Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=C(N)[N:5]=1.CI.[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:18]([N:16]([CH3:15])[CH3:17])[N:5]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(Cl)nc(N(C)C)n1
Yield: 38 %

Procedure:
NaH (60% dispersion in oil, 0.201 g, 5.02 mmol, 2 eq) was added to a stirred solution of 4-chloro-6-methoxypyrimidin-2-amine (0.400 g, 2.51 mmol, 1 eq, Aldrich) and MeI (0.5 ml, 1.07 g, 7.52 mmol, 3 eq) in 2 ml anhydrous DMF at 0° C. After 1 h the reaction was quenched with water and diluted with EtOAc. The layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.180 g (0.96 mmol, 38% yield) of 4-chloro-6-methoxy-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[NH:10][C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]([F:19])([F:17])[F:18])[N:10]([CH3:24])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(F)(F)F)[nH]c(=O)n(-c2ccc(Br)cc2F)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2ccc(Br)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
3-(4-Bromo-2-fluorophenyl)-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (16.52 g), methyl iodide (7.99 g) and potassium carbonate (7.76 g) were suspended in DMF (90 ml), and the mixture was stirred at room temperature for about 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-2-fluoro-phenyl)-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (14.92 g).
Reaction SMILES: [CH2:1]([C:4]([OH:6])=[O:5])[CH2:2][SH:3].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:13]([S:3][CH2:2][CH2:1][C:4]([OH:6])=[O:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCS
Solvent: ClCCl
Product: O=C(O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.7 %

Procedure:
Mercaptopropionic acid 12 (3.14 g) was dissolved in 50 ml of methylene chloride. Triphenylmethylchloride 13 (8.36 g) was added to that, and 19-hour reactions were carried out at room temperature. The precipitate generated through the reactions was gathered by filtration, and the solid components obtained here were dried under reduced pressure, to form 9.86 g of 3-(tritylthio)propionic acid 14, which is a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([O:4][C:5]([N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:17])[NH:15][OH:16])=[N:12][CH:13]=1)=[O:6])[CH3:3].Cl[C:27]([O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].[Cl-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C.O>[CH3:22][C:21]([CH3:24])([O:20][C:18]([N:7]([C:5]([O:4][C:2]([CH3:25])([CH3:1])[CH3:3])=[O:6])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:17])[NH:15][O:16][C:27]([O:29][CH2:30][CH:31]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:38]3[C:43]2=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:28])=[N:12][CH:13]=1)=[O:19])[CH3:23]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NO)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NOC(=O)OCC2c3ccccc3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-hydroxy-2-pyrazinecarboximidamide (77.0 mg, 0.218 mmol) in pyridine (2 mL) at 25° C. was treated with 9-fluorenylmethyl chloroformate (68.0 mg, 0.263 mmol). The reaction mixture was stirred at 25° C. for 45 min. The reaction mixture was then diluted with ethyl acetate, water, and a saturated aqueous sodium chloride solution. The mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/9 to 1/1 ethyl acetate/hexanes) afforded the desired 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-[[[(9H-fluoren-9-yl)methoxy]carbonyl]oxy]-2-pyrazine carboximidamide. This material was dissolved in methylene chloride (0.5 mL). The solution was cooled to 0° C. and then was treated with trifluoroacetic acid (0.16 mL, 2.077 mmol). The reaction mixture was stirred at 0° C. for 30 min and at 25° C. for 30 min. The reaction mixture was then treated with additional trifluoroacetic acid (1.0 mL, 12.99 mmol) and stirred at 25° C. for 2 h. The reaction mixture was further treated with trifluoroacetic acid (1.0 mL, 12.99 mmol) and stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride, washed three times with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then dried under high vacuum to afford 5-amino-N-[[[(9H-fluoren-9-yl)methoxy]carbonyl]oxy]-2-pyrazinecarboximidamide (36.7 mg, 44.9%) as a white solid: LRMS for C20H17N5O3 (M+H)+ at m/z=376
Reaction SMILES: C1(CC(=O)CC(=O)CC)C=CC=CC=1.Cl.[NH2:16][OH:17].[OH-].[Na+].[CH2:20]([C:32]1ON=[C:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)(=O)C>[CH2:20]([C:32]1[CH:33]=[C:34]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:17][N:16]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)no1
Reactant: NO
Agent: CCC(=O)CC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Temperature: 65 °C
Reaction time: 23 h

Procedure:
A mixture of 1-phenyl-2,4-hexanedione (66.5 g, 0.201 mol), hydroxylamine hydrochloride (27.9 g, 0.402 mol), and 1M sodium hydroxide (201 mL, 0.201 mol) in glacial acetic acid (1.5 L) was stirred at 65° C. under nitrogen for 23 hours. The solution was allowed to cool, and the resulting suspension was filtered off and washed with CH3CO2H--H2O (9:1). The filtercake was washed separately with H2O and dried under house vacuum/air stream to give a white crystalline solid containing the title compound and 5-dodecyl-3-(phenylmethyl)isoxazole; yield 41.8 g (64%); mp 41°-43° C. Additional product was obtained by reheating the CH3CO2H filtrate and washings to 60° C.; adding H2O (150 mL) dropwise until cloudy, and following the previous procedure; yield 15.2 g (23%).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:17]([C:8]1[CH:9]=[C:4]2[CH2:3][C:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 0 °C
Yield: 51 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (325 mg, 1.5 mmol) and fuming nitric acid (0.27 mL, 5.74 mmol) in sulfuric acid (0.75 mL) was heated at 70° C. to 80° C. for 24 hours. The resulting viscous solution was poured onto 15 g of ice and basified to pH>10 with solid sodium carbonate. The resulting mixture was extracted with chloroform (4×15 mL), dried (MgSO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (95:5), provided the title compound (200 mg, 0.765 mmol, 51%) as a light yellow solid: electrospray MS 262 ([MH]+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1[C:2]([NH:1][C:44](=[O:45])[C:43]2[CH:47]=[C:39]([CH2:38][C:32]3[C:33](=[O:37])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[C:30](=[O:53])[C:31]=3[CH3:52])[CH:40]=[CH:41][C:42]=2[O:48][C:49](=[O:51])[CH3:50])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)c1ncccc1N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
3-Amino-2-dimethylaminopyridine (0.154 g, 1.125 mmol), triethylamine (0.114 g, 1.125 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.190 g, 1.125 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.139 g, 0.282 mmol, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4].[CH3:20][C:21]([O-])(C)[CH3:22].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1([CH2:22][CH:21]=[CH2:20])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CN(Cc2ccccc2Cl)CCC1=O
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)(C)O
Product: C=CCC1(C(=O)OC)CN(Cc2ccccc2Cl)CCC1=O
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
14.60 g (51.8 mmol) of methyl-1-[(2-chlorophenyl)methyl]-4-oxo-3-piperidine carboxylate was dissolved in 40 ml of tertbutanol and warmed to 30° C. Within 2 minutes 6.57 g (58.4 mmol) of potassium tert-butylate in 45 ml of tert-butanol was added. After 15 minutes of stirring, 25 ml of tert-butanol was added once more. Then 6.34 g (51.4 mmol) of allylbromide was added within 10 minutes and stirred for 2 more hours at 30° to 35° C. The reaction mixture was concentrated by evaporation and 70 ml of water and 70 ml of ether were added to the residue. The organic phase was washed with 50 ml of sodium sulfate solution, dried on magnesium sulfate and concentrated by evaporation. The yield was 40.68 g of methyl1-[(2-chlorophenyl)methyl]-4-oxo-3-(2-propenyl)-3-piperidine carboxylate, which equals 88.1 percent. Data concerning the compound was:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2OC)[C:17]=1[OH:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].CC1CC2C(=CC=CC=2)C(=O)C1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH:5]([C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:29])[C:4]([O:3][CH2:1][CH3:2])=[O:30])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1O
Agent: CC1CC(=O)c2ccccc2C1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2ccccc2c1O

Procedure:
Ethyl 2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate was prepared in a similar manner as (1-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-acetic acid ethyl ester of Example 32, except using 3-methyl-3,4-dihydronaphthalen-1(2H)-one. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.48-7.36 (m, 2H), 7.27 (d, 8.5 Hz, 2H), 7.18 (s, 1H), 6.89 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 4.67-4.55 (m, 2H), 4.27-4.08 (m, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:14])=[N:8][N:9]=1
Reactant: COc1ccc2c(C)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-methyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[OH:11][C:12]([CH3:30])([CH3:29])[CH2:13][N:14]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][C:23]=1[Cl:28])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CO>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[OH:11][C:12]([CH3:30])([CH3:29])[CH2:13][N:14]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][C:23]=1[Cl:28])[CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Add L-tartaric acid (0.1504 g, 1.00 mmol) to a stirred solution of methanol (12 mL), and N-(2-hydroxy-2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine (0.3386 g, 1.00 mmol). Stir the reaction for 2 hours at room temperature. Concentrate on a rotary evaporator to yield 0.4775 g (97%) of the title product: mass spectrum (ion spray): m/z=338.1 (M+1); LC/MS (90/5/5 to 0/95/5 water/acetonitrile/5% formic acid in water) XTerra MS C18 2.1 mm×50 mm×3.5 micron: Rt 1.64 minutes, Purity: >99%; 1H NMR (CD3OD): δ=4.44 (s, 2H), 4.04 (s, 2H), 3.49-3.46 (m, 2H), 2.99-2.86 (m, 3H), 2.55 (s, 2H), 2.05-2.02 (m, 2H), 1.80-1.71 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:16]2[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=2)[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][N:3]=1.[NH3:29]>C1COCC1>[NH2:29][C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:16]2[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=2)[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][N:3]=1
Reactant: COC(=O)[C@H](C)N(Cc1ncc(C)c(OC)c1C)c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)N(Cc1ncc(C)c(OC)c1C)c1nc(N)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]propanoate (Intermediate 3)(1.0 g, 2.44 mmol) in THF (30 mL) was treated with ammonia (28% in water, 3 mL). The reaction mixture was stirred at room temperature for 2.5 hours, then partitioned between DCM and water. The organic solution was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC on silica using gradient elution (30% ethyl acetate/isohexane to 100% ethyl acetate). Intermediate 1 was obtained as a yellow foam (770 mg, 81%); 1H NMR spectrum: (400 MHz CDCl3) δ1.63 (3H, d), 2.10 (3H, s), 2.22 (3H, s), 3.65 (3H, s), 3.74 (3H, s), 4.44 (1H, d), 4.64-4.72 (2H, m), 5.24 (2H, s), 8.14 (1H, s), 8.66 (1H, s); Mass spectrum: (M+H)+ 391.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:18]([C:6]1[CH:7]=[CH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[CH:5]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2oc3ccccc3c2c1
Reaction time: 8 h
Yield: 28.3 %

Procedure:
Aluminum chloride (23.8 g, 178.4 mmol) was added portionwise to a solution of dibenzofuran (30.0 g, 178.4 mmol) and acetyl chloride (14.0 g, 178.4 mmol) in dichloroethane at 0° C. After 8 hours, the reaction was quenched with 6N HCl. The layers were separated and the methylene chloride layer was dried (MgSO4), filtered and concentrated to provide a yellow solid. The solid was recrystallized 3 times from hexane to provide 10.6 g (28%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ 2.7 (s, 3H), 7.4 (dt, J=7.5 Hz, 0.5 Hz, 1H), 7.5 (dt, J=7.5 Hz, 0.5 Hz, 1H), 7.65 (d, J=7.5 Hz, 2H), 8.0 (d, J=7.5 Hz, 1H), 8.15 (dd, J=7.5 Hz, 0.5 Hz), 8.6 (d, J=0.5 Hz). MS (DCl/NH3) m/e 211 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]([CH3:13])=[C:7]([C:10](=[O:12])[CH3:11])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(Cl)([Cl:23])(=O)=O>ClCCl>[Cl:23][CH2:13][C:6]1[NH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:8]([CH3:9])[C:7]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1[nH]c(C)c(C(C)=O)c1C
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1[nH]c(CCl)c(C(C)=O)c1C
Temperature: 0.5 °C

Procedure:
To a stirred mixture of 2,4-diacetyl-3,5-dimethylpyrrole (1.0 g), dichloromethane (35 cm3) and potassium carbonate (7.73 g) at 0°-5° C. was added a solution of sulphuryl chloride (0.79 g) in dichloromethane (15 cm3). The temperature of the mixture was maintained at 0.5° C. during the addition by external cooling and then the mixture was stirred at this temperature until adjudged complete by t.l.c. (ca 2 h). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl-4-methylpyrrole. This material was dissolved in acetic acid (10 cm3), sodium acetate (1.83 g) added, and then more acetic acid (10 cm3) added. The mixture was stirred overnight at room temperature, evaporated in vacuo, and the residue stirred with ice-cold water for 2 h. A solid was collected by filtration and the filtrate extracted twice with ethyl acetate. The extracts were dried (MgSO4), evaporated and the residue combined with the solid above, to give the crude product. Chromatography on silica eluting with ethyl acetate-hexane (1:1) gave 0.075 g. of pure product as an off-white solid m.p. 112.5°-114.5° C.; m/z 238 (M+ +1, FAB), δH, CDCl3) 2.16 (3H, s, OCOCH3), 2.50 (3H, s, CH3), 2.53 (3H, s, CH3), 2.62 (3H, s, CH3), 5.38 (2H, s, OCH2).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13]2/[C@H:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15]CC[CH2:18]/2)=[C:9]([O:23][CH3:24])[C:8]([CH3:25])=[C:7]2[C:3]=1[C:4](=[O:26])[O:5][CH2:6]2>C(OC)(C)(C)C>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:18])/[CH:14]([CH3:15])[CH2:19][C:20]([OH:22])=[O:21])=[C:9]([O:23][CH3:24])[C:8]([CH3:25])=[C:7]2[C:3]=1[C:4](=[O:26])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(N)c1C/C=C1\CCCC[C@H]1CC(=O)O)C(=O)OC2
Solvent: COC(C)(C)C
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)C(C)CC(=O)O)C(=O)OC2

Procedure:
(E)-2-[2-[2-[4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetic acid, mp 175°-177° C. (tert butylmethyl ether); and
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(-c2nccn2Cc2ccccc2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nccn2Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-benzyl-imidazol-2-yl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=20:1) C33H26N4O3
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:9]=1)=[O:4].[OH-].[Na+].CO>C1COCC1.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=[C:10]([N:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]3)[CH2:14]2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1cnn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of methyl ester of example 19.1 (513 mg) in 12.5 ml THF:water (4:1) was added sodium hydroxide (75 mg). The reaction mixture was stirred at room temperature for 3 hours before adding 2 ml of methanol. The reaction was stirred overnight before evaporation of the solvent in vacuo. The aqueous layer was extracted with ethyl acetate before being acidified. It was then extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the title acid (452 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz): 8.55 (s, 1H), 8.05 (s, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 4.35 (d, 1H), 4.00 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4].C(Cl)(=O)[C:21](Cl)=[O:22]>C(Cl)CCl>[F:1][C:2]([F:18])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([N:12]=[C:21]=[O:22])=[O:11])=[O:4]
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)N=C=O

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzamide (1.0 g, 3.6 mmol), oxalyl chloride and EDC (10 mL) to afford 0.900 g of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[OH:10][CH2:11][C:12]([NH:14][CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])=[O:13]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[CH:28][C:19]=3[O:18][C@H:16]([CH3:17])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][OH:10])[N:24]=[CH:23][N:22]=2)=[CH:31][C:32]=1[CH3:37]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Reactant: Fc1cccc(CCl)c1
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1cccc(F)c1
Yield: 25 %

Procedure:
The procedure described in Example 3 was repeated using 1-(chloromethyl)-3-fluorobenzene and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a light yellow solid in 25% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.25 (s, 3H), 3.42 (dt, 1H), 3.72 (dt, 1H), 3.81 (d, 2H), 4.94 (m, 1H), 5.17 (s, 2H), 5.47 (t, 1H), 6.99 (d, 1H), 7.16 (td, 1H), 7.22 (d, 1H), 7.30 (m, 3H), 7.43 (m, 1H), 7.56 (d, 1H), 7.61 (dd, 1H), 7.68 (t, 1H), 8.16 (t, 1H), 8.43 (s, 1H), 9.94 (s, 1H); Mass spectrum MH+ 491.