Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[S:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(N)=O)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=S)cc1OC
Yield: 68.1 %

Procedure:
To a 25 ml eggplant-shaped bottle were added 0.15 g (0.717 mmol) 3-(3,4-dimethoxy-phenyl)-propanamide prepared in step 2, 0.16 g (0.717 mmol) P2S5 and 10 ml THF. A reflux condensing tube carrying a calcium chloride drying tube was mounted. The mixture was refluxed for 1 hour under magnetic agitation, concentrated under a reduced pressure, partitioned between ethyl acetate and saturated NaHCO3 solution each of 15 ml. The aqueous layer was extracted with ethyl acetate twice ×10 ml. The organic phase was combined, washed with saturated brine twice ×15 ml, dried over Na2SO4, filtered and concentrated to obtain a solid crude product which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 10:1 (V:V) to obtain a 0.11 g product as a white solid in a yield of 68.8%, mp: 140-141 └. 1H-NMR (CDCl3, 600 MHz) δ: 2.93 (2H, t, J=7.20 Hz, CH2), 3.07 (2H, t, J=7.84 Hz, CH2), 3.86 (3H, s, CH3O), 3.87 (3H, s, CH3O), 6.62 (1H, br), 6.75˜6.82 (3H, m, ArH), 7.35 (1H, br); ESI-MS (m/e, %): 248.3 (M+Na, 100), 226.3 (M+H, 64).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonic acid amide (1.7 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A19. A solution of 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (231.2 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B19. Solution B19 was added to Solution A19 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid (4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (94.7 mg, 30%) as a white solid: MS (ESI) M+1=386.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:13])[C:10]([O:12][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(Br)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)Cc1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 68 %

Procedure:
To a solution of 3-(4-bromophenyl)-2-oxopropionic acid (70.0 mg, 0.288 mmol) in DMF (2 mL) at 0° C. was added DBU (72.2 mg, 0.288 mmol) and iodomethane (204 mg, 1.440 mmol). The reaction mixture was stirred for 2.5 hours at the same temperature. The reaction was acidified with 1 M HCl and extraction with ether (3×25 mL), drying (MgSO4), concentrated under reduced pressure and dried on vacuum to get the light brown oily compound B18 in 68% yield and used as such in next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22](I)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(I)cc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(Br)c1N
Temperature: 70 °C
Yield: 174 %

Procedure:
N-Bromosuccinimide (13.5 g, 76.0 mmol) was added in portions over 1.5 h to a stirred solution of methyl 2-amino-5-iodobenzoate (20 g, 72 mmol) in CHCl3 (320 mL) at RT. This was stirred overnight and then silica gel chromatography (step gradient elution with hexane containing 10 to 30% DCM) afforded impure methyl 2-amino-3-bromo-5-iodobenzoate (21 g) as a white solid that was used as such. A flask containing a mixture of 3- (trifluoromethyl)phenylboronic acid (3.73 g, 19 6 mmol), methyl 2-amino-3-bromo-5-iodobenzoate (7.0 g, 16 mmol), K2CO3 (6.85 g, 49 6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.4 g, 1 7 mmol), dioxane (140 mL), and water (28 mL) was degassed and flushed with N2 twice and then heated at 70° C. for 3 h. It was cooled to RT, diluted with EtOAc, washed with water (2×), brine, and then dried over Na2SO4. Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0 to 7% MeOH) afforded impure methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (6.2 g, 10.44 mmol, 63.2% yield) as a white solid that was used as such. A mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg, 1.00 mmol), methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (250 mg, 0.668 mmol), tetrakistriphenylphosphine palladium(0) (77 mg, 0.067 mmol), K2CO3 (369 mg, 2.67 mmol) in a microwave vial was flushed with nitrogen and DMF (2.7 mL) was added. The vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried over sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with hexane containing 0, to 20% EtOAc) afforded methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (150 mg, 0.532 mmol, 80% yield). MS (ESI) m/z 470.20 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=2.14 Hz), 7.81 (1H, s), 7.73-7.78 (1H, m), 7.49-7.56 (3H, m), 7.37 (2H, d, J=8.55 Hz), 7.05 (2H, d, J=8.55 Hz), 6.15 (2H, br, s.), 3.95 (3H, s), 3.26-3.38 (4H, m), 2.60-2.69 (4H, m), 2.39 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1>C(O)C.[OH-].[Na+]>[C:23]([C:22](=[CH:5][C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)#[N:24]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: N#CCc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1C=C(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A mixture of 1.96 g (10.0 mmol) of 2,4,5-trimethoxybenzaldehyde (purchased from Lancaster), and 1.96 g (10.0 mmol) of 4-bromophenylacetonitrile (purchased from Tokyo Kasei) in 5 ml of ethanol (purchased from Kokusan Kagaku) was heated to dissolve. Two drops of 20% aqueous sodium hydroxide solution was then added and the reaction mixture was stirred over night at ambient temperature. To the resultant reaction mass was added ethanol and crushed, and the precipitate was collected and washed with ethanol twice and with hexane twice, and dried to give 3.58 g (yield: 95.6%) of α-cyano-4-bromo-2',4',5'-trimethoxystilbene (as a yellow crystalline).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([C:14]2([OH:17])[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccsn1
Solvent: CCOCC
Product: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1

Procedure:
The title compound was prepared as a white solid from 3-methyl-isothiazole (Focus Synthesis) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 33.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO.C(OCC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Yield: 44.6 %

Procedure:
0.2 g (0.769 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate is added at a temperature in the region of 20° C. to a suspension of 0.02 g (0.188 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.079 g of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate, in the form of a brown solid; EI: m/z=230 (M+) base peak, m/z=202 (M-C2H4+), m/z=157 (M-C2H5O+).
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH2:18]C)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:50][O:51][C:52](=[O:57])C(Br)(C)C>CC#N>[CH3:50][O:51][C:52](=[O:57])[C:17]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:18])[CH3:14]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (30 mg, 0.0922 mmol), Cs2CO3 (75 mg, 0.23 mmol) and 2-bromo-2-methylpropionic acid methyl ester (36 uL, 0.277 mmol) in CH3CN (2 mL) was heated at reflux temperature for 2 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid methyl ester as a colorless gum (40 mg, quantitative). LCMS: RT 3.25 min [M+H]+ 426.1
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:16][NH:15][CH:14]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[C:27]#[N:28])[CH2:21][CH2:20]4)=[O:18])[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:33]([N:15]1[CH2:16][CH:12]([N:10]2[N:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11]2)[CH2:13][CH:14]1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[CH2:21][CH2:20]1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
2-(4-{4-[5-(Phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (2), benzaldehyde and acetic acid (cat) is dissolved in DCM and the solution is stirred for 20 min. Then NaBH(OAc)3 is added. The resulting mixture is warmed to r.t and stirred overnight. The solution is then washed with sat NaHCO3, brine, dried and concentrated to afford 2-(4-{1-Benzyl-4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (I).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Yield: 96 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), sec-butylamine (E, 0.155 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-sec-Butylsulfamoyl-2-fluoro-benzoic acid (F, 0.56 g, 96%). After drying overnight under vacuum, F (0.56 g, 0.0020 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 0.26 g, 0.0020 mol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.45 g (57%) of 5-sec-butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-23) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:21][C:19]1[CH:18]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([CH:20]=1)[O:5][C:4]1[C:3]([CH3:28])=[C:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Reactant: CCS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
1.18 g 3-(3-amino-2-methylphenoxy)-5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (2.3 mmol, 1 eq.) were dissolved in 9.6 mL pyridine, cooled to 0° C., treated with 292 μL ethyl sulfonyl chloride (3.1 mmol, 1.2 eq.) and stirred at 0° C. for 3 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo to yield 1.6 g of the crude product, which was taken up in toluene and again concentrated in vacuo. The crude product was used in the subsequent transformations without further purification.
Reaction SMILES: [C:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6])(=[O:3])[CH3:2].[CH3:13]C([O-])(C)C.[K+].C(Cl)(=O)CC>O1CCCC1>[C:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6])(=[O:3])[CH2:2][CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: C=C(OC(C)=O)c1ccccc1
Agent: CCC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(OC(=O)CC)c1ccccc1
Reaction time: 1 h
Yield: 14 %

Procedure:
A solution of 8.11 g (50 mmol) of 1-phenylvinyl acetate (prepared as described in Example 1) in 80 ml of anhydrous tetrahydrofuran was placed in a 500 ml round bottomed flask and cooled to −75°. A solution of 6.16 g (55 mmol) of potassium tert-butylate in 60 ml of anhydrous tetrahydrofuran was slowly added (40′) and the mixture was stirred for 1 h at −75°. A solution of propionyl chloride (55 mmol) in 20 ml of anhydrous tetrahydrofuran was slowly added (20′) and, after 2 h at −75°, the cooling bath was removed and 60 ml of a saturated solution of NaHCO3 was rapidly added. The temperature rose rapidly to −10° and the mixture was extracted with ether. After usual workup, the product was purified by flash chromatography (SiO2, pentane/ether 8/2), bulb-to-bulb distillation and preparative GC using a 1.2 m×6 mm column loaded with 10% SE-30 on Supelcoport® 80–100 mesh, vector gas: helium at 30 ml/min. The product was obtained in 14% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.Cl.C([O:18][N:19]=O)CCC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:19][OH:18])[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CC(=NO)C2=O
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 5-methoxy-1-indanone (25 g, 0.15 mol) in 300 ml MeOH was added 15 ml concentrated HCl, and then n-butylnitrite (19.5 ml, 0.17 mol) in 50 ml MeOH at 40° C. The solution was stirred for 2 hours during which time a precipitate was formed. The precipitate was collected and dried to yield a white solid (22.3 g, 75% yield). LC-MS: 192 (MH+)
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:15][C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[N:25][C:24]([Cl:29])=[CH:23][CH:22]=2)=[O:17]>CC(C)=O>[C:1]([O:4][CH2:15][C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[N:25][C:24]([Cl:29])=[CH:23][CH:22]=2)=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(CCl)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
To a solution of acetic acid (0.32 mL, 5.5 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol) in acetone (20 mL) was added 2-chloro-1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (0.26 g, 0.96 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with satd. aq. sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the desired product (0.12 g, 42%) as a white solid. ESI MS m/z 299 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Temperature: 170 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
5-(2,2-diethoxyethoxy)-2-fluoropyridine (502 mg, 2.19 mmol) and potassium tert-butoxide (279 mg, 2.49 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (240 mg, 1.00 mmol), and stirred at 170° C. for 15 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled to room temperature, then water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (292 mg, yield: 65%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(N(CC)CC)C>C(OCC)(=O)C.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.[Cu]I>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][CH2:16][OH:22])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: C#CCCCCO
Reactant: COc1cc(Br)ccc1-n1cnc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C#CCCCCO)ccc1-n1cnc(C)n1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(4-bromo-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.00 g), 5-hexyn-1-ol (2.45 mL), dichlorobis(triphenylphosphine)palladium(II) (786 mg), copper(I) iodide (213 mg) and triethylamine (110 mL) was stirred at 70° C. for 14 hr, allowed to cool to room temperature, and diluted with ethyl acetate, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.80 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27].C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH:27][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: COC(CN)OC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 85 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a solution of methyl [4-chloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.70 g, 8.39 mmol) and aminoacetoaldehyde dimethyl acetal (1.83 mL, 16.78 mmol) in dioxane (40 mL) was added N,N-diisopropylethylamine (1.46 mL, 8.39 mmol). The mixture was stirred at 85° C. for 1 day. After cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (ethyl acetate) to give methyl [4-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)-pyrimidin-5-yl]acetate (2.41 g, 74%) as brown oil.