved in 46 ml of acetic acid are oxidised by adding 4.6 ml of hydrogen peroxide of 110 volumes strength. The reactants are left in contact for 3 hours, the mixture is evaporated to dryness in vacuo, the residue is taken up in ethyl acetate and the product is filtered off and recrystallised from ethanol.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][C:4]=1[I:25].[SH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[CH3:33][N:32]([CH3:34])[C:30]([C:29]1[CH:28]=[C:27]([S:26][C:3]2[CH:12]=[C:11]3[C:6]([C:7]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]3)=[CH:5][C:4]=2[I:25])[CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(Cl)c(I)cc23)c1
Reactant: CN(C)C(=O)c1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(Sc4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 24.6 %

Procedure:
A stirred mixture of Intermediate 63 (0.4 g), Intermediate 28 (0.16 g) and potassium carbonate (0.38 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 100° C. under nitrogen for 3 h. A further portion of Intermediate 28 (0.07 g) was added and the mixture stirred at 60° C. for 23 h. The cooled mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methanol followed by mass directed preparative HPLC (Method A) to give the title compound as a yellow foam (0.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 20 step B, 150 mg, 0.44 mmol) and 3-chloro-4-fluorophenylboronic acid (62 mg, 0.35 mmol) as off white solid (70 mg, 41%). LC-MS: 392 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16](/[CH:19]=[CH:20]/OCC)=[CH:17][N:18]=1)[C:12](OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH3:36]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:19]=[CH:20][N:36]=[C:12]2[OH:13])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO/C=C/c1cnc(OCc2ccccc2)cc1C(=O)OC
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Oc1nccc2cnc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 97 %

Procedure:
(E)-methyl 2-(benzyloxy)-5-(2-ethoxyvinyl)isonicotinate (Preparation 85, 1.2 g, 3.83 mmol) was dissolved in methanolic ammonia (7M, 28 mL) in 3 microwave tubes. The reaction mixture was sealed and heated to 80° C. for 3 days. The reaction mixture was concentrated in vacuo. The residue was dissolved in toluene (30 mL) and pTsOH.H2O (150 mg, 0.789 mmol) was added. The reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was filtered and dried under vacuum, to give the title compound (937 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][N:36]1[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]1)[CH:9]=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc1OC
Solvent: CO
Product: COc1ccc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)cc1OC

Procedure:
3′,4′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 33 (300 mg, 0.85 mmol) and 1-phenyl piperazine (0.13 mL, 0.85 mmol) in dry methanol (60 mL) were reacted in a similar manner to that described under 34 to afford 47. Yield 410 mg (94%); mp 191-193° C.; MS (FAB) 517 (M++1); IR (KBr) 3416, 1627; 1H NMR (200 MHz, CDCl3) δ 8.16 (d, J=9.5 Hz, 1H), 7.54 (dd, J=8.3 Hz, 2.1 Hz, 1H), 7.34 (d, J=1.9 Hz, 1H), 7.31-7.23 (m, 2H), 7.04-6.87 (m, 6H), 6.70 (s, 1H), 4.21-4.16 (m, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.28 (t, J=4.8 Hz, 4H), 2.90-2.71 (m, 2H), 2.71-2.65 (m, 4H). Analysis Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.96; H, 6.57; N, 5.51.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:32]=[CH:31][C:16]([CH2:17][CH2:18][N:19]([CH3:30])[C:20](=O)OCC4C=CC=CC=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C=O.[H][H]>CO.[Pd]>[CH3:30][N:19]([CH3:20])[CH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: CN(CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=O
Solvent: CO
Product: CN(C)CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 46.8 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)phenethyl(methyl)carbamate (30 mg, 0.069 mmol), paraformaldehyde (4 mg, 0.14 mmol), and 10% Pd/C (10 mg) in methanol (10 ml) was stirred at room temperature over 1 atm of hydrogen for 4 h. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-HPLC to obtain 2-(4-(2-(dimethylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide (10 mg, yield 48%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.34 (s, 6H), 2.62-2.66 (m, 2H), 2.89-2.93 (m, 2H), 7.46-7.52 (m, 3 H), 7.88-7.91 (m, 2H), 8.224-8.26 (d, J=8.4 Hz, 2H). LC-MS (ESI) m/z: 310 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>ClCCl>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(=O)Cl
Reactant: NCCCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)NCCCC(=O)O
Reaction time: 0.17 h
Yield: 22 %

Procedure:
To a solution of 20 gm (194 mMol) 4-aminobutyric acid in dichloromethane (700 ml) was added 56.8 ml (407 mMol) triethylamine and the mixture was stirred for 10 minutes. To the reaction mixture was then added a solution of 47.4 ml (388 mMol) isovaleryl chloride in dichloromethane (200 ml) dropwise and the resulting mixture was then stirred at room temperature for 2 hours. The reaction mixture was then filtered and the volatiles removed under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide (150 ml) and the solution was stirred for 1.5 hours at room temperature. The aqueous solution was extracted with diethyl ether and the combined ether extracts were washed with water. All aqueous phases were combined and then acidified with concentrated hydrochloric acid. This mixture was then extracted well with ethyl acetate. These organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was slurried in hexane and the hexane decanted from the residue. Remaining residue was distilled in a bulb to bulb apparatus at 220° C. at 0.05 mmHg to give 8.0 g (22%) N-isovaleryl-4-aminobutyric acid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:26])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.CO.[CH2:33](N(CC)CC)C>ClC(Cl)C.CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C:5]1[C:22]([C:23]([O:25][CH3:33])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:26])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)Oc1cc2c(cc1C(=O)O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 3-acetoxyestra-1,3,5(10)-trien-17-one-2-carboxylic acid (62, 1.07 g, 3.0 mmol) in dichloroethane (10 mL) was added thionyl chloride (0.28 mL, 3.9 mmol) and DMF (1 drop) at room temperature. The reaction mixture was stirred for 30 min at 80° C. After the reaction mixture was cooled to 0° C., MeOH (5.0 mL) and triethylamine (1.0 mL) were added, and stirred for 1 h. The reaction mixture was diluted with EtOAc and washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (3:1→3:2, v/v) to afford 0.764 g of 63 (69% yield) mp: 182-183° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[CH:39]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.O>[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[C:39][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#Cc1ccc(C#N)cc1
Temperature: 90 °C
Yield: 91.1 %

Procedure:
Dissolve 4-bromobenzonitrile (3 g, 16.48 mmol) in anhydrous DMF (30 mL) in a sealed tube. Degas the solution, purge with nitrogen and add tris(dibenzylideneacetone)dipalladium(0) (453 mg, 0.49 mmol), copper(I) iodide (188 mg, 0.99 mmol), triphenylphosphine (1.08 g, 4.12 mmol), triethylamine (10 mL) and 3,3-dimethylbutyne (6.1 mL, 49.44 mmol). Heat the mixture at 90° C. overnight. Cool to room temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1) to give the desired intermediate as a solid (2.75 g, 92%).