Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.[C:54]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[C:73]([CH3:74])=[C:72](Cl)[C:71]3[C:66](=[CH:67][C:68]([F:77])=[CH:69][C:70]=3[F:76])[N:65]=2)=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[N:38]1([C:41]2[C:46]([NH:47][C:72]3[C:71]4[C:66](=[CH:67][C:68]([F:77])=[CH:69][C:70]=4[F:76])[N:65]=[C:64]([C:61]4[CH:62]=[CH:63][C:58]([C:54]([CH3:56])([CH3:55])[CH3:57])=[CH:59][CH:60]=4)[C:73]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(C(C)(C)C)cc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(C(C)(C)C)cc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.022 g, 0.046 mmol), 2,5-dimorpholinopyridin-3-amine (0.092 g, 0.35 mmol), 2-(4-tert-butylphenyl)-4-chloro-5,7-difluoro-3-methylquinoline (0.1 g, 0.29 mmol) and Pd2dba3 (10.6 mg, 0.012 mmol) in toluene (2.89 mL) was added sodium t-butoxide (0.069 g, 0.72 mmol). The reaction mixture was heated to 120° C. and stirring continued for 1.5 h. The reaction was cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(4-(2-methyl-2-propanyl)phenyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 7.59-7.73 (3H, m), 7.50-7.57 (4H, m), 6.98 (1H, m), 6.37 (1H, br. s.), 3.92 (4H, br. s.), 3.79-3.87 (4H, m), 3.25 (4H, br. s.), 2.99-3.09 (4H, m), 2.18 (3H, s), 1.36-1.45 (9H, s). Mass Spectrum (ESI) m/e=574.3 (M+1).
Reaction SMILES: CON(C)[C:4]([CH2:6][C:7]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8]1)=[O:5].[CH3:15][Li]>C1COCC1>[O:5]=[C:4]([CH3:15])[CH2:6][C:7]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:9]1
Reactant: CON(C)C(=O)CC1(CC(=O)O)CC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)CC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.6 g crude {1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid (18 mmole) in 54 ml of THF are added 24.5 ml of methyllithium (1.6 M solution in diethyl ether, 39.2 mmole, 2.2 eq) at <−75° C. Stirring is continued for 2 hours, then the mixture is quenched by addition of 2 ml of methanol and warmed to room temperature. 54 ml of water are added and the phases are separated. The aqueous product phase is washed with 27 ml of methyl tert-butyl ether, acidified to pH 2.5 by addition of conc. HCl and extracted three times with 27 ml ethyl acetate each. The combined organic phases are concentrated to dryness and the residue is directly used in the next step (esterification to [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[CH:5][N:6]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:26][C:23]3[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=3)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[CH:5][N:6]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(OCc2cnc(Cl)s2)ccc1Cl
Solvent: CCO
Product: Nc1ccc(Sc2ccc(OCc3cnc(Cl)s3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole (from Example 25A) was reacted with 4-aminothiophenol in anhydrous ethanol and at reflux under a nitrogen atmosphere. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was taken up in water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride afforded 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)aniline. A mixture of 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)aniline and di-tert-butyl dicarbonate in 1,4-dioxane was heated at reflux under a nitrogen atmosphere, and then additional Boc anhydride was added and the reaction allowed to reflux. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The resulting solid was triturated with 2.5% ethyl acetate/methylene chloride to obtain tert-butyl 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate. A suspension of 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate, iron powder, and ammonium chloride in water and ethanol was heated. The reaction was cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:39])[C:35]([N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH:11]=[C:10]([C:9]2[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=2)[N:19]=4)[CH2:25][CH2:26]1)([CH3:37])[CH3:36])[CH3:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (100 mg, 0.255 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (45 uL, 0.31 mmol), cesium carbonate (187 mg, 0.57 mmol) and DMF (0.5 mL) was heated at 70° C. for 3 h the then stirred at RT for 18 h then heated again at 70° C. for 4 h before concentrating in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionic acid ethyl ester (47 mg, 36%). LCMS RT=2.24, [M+H]+=507.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate (170 mg, 0.571 mmol) was dissolved in MC (3 ml), followed by addition of trifluoroacetic acid (3 ml), and then the resulting mixture was stirred at room temperature for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous NaHCO3 solution (15 ml), and extracted with MC (15 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 112 mg of white solid (99%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1)=O>>[OH:3][N:2]=[CH:4][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Reactant: NO
Agent: Cl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=NO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using hydroxylamine hydrochloride (77 mg, 1.11 mmol) and 3′-(7-formylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (120 mg, 0.37 mmol) to afford a white crystalline solid (105 mg, 83%), essentially as a single geometric isomer. 1H NMR (400 MHz, d6-DMSO) δH 7.27 (1H, dd, J 1 and 7), 7.61-7.90 (8H, m), 7.90 (2H, s), 8.00 (1H, dd, J 8 and 1), 8.25 (1H, s), 8.68 (1H, d, J 7), 11.53 (1H, s); m/z (ES+) 339 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:34]([N:24]3[CH2:25][CH2:26][N:27]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:23]3=[O:22])=[O:35])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 118.9 %

Procedure:
A 0° C. mixture of Example A5 (1 g, 4.51 mmol) and pyridine (1.1 mL, 13.6 mmol) in DCM (25 mL) was treated with a solution of Example B2 (1.680 g, 7.22 mmol) in DCM (8 mL), warmed to RT and stirred 45 min. The mixture was concentrated to dryness, the residue treated with DCM and Et2O, sonicated and the resulting solid collected via filtration. The solid was dissolved in DCM, washed with water, the aqueous layer back-extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (2.24 g, 119%) which was used without further purification. MS (ESI) m/z: 418.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C[O-]
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (8.8 g, 40 mmol), sodium methoxide (4.3 g, 80 mmol), and methanol (50 mL). The reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (60 mL) and water (60 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford 336a as a yellow oil (6.1 g, 90%). MS-ESI: [M+H]+ 172.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[N:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 66 %

Procedure:
3.4 g of methyl chloronicotinate, 5.5 g of potassium carbonate, 3.3 g of 4-pyridylpiperazine and a spatula tipful of 18-crown-6 were heated at 100° C. for 5 h in 75 ml of DMF and then stirred at room temperature for 60 h. The excess potassium carbonate was filtered off, the filtrate was concentrated and the residue was partitioned between water and ethyl acetate. After drying the organic phase over magnesium sulfate and concentrating the solvent, 3.9 g (82%) of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:35][CH:36]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.11 g, 0.352 mmol) and 4-(4-bromobenzoyl)morpholine (0.095 g, 0.352 mmol) as the starting materials.
Reaction SMILES: C([O:4][P:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[NH:22][C:21]3[CH:23]=[C:24]([Cl:37])[C:25]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[N:32]([CH3:36])[CH:31]=[CH:30]5)=[CH:26][C:20]=3[N:19]=2)[CH:12]=1)(=[O:10])[O:6]C(C)C)(C)C.C[Si](N[Si](C)(C)C)(C)C.Br[Si](C)(C)C>C(Cl)Cl>[Cl:37][C:24]1[C:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[CH:31]=[CH:30]3)=[CH:26][C:20]2[N:19]=[C:18]([O:17][C:13]3[CH:12]=[C:11]([P:5](=[O:4])([OH:10])[OH:6])[CH:16]=[CH:15][CH:14]=3)[NH:22][C:21]=2[CH:23]=1
Reactant: CC(C)OP(=O)(OC(C)C)c1cccc(Oc2nc3cc(-c4ccc5c(ccn5C)c4)c(Cl)cc3[nH]2)c1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: Cn1ccc2cc(-c3cc4nc(Oc5cccc(P(=O)(O)O)c5)[nH]c4cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 16-8 (70 mg, 0.13 mmol) in 2 mL of CH2Cl2 was added hexamethyldisilizane (0.3 mL), followed by bromo trimethylsilane (0.17 mL, 1.3 mmol). The reaction was allowed to stir for 18 h at ambient temperature. Organic solvent was removed in vacuo, followed by the addition of H2O (2 mL). The crude product was sonicated and yielded a yellow suspension. The product was collected by vacuum filtration and washed three times with CH2Cl2 and two times with MeOH. The resulting solid was dried in vacuo to give the title compound 16-9 as a white solid. 1H NMR δ 3.83 (3H, s), 6.46 (1H, d, J=3 Hz), 7.19 (1H, d, J=8.5 Hz), 7.36 (2H, m), 7.47 (1H, d, J=9 Hz), 7.53-7.63 (6H, m); LC-MS: m/e 454(M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[O:11]=[P:12](Cl)(Cl)Cl>BrCCBr.C1COCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:12](=[O:11])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(P(=O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A reaction flask under nitrogen containing magnesium turnings (223.9 g, 9.21 mol) and 1950 mL THF was charged with 1 drop of 1,2-dibromoethane and heated to reflux for 1 h. Heating was removed and p-bromoanisole (1683 g, 9.00 mol) was added dropwise at a rate to maintain reflux. After holding the reaction mixture overnight, POCl3 (460.0 g, 3.00 mol) was added slowly over 2 h at 50–79° C. and the resulting mixture was held overnight at 50° C. The product was isolated by aqueous workup to give 984.5 g of tris(4-methoxyphenyl)phosphine oxide (89.0% yield). Recrystallized analytical specimen (from ethyl acetate): mp 145.2° C. (DSC), lit. 143–144° C. (J. Org. Chem. 1960, 25, 2001).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:28]=[C:27]([CH2:37][C:38]([O-])=[O:39])[N:26]=1.[Na+]>CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:38](=[O:39])[CH2:37][C:27]1[N:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:28]=1
Reactant: COc1cc(N2CCOCC2)nc(CC(=O)[O-])n1
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(N2CCOCC2)nc(CC(=O)N2CCc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.2 g of 4-fluoro-2,3-dihydro-1H-indole and 1.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 1.7 g of sodium (4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetate in 15 ml of DMF and 5 ml of pyridine. The reaction medium is stirred at ambient temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and then diluted in 80 ml of water and 15 ml of ethyl acetate. The precipitate formed is washed with 15 ml of ethyl ether and then with 15 ml of petroleum ether. After drying under reduced pressure, 1.53 g of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)ethanone are obtained in the form of a pink solid used as it is in the next step.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C(OC(C)(C)C)(=O)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])OC(C)(C)C)=[C:24]([CH:36]=O)[CH:23]=1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.O1CCCC1.O1CCOCC1.O>[Cl:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:26][N:27]=1)[NH:28][C:29](=[O:35])[CH:1]=[CH:36]2
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1ccc2cc(Cl)ncc2[nH]1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a solution of N,N-diisopropylamine (4.6 mL, 33 mmol) in anhydrous ethyl ether cooled at −78° C. was added n-butyllithium (1.0M solution in hexanes, 22 mL, 36 mmol). After 30 minutes at this temperature, tert-butyl acetate (3.8 g, 33 mmol) was added slowly to the reaction mixture as a solution in anhydrous diethyl ether (10 mL). After another 20 minutes of stirring at −78° C., tert-butyl 6-chloro-4-formylpyridin-3-ylcarbamate (4.0 g, 16 mmol) was slowly added to the mixture as a solution in tetrahydrofuran (10 mL). The reaction mixture was warmed to room temperature and then poured onto ice. The organic layer was separated, dried over sodium sulfate, and evaporated in vacuo to afford a residue that was redissolved in 1,4-dioxane (30 mL), treated with a 5.0M solution of hydrogen chloride in water (30 mL), and heated at 90° C. for 2 hours. The cooled reaction mixture was neutralized by addition of solid sodium bicarbonate, producing a fine white precipitate. Solids were collected via vacuum filtration, washing with water (25 mL) and then tetrahydrofuran (25 mL) to afford the title compound as a white solid (2.3 g, 82%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:26][O:25][C:23](=[O:24])[C:22]([C:21]1[N:18]=[C:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:20]=1)([CH3:28])[CH3:27]
Reactant: N=C(Nc1ccc(Br)cc1)c1c(Cl)cccc1Cl
Reactant: COC(=O)C(C)(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C(C)(C)c1cn(-c2ccc(Br)cc2)c(-c2c(Cl)cccc2Cl)n1
Temperature: 170 °C
Yield: 57 %

Procedure:
A mixture of N-(4-bromophenyl)-2,6-dichlorobenzamidine (1.03 g, 3.0 mmol), methyl 4-bromo-2,2-dimethylacetoacetate (1.78 g, 8.0 mmol) and NaHCO3 (0.76 g, 9.0 mmol) in isopropanol (12 mL) was heated in a microwave unit (Biotage Initiator™) at 170° C. for 25 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 15:85 to 50:50) to give the title compound (0.80 g, 57%) as a pale yellow solid. 1H-NMR (DCM-d2): δ 7.44 (d, 2H), 7.27-7.34 (m, 3H), 7.09 (m, 2H), 3.67 (s, 3H), 1.61 (s, 61-1); MS (ES): 467, 469, 471 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C@@H:2]1[C@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@@H](C)NC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1NC(=O)c2cc3ccc(C(=O)O)cc3n2[C@H]1C
Temperature: 70 °C
Yield: 90 %

Procedure:
To a solution of ethyl (3R,4S)-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (851 mg, 3.0 mmol) in ethanol (20 mL) is added 1M NaOH solution (7.0 mL, 7.0 mmol). The reaction mixture is heated at 70° C. for 2 h. The solvent is removed and the residue is acidified using 1M HCl solution until the pH is 5. The resulting white solid is filtered and dried to afford the title compound (697 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[CH2:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][C:22]#[CH:23]>CCCCCCC.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=[CH:6][N:7]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C#CCCCc2ccccc2)ncn1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (36.6 mg, 31%); 1H NMR δ (CDCl3): 9.01 (s, 1H), 7.31-7.25 (m, 2H), 7.22-7.16 (m, 4H), 2.78 (t, J=7.18 Hz, 2H), 2.51 (s, 3H), 2.41 (t, J=7.17 Hz, 2H), 1.93 (p, J=7.22 Hz, 2H); LCMS m/z: 236.