Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:29]=2)[C:19]([C:34]#[N:35])=[C:18]([SH:36])[N:17]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:29]=2)[C:19]([C:34]#[N:35])=[C:18]([S:36][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[S:6][CH:7]=2)[N:17]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
63 mg (0.26 mmol) of 4-chloromethyl-2-(4-chlorphenyl)thiazole, 100 mg (0.23 mmol) of the compound from example 2A and 78 mg (0.93 mmol) of sodium bicarbonate are dissolved in 1.5 ml of DMF, and the reaction solution is stirred at RT for 20 h. The mixture is then filtered through a paper filter, and the filtrate is directly purified chromatographically by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). This gives the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])C.C(OCC)(=O)C>O>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:1])[C:3]([O:20][CH3:18])=[O:4]
Reactant: CC(C)(CO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-methyl-2-phenyl-propanol (Intermediate 3) (0.5 kg) and pyridine (268 ml) were charged to a reactor and chilled to 0° C. Acetic anhydride (680 gms) was slowly added through a dropper at 10-20° C. The mixture was stirred for 2 hours at 10-20° C. Ethyl acetate (1.5 ltr) was added and chilled water (2 ltrs) was slowly added through a dropper at 10-20° C. The mixture was stirred for ½ hr. The ethyl acetate layer was separated and 10% chilled dilute HCl was added. The ethyl acetate layer was then washed with sodium bicarbonate until a pH of 7 was obtained. The ethyl acetate layer was dried with sodium sulphate and concentrated under vacuum The resulting oil was distilled under vacuum (15 mm of Hg). at 80-100° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:28][CH:27]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: COc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 2.01-2.32 (m, 2H), 2.50 (m, 2H), 3.06 (m, 2H), 3.24 (m 2H), 3.88 (s, 3H), 6.67 (s, 1H), 7.05 (d, 2H, J=8.9 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.68 (d, 2H, J=8.9 Hz), 7.80 (d, 2H, J=8.9 Hz), 7.92 (s, 1H); MS (ESI) m/z 364.1 (M++1).
Reaction SMILES: C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C(N(CC)CC)C.FC(F)(F)[C:34]([OH:36])=O.FC(F)(F)C(O)=O.[Cl:46][C:47]1[CH:48]=[N:49][C:50]2[NH:51][C:52]3[CH:53]=[N:54][CH:55]=[C:56]([CH:69]=3)[CH2:57][CH2:58][C:59]3[CH:67]=[C:63]([NH:64][C:65]=1[N:66]=2)[CH:62]=[CH:61][C:60]=3[NH2:68]>C1COCC1>[Cl:46][C:47]1[CH:48]=[N:49][C:50]2[NH:51][C:52]3[CH:53]=[N:54][CH:55]=[C:56]([CH:69]=3)[CH2:57][CH2:58][C:59]3[CH:67]=[C:63]([NH:64][C:65]=1[N:66]=2)[CH:62]=[CH:61][C:60]=3[NH:68][C:34]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of 20% phosgene in toluene (0.49 mL, 0.93 mmol) was added a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (38 mg, 0.20 mmol) and triethylamine (102 μL, 0.734 mmol) in THF (0.5 mL). The resulting solution was stirred for 2 hours then concentrated. To the isolated solids was added DCM (0.75 mL) followed by 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) (70 mg, 0.1 mmol) and triethylamine (73 μL, 0.52 mmol). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash column chromatography to yield the desired product (34 mg, 50%). LCMS calculated for C27H32ClN8O3(M+H)+: m/z=551.1.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[N+:23]([C:26]1[N:27]=[CH:28][N:29]([CH:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([OH:34])=[O:33])[CH:30]=1)([O-:25])=[O:24].C(N(CC)CC)C>O.C(O)C>[N+:23]([C:26]1[N:27]=[CH:28][N:29]([C@H:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([OH:34])=[O:33])[CH:30]=1)([O-:25])=[O:24]
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 35.9 %

Procedure:
To a solution of (-)-cinchonidine (48.0 g, 163 mmol) in 880 mL of distilled H2O at room temperature was added 2-(4-nitro-1H-imidazol-1-yl)-octanoic acid 83.0 g, 326 mmol) as a solution in 440 mL of ethanol. To this mixture was added triethylamine (11.7 mL). The mixture was then heated to 80° C., and the pH was maintained between 6.9 and 7.1 by the dropwise addition of triethylamine (5-10 mL). After the pH stabilized at 7.01, the solution was allowed to cool to room temperature, and let stand overnight whereupon crystallization of the (R)-2--(4-nitro-1H-imidazol-1-yl)-octanoic acid-cinchonidine salt occurred. The crystalline salt was collected by filtration. The salt was then suspended 200 mL ea. of ethyl acetate/H2O. To this suspension was added in HCl (750 mL). The layers were separated, and the aqueous was extracted with ethyl acetate (2×500 mL). The organic was combined, dried (Na2SO4 ), and concentrated in vacuo to provide 29.9 g (72%) of (R)-2-(4-nitro-1H-imidazol-1-yl)-octanoic acid as an off-white solid. M.Pt. 116°-118° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>O1CCCC1>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:36]([CH3:37])[CH3:38])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (207) (125 mg, 0.22 mmol) in tetrahydrofuran (5 mL) were added triphenyl phosphine (117 mg, 0.45 mmol) and diisopropyl azodicarboxylate (0.09 mL, 0.45 mmol) at room temperature, a yellow clear solution was formed, after 5 min it turned into a light yellow hazy solution. The solution was stirred for 2 h at room temperature. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.3). The mixture was concentrated under reduced pressure to get a crude product, which was purified by a CombiFlash column (eluted at 2-5% methanol in dichloromethane) to get 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208) (40 mg, 33.07%) as a white sticky solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[CH3:22][C:23](C)([O-])C.[K+].ICC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[C:11]([CH2:22][CH3:23])([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1C(=O)OC
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1(CC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To 27.0 g (81.8 mmol) of 2-(2,6-dichloro-4-pyridyl)-6-ethyl-5-methoxycarbonyl5,6-dihydropyrimidin-4-one in 500 mL of dimethylformamide was added at 0° C. over 30 min via a solid addition funnel 19.3 g (172 mmol) of potassium-t-butoxide followed by the dropwise addition over 15 min of 13.3 g (85.2 mmol) of iodoethane. The reaction was stirred at 0° C. for one hour before quenching onto 700 mL of ice water. The aqueous was acidified to pH=1 (conc. HCl) and extracted with EtOAc (3×400 mL). The organics were combined before washing with water (2×500 mL), and saturated NaCl (1×300 mL) drying over MgSO4, filtering and evaporating to dryness in vacuo to give 27.32 g (76.3 mmol, 93%) of the desired product as a pale yellow solid with mp=202°-203° C.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:13]1[CH:12]=[CH:11][C:10]2[N:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH:8]=[CH:7][C:6]=2[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: C=CCOc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1O

Procedure:
Refluxing a solution of 4-(allyloxy)-1-[(4-methylphenyl)sulfonyl]-1H-indole in mesitylene followed by removal of the solvent and subsequent purification by flash column chromatography provides 5-allyl-1-[(4-methylphenyl)sulfonyl]-1H-indol-4-ol.
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]([CH3:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[CH2:26][CH2:25][CH2:24][C@@H:20]2[C:21]([OH:23])=O)=[O:18])=[CH:12][CH:11]=1.ClC(OCC)=O.Cl.[Br:35][C:36]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:37]=1[CH2:38][O:39][C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH2:42]>O.C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:37]=1[CH2:38][O:39][C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH:42][C:21]([C@H:20]1[CH2:24][CH2:25][CH2:26][N:19]1[C:17](=[O:18])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:9]([CH3:8])[CH3:27])=[CH:15][CH:14]=1)=[O:23]
Reactant: CN(C)c1ccc(CC(=O)N2CCC[C@@H]2C(=O)O)cc1
Reactant: Nc1ccccc1OCc1ccc(Cl)cc1Br
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CN(C)c1ccc(CC(=O)N2CCC[C@@H]2C(=O)Nc2ccccc2OCc2ccc(Cl)cc2Br)cc1
Reaction time: 2 h

Procedure:
Toluene (111 ml) and N-methylmorpholine (3.85 ml, 35.0 mmol) were added to N-[(4-dimethylaminophenyl)acetyl]-D-proline (8.56 g, 31.0 mmol). Ethyl chloroformate (3.26 ml, 34.1 mmol) was added to the obtained mixture, and they were stirred for 2 hours. 2-(2-Bromo-4-chlorobenzyloxy)aniline hydrochloride (10.8 g, 31.0 mmol) and N-methylmorpholine (4.09 ml, 37.2 mmol) were added thereto and they were stirred at room temperature overnight. Water (40 ml) was added to the reaction mixture. The organic layer was washed with water (40 ml) and then dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with methylene chloride and methanol (30:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a yellow solid (16.3 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10](=[O:17])[N:11]([CH2:13][C:14](O)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46](Cl)[C:45]=1Cl)[NH2:40].Cl>CN(C=O)C>[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH:52][C:14](=[O:15])[CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10]1=[O:17])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:20]([F:23])([F:22])[F:21])[CH:45]=1)[NH2:40]
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reactant: NC(=O)OCC(N)c1cccc(Cl)c1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 58 mg (0.11 mmol) of [4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetic acid from Example 184A was dissolved in 2 ml of DMF, and the solution was admixed with 28 mg (0.15 mmol) of EDC and with 20 mg (0.15 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 42 mg (0.12 mmol) of the compound from Example 183A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 100 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 13 mg (18% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[O:12][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=1)[C:19]([C:23](Cl)=[O:24])=[CH:18][CH:17]=[CH:16]3)=[CH:9][C:8]([O:26][CH3:27])=[C:7]([O:28][CH3:29])[CH:6]=2.FC1C=NC2C(C=1OC1C=C3C(=CC=1)C(C(O)=O)=CC=C3)=CC(OC)=C(OC)C=2.C(Cl)(=O)C(Cl)=O.[NH2:65][C:66]1[CH:70]=[C:69]([C:71]([CH3:74])([CH3:73])[CH3:72])[O:68][N:67]=1>N1C=CC=CC=1>[CH3:72][C:71]([C:69]1[O:68][N:67]=[C:66]([NH:65][C:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][C:11]4[C:10]5[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=5)[N:4]=[CH:3][C:2]=4[F:1])=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[O:24])[CH:70]=1)([CH3:74])[CH3:73]
Reactant: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)Cl)cccc4c3)c2cc1OC
Reactant: CC(C)(C)c1cc(N)no1
Agent: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)Nc5cc(C(C)(C)C)on5)cccc4c3)c2cc1OC
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Pyridine (1.0 mL) was added to a mixture of 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoyl chloride (prepared from 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid and oxalyl chloride by the procedure described in Example 273) (0.044 g, 0.107 mmol) and 3-amino-5-t-butylisoxazole (0.075 g, 0.535 mmol). The mixture stirred at 80° C. for 10 h and was then cooled to RT. The mixture was concentrated and the residue was purified by preparative thin layer chromatography on silica gel plates (eluting with 5% MeOH—CH2Cl2). Further purification via preparative thin layer chromatography on silica gel plates (eluting with 90:10:1 CH2Cl2:MeOH1:NH4OH) afforded N-(5-(1,1-dimethylethyl)-3-isoxazolyl)-6-((3-fluoro-6,7-bis(methoxy)-4-quinolinyl)oxy)-1-naphthalenecarboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 516.0 (M+H). Mass Calc'd for C29H26FN3O5: 515.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[CH2:14][CH2:15][NH:16][CH2:17][C:12]2=[CH:11][N:10]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([N:16]1[CH2:15][CH2:14][N:13]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:10][CH:11]=[C:12]2[CH2:17]1)=[O:22]
Reactant: Fc1ccc(-c2ncc3n2CCNC3)c(F)c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: O=C(c1ccc(F)cc1F)N1CCn2c(cnc2-c2ccc(F)cc2F)C1

Procedure:
This compound 2 was prepared as described for Example 1 (Step H) starting from 50 mg of 3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step D) and 2,4-difluorobenzoyl chloride. Yield: 14 mgs, [M+H]+ 376.18.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[CH2:14][N:13]([CH:17]([CH3:19])[CH3:18])[C:12]2=[O:20])=[C:4]([F:21])[CH:3]=1>C(O)(=O)C.O.C(OCC)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[CH2:14][N:13]([CH:17]([CH3:19])[CH3:18])[C:12]2=[O:20])[CH:6]=1
Reactant: CC(C)N1CC(=O)N(c2cc([N+](=O)[O-])c(Cl)cc2F)C1=O
Agent: [Fe]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1CC(=O)N(c2cc(N)c(Cl)cc2F)C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred mixture of 4.4 g (0.014 mole) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-(1-methylethyl)hydantoin in 70 mL of acetic acid and 10 mL of water was added slowly 4.5 g (0.083 mole) of iron powder. The reaction mixture was heated briefly at 50° C, then was cooled to room temperature and was stirred for 0.5 hour. The mixture was diluted with diethyl ether and was filtered through a pad of Celite® filter aid. The filter pad was rinsed with diethyl ether. The filtrate, containing the diethyl ether wash, was transferred to a separatory funnel and was washed with water and an aqueous dilute sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 3.0 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-(1-methylethyl)hydantoin.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Br)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cu][C:14]#[N:15]>CN1CCCC1=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:14]#[N:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1ccc2cccc(Br)c2n1
Solvent: CN1CCCC1=O
Product: Cc1ccc2cccc(C#N)c2n1

Procedure:
Prepared by reacting 2-methyl-8-bromo-quinoline with copper(I)cyanide in N-methylpyrrolidinone under a protective gas atmosphere at 180° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C1CCCCC1>[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:5]2[S:1][N:2]=[CH:3][CH:4]=2)[OH:17])=[CH:14][CH:13]=1
Reactant: c1cnsc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of isothiazole in 20 ml of tetrahydrofuran were added 8.1 ml of a 1.52M solution of n-butyllithium in hexane at -78° C. The mixture was allowed to stir for 15 minutes at which time 3.2 g of 4,4'-dichlorobenzophenone were added as a solution in 25 ml of tetrahydrofuran. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Twenty-five milliliters of a saturated ammonium chloride solution were added and the tetrahydrofuran was removed by evaporation. The resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with a saturated ammonium chloride solution, water, and a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed over silica gel. The appropriate fractions were combined and evaporated resulting in an oil. Cyclohexane was added and 1.21 g of the desired title product were recovered by filtration as white crystals, m.p. 118°-119.5° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:9][N:10]([CH3:37])[C:11]1[CH:36]=[CH:35][C:14]([CH:15]=[N:16][N+:17]2[CH:21]=[CH:20][N:19]([N:22]=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:18]=2SC)=[CH:13][CH:12]=1.CN(C)C=O>C(OCC)C>[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:9][N:10]([CH3:37])[C:11]1[CH:36]=[CH:35][C:14]([CH:15]=[N:16][N+:17]2[CH:21]=[CH:20][N:19]([N:22]=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:18]=2[N:2]([CH3:3])[CH3:1])=[CH:13][CH:12]=1
Reactant: CSc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)c1ccc(C=Nn2cc[n+](N=Cc3ccc(N(C)C)cc3)c2N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Gaseous dimethylamine is passed through a mixture of 2.47 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2(methylthio)imidazolium tetrafluoroborate and 30 ml of absolute dimethylformamide until a weight increase of 0.4 g (corresponding to 1.8 equivalents) is achieved and the mixture is subsequently stirred at room temperature overnight. From the resulting reddish solution, there is obtained by the addition of diethyl ether a crystalline precipitate which is removed by filtration under suction and washed twice with water and ethanol each time. After re-precipitation from dimethylformamide/diethyl ether, there is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(dimethylamino)imidazolium tetrafluoroborate as a yellow solid of melting point 248°-252° (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[OH:27][CH2:28][CH2:29][NH:30][CH3:31]>>[ClH:26].[OH:27][CH2:28][CH2:29][N:30]([CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: ClCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: CNCCO
Product: CN(CCO)CCCCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1
Product: Cl

Procedure:
The compound was prepared by a method similar to Example 1 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and 2-hydroxyethylmethylamine: mp 134°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncccc1C(=O)O
Product: Cc1nc2ncccc2c(=O)o1

Procedure:
2-Aminonicotinic acid (5 g, 36 mmole) was suspended in acetic anhydride (25 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum. The resulting residue was slurried with ethyl acetate and hexane then filtered to provide 5 g of 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one.