Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.O.I(O)(=O)(=O)=[O:26].P(O)([O-])([O-])=O.[Na+].[Na+]>C(#N)C.[Cr]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]([OH:26])=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Agent: [Cr]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol (3.28 g, 8.65 mmol) in acetonitrile (50 mL) containing water (0.375 mL) at 0-5° C. was added, over 20 minutes, a solution of periodic acid and chromium [VI] oxide in acetonitrile (50 mL: prepared by dissolving 11.4 grams of H5IO6 and 23 mg of CrO3 in 100 mL of CH3CN and stirring for 2 hours at room temperature according to the procedure described in Tetrahedron Letters, 1998, vol. 39, p. 5323-5326). The reaction mixture was stirred overnight while warming to room temperature. Disodium phosphate (1.8 g/100 mL water) was added. The reaction mixture was extracted with toluene (150 mL), washed with 1:1 brine/water (50 mL), freshly prepared sodium bisulfite solution (2 g/50 mL water), brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (30% ethyl acetateihexane elution to remove non-polar impurities, then 50% ethyl acetate/dichloromethane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:21]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:23]=[N:22]1>>[CH2:17]([C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:23]=[N:22][N:21]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1cccnc1NC=C(C#N)C(=O)OCC
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: CCCCc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 30 %

Procedure:
The title compound (m.p. 255.5°-257.5° with decomposition, 30% yield) was prepared from ethyl 2-cyano-3-(3-n-butyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.[Cl:12][C:13]1C=C(Cl)[N:16]=[CH:15][N:14]=1.CO>O1CCOCC1>[Cl:12][C:13]1[CH:7]=[C:5]([CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(Cl)ncn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.7 g (50 mmol) of sodium hydride (80% dispersion in oil) were placed in 100 ml of dry dioxane, and 11.7 g (90 mmol) of ethyl acetoacetate were added dropwise. The mixture was then stirred at 50° C. for 1 hour. After cooling to room temperature, a solution of 4.5 g (30 mmol) of 4,6-dichloropyrimidine in 50 ml of dioxane was added dropwise. After heating at reflux for 6 hours the mixture was cooled to room temperature, 10 ml of methanol were added dropwise in order to destroy superfluous sodium hydride, and the mixture was concentrated. The residue was taken up in water and brought to a pH of 3 to 4 with conc. hydrochloric acid. After extractive stirring with toluene, the organic phase was dried and concentrated. Chromatography on silica gel left 1.8 g (30% of theory) of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=2)=[O:32])=[CH:29][CH:28]=1)=[O:26]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Nc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
Commercially available 4-formylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (100 ml) and anhydrous N,N-dimethylformamide (1 ml) and the mixture was cooled with stirring to 0° C. To the resulting mixture was added dropwise oxalyl chloride (3.8 ml, 43.3 mmol). The mixture was stirred at room temperature for 30 minutes and then at 40° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and then in vacuo to afford 4-formylbenzoyl chloride. 4-(2,2,3,3-Tetrafluoropropoxy)aniline (646 mg, 2.9 mmol), described in Chem. Pharm. Bull., 44 (2), 314 (1996), and N,N-diisopropylethylamine (1.21 ml, 7.0 mmol) were dissolved in anhydrous tetrahydrofuran (8 ml) and the mixture was cooled to 0° C. with stirring. To the resulting mixture was added dropwise a solution of 4-formylbenzoyl chloride (561 mg, 3.33 mmol) obtained above in anhydrous tetrahydrofuran (2 ml). This mixture was stirred at room temperature for 17 hours and then at 40° C. for 20 minutes. At the end of this time, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture in an ice bath and the mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (634 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[CH3:29])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:34]=[O:35]>>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:34]=[O:35])=[C:21]2[CH3:29])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (3 mL) was added to anhydrous dimethylformamide (6 mL) and the mixture was stirred at room temperature for 15 min. A mixture of 1-(4-benzyloxyphenyl)-2-methyl-1H-indole (0.94 g, 3 mmol) in dimethylformamide (10 mL) was added and the mixture heated to 80° C. for 18 hr. The reaction mixture was poured onto ice and adjusted to a pH of 7 by the addition of 2 N NaOH. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer washed with water and brine and dried over MgSO4. Evaporation to provide the product as a dark solid. Purification by silica gel chromatography (10% EtOAC-hexanes) provided a white solid (63%): mp 150-152° C.; 1H NMR (DMSO-d6): δ 2.54 (3H, s), 5.22 (2H, s), 6.99 (1H, d, J=7.9 Hz), 7.17-7.42 (4H, m), 7.45-7.54 (7H, m), 8.17 (1H, d, J=7.5 Hz), 10.19 (1H, s); MS m/z (M+H)+ 342. Anal. for C23H19NO2: Calc'd: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.76; H, 5.70; N, 3.93.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.FC1C=C([N+]([O-])=O)C=CC=1OC1C=CN=C2C=C(C3SC=CN=3)SC=12.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([OH:53])[CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51]>>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51])[O:53][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1[N+](=O)[O-]
Yield: 9 %

Procedure:
Starting from compound 214, following the procedure described above for the synthesis of compound 11 (scheme 2, step 3, example 12) but replacing 2-fluoro-4-nitrophenol with 3-methoxy-4-nitrophenol [Hodgson, C., J. Chem. Soc., 1929, 2778], title compound 215 was obtained in 9% yield. MS (m/z) 383.1 (M+H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(NC2C=CC(C3C=CC(NC4C=CC=CC=4)=CC=3)=CC=2)C=CC=CC=1.[C-]#N.[K+].[C:37]([O:42][CH3:43])(=[O:41])[C:38]([CH3:40])=[CH2:39].CO>C(O)CO.CO>[C:1]([O:6][CH2:7][CH2:43][O:42][C:37](=[O:41])[C:38]([CH3:40])=[CH2:39])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Solvent: CO
Solvent: OCCO
Product: C=C(C)C(=O)OCCOC(=O)C(=C)C

Procedure:
1200 g of methyl methacrylate (12 mole), 20 g of ethylene glycol and 0.65 g of N,N'-diphenyl benzidine (500 ppm) are added to a 2 liter round-bottomed flask. After the addition of 12.9 g of potassium cyanide (1%), a quantity of methanol equivalent to the ethylene glycol employed is taken off as methyl methacrylate/methanol-azeotrope while conducting air through at a temperature of 65° C. at the head of the column (approximately 1/2 hour). After that, an additional 73g of ethylene glycol are dosed in within 2 hours (total quantity of ethylene glycol 93g=1.5 mole). After altogether 4.5 hours of removing azeotrope, the trans-esterification is completed. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A residue of ethylene glycol dimethacrylate of 286 g = 96.5% results. The ethylene glycol dimethacrylate obtained in such a way can be used either without any further processing or optionally after destabilization.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:51])[CH:47]([CH3:48])[CH3:49])=[O:44])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(N)=O)C(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
25 g (43.3 mmol) of Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) of H-Pro-Val-Phe-NH2 were suspended in 430 ml of dry dichloromethane. After cooling to 0° C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) of HOBt and 8.33 g (43.3 mmol) of EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml of dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (4×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/hexane. 18.32 g of the desired product were obtained.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:12](O)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>C(OCC)(=O)C.CCCCCC>[C:1]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCO
Reactant: C=CCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCCCCCCCCOC(=O)CCCCCCCC=C
Yield: 92.7 %

Procedure:
Compound G was prepared from 9-decen-1-ol and 9-decenoic acid following the general procedure already discussed and shown in FIG. 12. Pure compound G was a colorless oil by column chromatography with Ethyl acetate/Hexane=1:50.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C1(C)C=CC=CC=1>[CH2:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1nn(Cc2ccccc2)c2ccccc12
Yield: 50 %

Procedure:
3-bromo-1H-indazole (90.4 g, 0.459 mol, 1.0 eq.) and toluene (450 mL) were placed in a 1 liter flask fitted with a mechanical stirrer under an atmosphere of nitrogen. Then potassium t-butoxide (t-BuOK, 54.2 g, 0.483 mol, 1.05 eq.) was added at room temperature over about half an hour and benzyl bromide (86.3 g, 0.505 mol, 1.1 eq.) was added over approximately 1.5 hours. The mixture was left stirred at the same temperature until the reaction was complete (checked by TLC, approximately 3 hours). Then 0.1 M HCl (45 mL) and water (90 mL) were added and the resulting phases were separated. The organic phase was washed with water, and the solvent was evaporated off at reduced pressure in order to obtain a red oily residue. The product was then precipitated through the addition of n-heptane, filtered and dried under vacuum at room temperature. Yield: 65.9 g of beige solid (yield 50%).
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[O:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC>C(O)C.O>[O:3]1[CH2:8][CH2:7][C:6](=[CH:12][C:11]([CH3:21])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: O=C1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=C1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
A solution of potassium hydroxide (4.66 g, 83.1 mmol) in ethanol (181 mL) and water (45 mL) was cooled to approximately 0° C. Tetrahydro-4H-pyran-4-one (7.56 g, 75.5 mmol) and diethyl (2-oxopropyl)phosphonate (16.1 g, 83.1 mmol) were sequentially added. The reaction was allowed to warm to room temperature and stirred for five hours. The reaction mixture was washed with brine and the organic layer was separated. The aqueous layer was extracted three times with tert-butyl methyl ether. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of 20% ethyl acetate in hexane and chloroform, dried again over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by automated flash chromatography (eluting with 35% to 45% ethyl acetate in hexane). The resulting colorless oil was dried under a stream of nitrogen to provide 8.03 g of 1-tetrahydro-4H-pyran-4-ylideneacetone.
Reaction SMILES: I[CH:2](C)C.[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[C@@H:25]3[C@@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4C=C5C(C=CC(=O)O5)=CC=4)[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>>[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[CH:25]3[CH:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:2])[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: CC(C)I
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(C)C)CC3)C(=O)C3CC=CCC23)cc1OC

Procedure:
Prepared from 2-iodopropane and starting compound A1 as described for compound 18. M. p. 158-159° C.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>CC(C)=O>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([O:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([OH:15])=[O:14]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC(CCCCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 12-Hydroxy stearic acid (450 grams, 1.5 moles), Triethylamine (313 ml, 2.35 moles) in Acetone (1 L) at 10-15° C., was added 4-Nitro Benzoyl Chloride (332 grams, 1.78 moles) and later stirred at room temperature for 10 hours. 75% of the solvent was distilled off. The resulting solution was cooled to room temperature and poured onto cold water. The pH of the solution was adjusted to 4-5 with dilute HCl, and resulting solid was filtered off and washed with chilled water. The solid was converted into slurry with 500 ml diisopropyl ether. The DIPE was filtered off and the resulting solid was dried in vacuum oven at 70-75° C. to yield pure 4-nitrobenzoic acid 11-carboxy-1-hexyl-undecyl ester product as white powder with a melting point of 98-101° C. The resulting compound was characterized by 1H NMR (DMSO-d6) δ 0.85 (t, 3H, CH3), 1.2-1.6 (m, 28H, 14×CH2), 1.8 (m, 2H, CH2), 2.32 (t, 2H, COCH2), 3.2 (m, 1H, CH) 8.1-8.25 (m, 4H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2
Reactant: ClCc1ccccn1
Reactant: Fc1cccc2ncnc(Nc3ccc4[nH]ncc4c3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a stirred partial solution of 5-fluoro-N-1H-indazol-5-ylquinazolin-4-amine (3.35 g, 12 mmol) and 2-picolyl chloride hydrochloride (2.07 g, 12.6 mmol) in DMF (60 ml) was added portion-wise, sodium hydride (60% dispersion in mineral oil, 1.01 g, 25.2 mmol). The reaction was maintained at ambient temperature by slight cooling and stirred for 18 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (5 ml) and evaporated under high vacuum. The residue was partitioned between 2.5M aqueous NaOH and DCM and the organic phase was dried over anhydrous Na2SO4 and evaporated. The product was purified by chromatography (5% methanol/ethyl acetate) and the crystallized by trituration with ether to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (1.8 g, 41%); NMR spectrum (300 MHz) 5.75 (s, 2H), 6.97 (d, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.54-7.75 (m, 4H), 7.84 (q, 1H), 8.12 (d, 2H), 8.50 (m, 2H), 9.23 (d, 1H); Mass spectrum MH+ 371.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]4[CH:28]=[C:27]([NH2:29])[C:26]([F:30])=[CH:25][C:24]=4[CH3:31])[C:15](=[O:22])[N:16]3[CH:19]([CH3:21])[CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:27]1[C:26]([F:30])=[CH:25][C:24]([CH3:31])=[C:23]([C:14]2[C:15](=[O:22])[N:16]([CH:19]([CH3:20])[CH3:21])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:28]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1C)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.8 %

Procedure:
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 2.2 mmol) in DCM (10 mL) was added TFA (3 mL) at RT. The resulting mixture was stirred at RT for 6 h, then washed with H2O (6×). The combined aqueous layers were neutralized with NH3H2O, extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.5 g, 66.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.60 (s, 1H), 6.95 (m, 1H), 6.90 (d, J=12.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.50 (s, 1H), 5.21 (br s, 1H), 4.95 (s, 2H), 2.92 (d, J=4.8 Hz, 3H), 2.02 (s, 3H), 1.58 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 341.2[M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>CC(O)=O>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c2ccccc2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 9-Isopropyl-9H-carbazole (Acros, 1.5 9, 7.2 mmol) in AcOH (50 ml) was treated dropwise with a solution of nitric acid (3.35 ml) in AcOH (10 mL) over 30 minutes. When the reaction was complete the mixture was poured into water and stirred for 15 minutes, then the solid filtered and washed with Et2O to afford the desired product as a solid (1.6 g, 87%).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>O.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:6]([O-:9])=[O:7])[C:13]=1[OH:18]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.932 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.516 mol) was added dropwise at such a rate that the reaction temperature was kept below 25° C. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid.