Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:21][CH:20]=1)=[O:31]
Reactant: Nc1ccc(C(=O)c2cccc(F)c2F)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cccc(F)c2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.02 g, 6.4 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.77 g, 6.4 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4'-Amino-2,3-difluorobenzophenone (1.00 g, 4.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution extracted with methylene chloride (2×50 mL). The combined organics were washed with water and 3N HCl (1×50 mL), dried (MgSO4) and concentrated in vacuo to yield a tan solid. The solid was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Recrystallization of the resulting solid from methylene chloride/hexane yielded the title propanamide as a white solid (1.13 g, 70%); mp 154°-155° C. 1H--NMR (250 MHz, d6--DMSO): 1.60 (s, 3H, CH3) 7.36-7.40 (m, 2H, aromatic) 7.57 (s, 1H, OH) 7.65-7.72 (m, 1H, aromatic) 7.89 (d, 2H, J=8.6 Hz, aromatic) 7.98 (d, 2H, J=8.6 Hz, aromatic) 10.40 (s, 1H, NH). MS (CI, CH4): 374 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:38][C:36]2[S:37][C:33]4[CH:32]=[C:31]([F:30])[CH:40]=[CH:39][C:34]=4[N:35]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc3ccc(F)cc3s2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 6-fluoro-1,3-benzothiazol-2-amine (44 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol), DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 15 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.59 (s, 2H), 7.19 (t, J=74.7 Hz, 1H), 7.21-7.28 (m, 1H), 7.32-7.38 (m, 1H), 7.42-7.48 (m, 2H), 7.57-7.62 (m, 1H), 7.70-7.76 (m, 1H), 7.84-7.93 (m, 2H), 8.05-8.12 (m, 1H), 8.47-8.53 (m, 1H), 13.48 (br s, 1H); ESI-MS (m/z) 573.46 (MH)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[F:22][C:19]1[CH:18]=[C:14]2[C:13](=[CH:21][CH:20]=1)[N:12]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[NH:17][C:15]2=[O:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cc(F)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution of 2-amino-5-fluorobenzamide (13.0 g, 84 mmol) and triethylamine (16 mL, 110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediately a precipitate started forming. Stirring of the solution was continued for 5 hours at room temperature. The formed precipitate was collected by filtration and was washed twice with diethyl ether and dried at 50° C. in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxide solution (250 mL) and heated at reflux until a clear solution was obtained (3 hours). The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified to pH<1 with concentrated aqueous HCl. The formed precipitate was collected by filtration and washed twice with water, twice with methanol, and twice with diethyl ether. The solid was dried in an oven at 45° C. to yield 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (18.2 g, 80%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCN)cc1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.04 g, 4 mmol) and 2-(4-methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (62%) of the title product:
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:10][C:9]2[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:20][C:21]#[N:22]>CN(C)C=O.O>[C:21]([CH2:20][N:8]1[C:9]2[CH2:10][C:2]([F:1])([F:16])[CH2:3][CH2:4][C:5]=2[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:22]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2c([nH]1)CC(F)(F)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(n1CC#N)CC(F)(F)CC2
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 113l (5.0 g, 21.81 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), followed by the addition of sodium hydride (1.3 g, 54.17 mmol, 1.40 equiv, 60%) in several batches at 0° C. over 10 min. (FIG. 14). To this was added 2-bromoacetonitrile (3.7 g, 30.85 mmol, 1.40 equiv) dropwise with stirring at 20° C. over 10 min. The resulting solution was stirred at room temperature for 7 h, diluted with 100 mL of water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to afford 3.3 g (56%) of 113m as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(N)nc(N)c1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1nc(N)nc(N)c1N1CCNCC1
Yield: 79.9 %

Procedure:
A solution of 33.5 g (0.107 mole) of 6-ethyl-5-[4-(phenylmethyl)-1-piperazinyl]-2,4-pyrimidinediamine in 400 ml of acetic acid was hydrogenated over 2 g of 20% palladium on charcoal under 3.5 atmospheres of hydrogen for 23 hours and filtered. The filtrate was concentrated in vacuo to dryness. The solid residue was poured into one liter of 2N sodium hydroxide solution. The solid was collected and washed with 500 ml of water. Recrystallization from acetonitrile and drying in vacuo at 59° C. for 16 hours gave 19.0 g of the product as a white solid; mp 204°-207° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:9]2[S:36][CH:35]=[CH:34][C:10]=2[C:11]2[CH:12]=[C:13]([O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:14]3[S:20][CH:19]=[CH:18][C:15]=3[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[Li+].CCC[CH2-].[CH3:53][Sn:54](Cl)([CH3:56])[CH3:55]>CCCCCC>[CH2:30]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][O:21][C:13]1[C:14]2[S:20][C:19]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:18][C:15]=2[C:16]2[CH:17]=[C:8]([O:7][CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:9]3[S:36][C:35]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:34][C:10]=3[C:11]=2[CH:12]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCC(CCCC)COc1cc2c3ccsc3c(OCC(CCCC)CCCCCC)cc2c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(CCCC)COc1cc2c3cc([Sn](C)(C)C)sc3c(OCC(CCCC)CCCCCC)cc2c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
5,10-Bis-(2-butyl-octyloxy)-1,6-dithia-dicyclopenta[a,f]naphthalene (1.41 g, 2.3 mmol) was added into a 200 mL flask. The system was vacuumed and backfilled with argon 3 times before 60 mL of anhydrous THF was injected. N-Butyllithium (2.2 mL, 2.5 M in hexane, 5.09 mmol) was added after the mixture was cooled to −78° C. A white precipitate was observed after the mixture was stirred at −78° C. for 30 minutes. Stirring was continued at room temperature for one more hour before the mixture was cooled down to −78° C. again. Trimethyltin chloride (1.20 g, 5.75 mmol) was added in portions and stirring was continued overnight at room temperature. Hexane (100 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of solvent under vacuum yielded a white solid. The colorless crystalline product, 5,10-bis-(2-butyl-octyloxy)-2,7-bis-trimethylstannanyl-1,6-dithia-dicyclopenta[a,f]naphthalene, (1.70 g, ˜79% yield) was obtained after recrystallization from a hexane/iso-propanol mixture. 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 2H), δ 7.69 (s , 2H), δ 4.25 (d , 4H, J=5.5 Hz), δ 1.99 (m , 2H), δ 1.33 (m , 32H), δ 0.96 (t , 6H, J=7.0 Hz), δ 0.90 (t, 6H, J=7.0 Hz), δ 0.51 (m , 18H).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N:7]1([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]2[CH:9]=[N:1][CH:2]=[N:3][C:4]=2[N:5]=[CH:6]1
Reactant: c1ncc2[nH]cnc2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc3ncncc32)cc1

Procedure:
Prepared from purine and 1-fluoro-4-nitrobenzene as described for Example 1, Step 1. The product precipitated from the reaction mixture as a single isomer; δ (D6 -DMSO) 8.16 (2H, d, J=9.0Hz, Ar--H), 8.48 (2H, d, J=9.0Hz, Ar--H), 9.13 (1H, s, Ar--H), 9.28 (1H, s, Ar--H), 9.39 (1H, s, Ar--H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=O)O2)=[CH:5][CH:4]=1.[OH2:32].[NH2:33][NH2:34]>C(O)C>[CH3:30][N:28]([CH3:29])[C:25]1[CH:24]=[CH:23][C:22]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:31])=[CH:8][CH:7]=3)[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=3)[C:11](=[O:32])[NH:34][NH:33]2)=[CH:27][CH:26]=1
Reactant: NN
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: O
Solvent: CCO
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)NNC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
With stirring, a mixture of 1200.0 ml of 80 percent aqueous ethyl alcohol, 25.0 g of 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide and 35.4 g of 85 percent hydrazine hydrate was maintained at reflux temperature, approximately 90° C., for approximately three hours. After setting overnight at ambient temperature, the resulting slurry was chilled to approximately 5° C. by means of an external ice bath. The solid was collected by filtration, washed four times each with 50.0 ml of cold water and air-dried to obtain 20.8 g of 4,4-bis(4-dimethylaminophenyl)-7-dimethylaminophthalazin-1(2H)-one (Formula III: R=N(CH3)2 ; R1 =R3 =R9 =H; R4 =R5 =R10 =R11 =CH3), a white-colored solid which melted at 265°-270° C. Significant infrared maxima appeared at 1660 cm-1 (C=O;s) and 3400 cm-1 (N-H;m). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Paper treated with an ink formulation of the product produced a blue-green-colored image when traced with an applied voltage stylus.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[ClH:15]>O>[Cl:15][C:10]1[C:9]2[O:12][CH2:13][C:7]3[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=3[C:8]=2[CH:7]=[C:6]2[CH:5]=[CH:4][C:3]([OH:14])=[CH:2][C:11]=12
Reactant: COc1ccc2ccc(O)c(Cl)c2c1
Reactant: Cl
Solvent: O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Cl

Procedure:
A mixture of Example 9 (2.25 g, 6.92 mmol) and pyridiumium hydrochloride (21.9 g, 162 mmol) was heated to 184° C. for 2 hrs. The reaction mixture was allowed to cool and poured into water (300 mL) and extracted with ethyl acetate (2×200 mL), washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the product was chromatographed (40% ethyl acetate-hexanes) to afford a white solid which was triturated with methylene chloride (25 mL) to afford 1.2 g (58%); mp 230-231° C.
Reaction SMILES: I[C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22](C=O)C>[Cu]I>[F:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:7](=[O:8])[C:6]2[CH:5]=[CH:4][O:3][C:2]=2[N:22]=[CH:21]1
Reactant: CN(C)C=O
Reactant: O=C(NCC(F)(F)F)c1ccoc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c2ccoc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 22 %

Procedure:
Into seven 20 ml microwave tubes were placed 2-iodo-N-(2,2,2-trifluoroethyl)furan-3-carboxamide (0.62 g, 1.94 mmol), formimidamide, HCl (0.78 g, 9.72 mmol), copper(I) iodide (0.037 g, 0.194 mmol) and potassium carbonate (0.81 g, 5.83 mmol) in anhydrous DMF (13 ml). The tubes were sealed and heated to 100° C. for approximately 68 h with stirring. After cooling, the combined mixtures were partitioned between brine/water (1:1, 900 ml) and ethyl acetate (225 ml). The mixture was filtered through a plug of Celite. The aqueous phase was separated and extracted with ethyl acetate (3×225 ml). The combined organic layers were washed with brine/water (1:1, 4×225 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-20% ethyl acetate in cyclohexane) to afford the title compound (647 mg, 22%). LCMS RT=0.79 min, M+H+=219.1.
Reaction SMILES: C([C:3]1([O:15]C)[CH:8]=[CH:7][C:6](C2C=CC=CC=2)=[CH:5][CH2:4]1)#N.[Cl-].[NH+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.N1C=CC=[CH:27][CH:26]=1>>[C:23]([C:22]1[CH:27]=[CH:26][C:19]([C:6]2[CH:7]=[CH:8][C:3]([OH:15])=[CH:4][CH:5]=2)=[CH:20][CH:21]=1)#[N:18]
Reactant: c1ccncc1
Reactant: c1cc[nH+]cc1
Reactant: COC1(C#N)C=CC(c2ccccc2)=CC1
Agent: Cl
Agent: [Cl-]
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 10 g of 4-cyano-4-methoxy biphenyl and 30 g of pyridinium chloride is taken to 200° C. for 2 hours. 50 ml of pyridine then 50 ml of 1N hydrochloric acid are added at 110° C. Extraction is carried out with chloroform (100 then 25 ml). The combined organic extracts are washed twice with 100 ml water, dried over magnesium sulphate, and the solvent is eliminated by distillation under reduced pressure. 7 g (75% yield) of 4-cyano-4'-hydroxy-biphenyl is obtained in the form of a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCCc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cccc(CCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 5-(3-methoxyphenyl)pentanoate (6.01 g, 25.4 mmol) in a mixed solvent of ethanol (50 mL) and tetrahydrofuran (50 mL) was added 2 M aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.28 g, yield 99%) as a red-brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([O:24][C:25](=[O:29])[CH:26](Br)[CH3:27])[CH3:23].CC#N>CC(C)=O.O>[CH2:22]([O:24][C:25](=[O:29])[CH:26]([N:6]1[C:5]2[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)c([N+](=O)[O-])cc21
Temperature: 70 °C
Yield: 112.6 %

Procedure:
To 7-methyl-6-nitro-4H-benzo[1,4]oxazin-3-one (50% purity; 0.870 g, 1.44 mmol) and K2CO3 (1.15 g, 8.36 mmol) in acetone (20 mL) was added 2-bromo-propionic acid ethyl ester (1.5 g, 8.36 mmol) and the mixture was heated at 70° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo and the residue was dissolved in DCM (15 mL). The solution was washed with water (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give a mixture of the title compound as a yellow solid (total 0.5 g crude, 48% desired product as indicated by HPLC at 254 or 220 nm), HPLC (Column: Ultimate XB-C18, 3 um, 50×3.0 mm; Mobile phase: MeCN (0.02% TFA) in water (0.04% TFA), from 30% to 90% within 7 min; Flow rate: 1.5 mL/min; Wavelength: 220 nm) Rt=3.42 min.), which was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)=[CH:3][CH:2]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:32]=[C:33]([CH2:35][O:36][C:37]5[CH:46]=[CH:45][C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[N:38]=5)[N:34]=[C:8]4[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(OCc3cn4c(-c5ccc(N6CCNCC6)nc5)cnc(-c5ccncc5)c4n3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of compound 87e (60.0 mg, 0.0976 mmol) in 3 mL of DCM at rt was added TFA (0.50 mL). The resulting mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was triturated with Et2O. The solid was collected by filtration and washed with Et2O. After drying under reduced pressure, the title compound 120 was obtained as an orange solid. 1H-NMR (CD3OD; 400 MHz) 9.36 (d, J=6.1 Hz, 2H), 8.92 (d, J=6.1 Hz, 2H), 8.62 (s, 1H), 8.30 (s, 1H), 8.05-8.20 (m, 3H), 7.82 (t, J=7.3 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.82 (s, 2H), 3.96-4.04 (m, 4H), 3.34-3.41 (m, 4H). Mass spectrum (LCMS, ESI pos.): Calcd. for C30H26N8O, 515.2 (M+H). found 515.2.
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OO>O.C(O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:1])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.0 g) in water (5 ml) was added to a solution of the product of (i) above (1.0 g) in ethanol (10 ml), followed by 30% hydrogen peroxide solution (2.5 ml). The mixture was stirred at 50° C. for 1.5 hours, at room temperature for 1 hour and then evaporated. The residue was triturated with water, the mixture was filtered and the solid was crystallised from n-propanol/water to give the title compound (0.28 g), m.p. 327°-330° C. Found: C,68.31; H,6.59; N,19.78. C16H18N4O requires: C,68.09; H,6.43; N,19.85%.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:11][CH:10]1[C:3]2[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][C:4]=2[O:7][CH:9]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC=CN1CCOCC1
Reactant: O=C1C=CC(=O)C=C1
Solvent: Cc1ccccc1
Product: CC1c2cc(O)ccc2OC1N1CCOCC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Benzoquinone (300 g, 2.8 mol) was added in toluene (1.5 L) and cooled with a dry ice/isopropyl alcohol (IPA) bath. 4-Propenyl-morpholine (prepared as above in EXAMPLE I) (380 g, 3 mol) was added dropwise with stirring. The reaction mixture was aged for overnight, filtered and subsequently air dried to provide 3-methyl-2-morpholin-4-yl-2,3-dihydro-benzofuran-5-ol (628 g, 2.7 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]([Cl:16])([Cl:15])[CH2:10][O:11][C:12](Cl)=[O:13].[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][CH:23]=1>>[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][C:23]=1[CH:7]1[CH:6]=[CH:5][N:4]([C:12]([O:11][CH2:10][C:9]([Cl:16])([Cl:15])[Cl:8])=[O:13])[CH:3]=[C:2]1[Cl:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Clc1cccnc1
Reactant: CC1=CSCC(=O)N1
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2Cl)SCC(=O)N1
Yield: 46.3 %

Procedure:
3-Chloropyridine (0.88 g), 2,2,2-trichloroethylchloroformate (1.33 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (0.5 g) were treated in the same manner as described in Example 2 (i) to give the titled compound (0.75 g, yield 46.3%) as milky white crystals. Chloroform-methanol (=30:1) was used as a developing eluant.