Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C[O:9][CH2:10][CH2:11]OC>>[OH:9][C@@H:10]1[C@H:2]2[C@H:1]([O:4][CH2:5][CH2:6]2)[O:3][CH2:11]1
Reactant: COCCOC
Reactant: CC(=O)OC(C)=O
Product: O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 23 °C
Yield: 42 %

Procedure:
To a stirred solution of reacemic alcohol 24 (2 g, 15.4 mmol) and acetic anhydride (4 g, 42.4 mmol) in 100 mL of DME was added 2.7 g (about 25% by weight of lipae PS30) of immobilized Amano lipase and the resulting suspension was stirred at 23° C. The reaction was monitored by TLC and 1H NMR analysis until 50% conversion was reached. The reaction mixture was filtered and the filter cake was washed repeatedly with ethyl acetate. The combined filtrate was carefully concentrated in a rotary evaporator, keeping the bath temperature below 15° C. The residue was chromatographed over silica gel to provide 843 mg (42%) of 25 (95% ee; aD23° −11.9°, MeOH); 1H-NMR (CDCl3) δ 1.85 (m, 2H), 2.3 (m, 1H), 2.9 (m, 1H), 3.65 (dd, J=7.0, 9.1, 1H), 3.85-4.0 (m, 3H), 4.45 (dd, J=6.8, 14.6, 1H), 5.7 (d, J=5.1, 1H); also, 1.21 g of 26 after washing with 5% aqueous sodium carbonate (45%, aD23° +31.8°, MeOH); 1H-NMR (CDCl3) δ 1.85-2.1 (m, 2H), 2.1 (s, 3H), 3.1 (m, 1H), 3.75 (dd, J=6.6, 9.2, 1H), 3.8-4.1 (m, 3H), 5.2 (dd, J=6.4, 14.5, 1H), 5.7 (d, J=5.2, 1H). Acetate 26 was dissolved in THF (5 mL) and 1 M aqueous LiOH solution (20 mL) was added to it. The resulting mixture was stirred at 23° C. for 3 h and the reaction was extracted with chloroform (3×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was chromatographed over silica gel to provide 733 mg of 27 (97% ee; aD23° −12.5°, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.ON1C2C=CC=CC=2N=N1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28]>C(O)C>[C:27]([C:26]1[CH:29]=[C:22]([NH:21][C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])[CH:23]=[CH:24][C:25]=1[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:28]
Reactant: Cc1c(C(=O)O)cnn1C
Reactant: N#Cc1cc(N)ccc1N1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc(N3CCCCC3)c(C#N)c2)cnn1C
Temperature: 78 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (1.2 g) and 5-amino-2-piperidinobenzonitrile (0.9 g) were added to ethanol (20 ml) and the mixture was stirred at 78° C. for 3 h. After evaporation of the solvent, aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.7 g), melting point: 217–218° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][C:7](=[O:15])[CH2:8]2)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CBr)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromoacetyl chloride (14.17 g) in methylene chloride (30 ml) is added dropwise to a stirred suspension of oxindole (6 g) and AlCl3 (13.31 g) in methylene chloride (200 ml). The reaction mixture is refluxed for 4 hours, cooled to RT, poured with stirring into an ice/water mixture, stirred for 30 minutes, filtered and washed with methylene chloride yielding the desired product as a solid which is recrystallized from isopropanol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[CH2:33]([O:32][CH2:31][C@@:13]12[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([NH:36][CH3:35])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:20][CH2:19][C:18]1=[CH:17][C:16]1[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:15]=1[CH2:14]2)[CH3:34]
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: CN
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(NC)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and methylamine. LCMS (Method B): 498 (M+H)+, Retention time 3.6 minutes.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([F:29])=[CH:10][C:11]3[C:12]([CH:28]=2)=[N:13][C:14]2[N:15]([CH3:27])[CH:16]=[C:17]([C:22]([O:24]CC)=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:31][CH3:32].[H-].[Na+]>CN(C)C=O>[CH:1]1([N:7]([CH2:31][CH3:32])[C:8]2[C:9]([F:29])=[CH:10][C:11]3[C:12]([CH:28]=2)=[N:13][C:14]2[N:15]([CH3:27])[CH:16]=[C:17]([C:22]([OH:24])=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCI
Reactant: CCOC(=O)c1cn(C)c2nc3cc(NC4CCCCC4)c(F)cc3cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C)C1CCCCC1

Procedure:
8-[(Cyclohexyl)(ethyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared from 0.5 g of ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate, 0.19 cm3 of iodoethane, 0.096 g of sodium hydride as a 60% dispersion in mineral oil and 10 cm3 of dimethylformamide. After treatment with 10 cm3 of water and 2 cm3 of 1N hydrochloric acid, the mixture was extracted 3 times with 20 cm3 of trichloromethane. The combined organic phases were washed 1 time with 20 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 0.25 g of 8-[(cyclohexyl)(ethyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 230° C.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCCC2)c(C)c1
Reaction time: 5 h
Yield: 84.9 %

Procedure:
4-{1-Ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 35-(1); 0.2 g, 0.51 mmol) was added to a solution of lithium aluminum hydride (38.9 mg, 1.02 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred for five hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound (0.17 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:4](=[O:7])[NH:5][N:6]=1.[H-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:4](=[O:7])[N:5]([CH2:16][CH:18]2[CH2:19][O:20]2)[N:6]=1
Reactant: BrCC1CO1
Reactant: Cc1n[nH]c(=O)n1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nn(CC2CO2)c(=O)n1-c1cccnc1
Temperature: 25 °C

Procedure:
After dissolving 5-methyl-4-pyridin-3-yl-2,4-dihydro[1,2,4]triazol-3-one (CAS 79369-46-3) (100 mg) in N,N-dimethylformamide (2 ml), sodium hydride (60% in oil) (27 mg) was added and the mixture was stirred at room temperature. Epibromohydrin (73 μl) was then added and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium carbonate was added to the reaction mixture, and extraction was performed with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (136 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C1C=CC=CN=1>O1CCOCC1.[Pd]>[O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17][CH2:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1=CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Agent: [Pd]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a solution of ethyl (6-((3-phenoxybenzyl)oxy)-3,4-dihydro-1-naphthalenyl)acetate (1.04 g, 2.51 mmol) and 2,2′-bipyridyl (0.197 g, 1.26 mmol) in 1,4-dioxane (10 mL) was added 10% palladium on carbon (50%, water wet, 0.2 g), and the mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 24 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-30% ethyl acetate/hexane) to give the title compound (0.481 g, yield 46%) as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)c1
Agent: Cl
Solvent: CO
Product: Cn1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)c1
Yield: 61.5 %

Procedure:
A solution of the compound (148 mg, 0.37 mmol) obtained in Example 58-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (90 mg, 61%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22]Cl>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:20][O:21][CH3:22])=[C:6]([Br:12])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COCOc1c(F)cc(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (637 mg) in acetone (7 mL) were added potassium carbonate (708 mg) and chloromethyl methyl ether (412 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (608 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CCOCC>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCC(=O)NCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Nα -t-butyloxycarbonyl-glycyl-glycine benzyl ester (3.22 g, 10 mmol) was dissolved in TFAOH -trifluoracetic acid - (30 ml) at 20° C. and left to stand for 2 h. After evaporation to dryness at 20° C. under reduced pressure, the glycyl-glycine benzyl ester trifluoracetate (3.23 g, 9.6 mmol) was obtained as a solid by trituration of the residual oil in ether and was coupled to Nα -BOC-aspartic acid β-t-butyl ester (2.78 g, 9.6 mmol) according to the procedure described for the preparation of dipeptide of formula V. After the usual work-up, the product which could not be induced to crystallize, was obtained after evaporation of the solvent (ethyl acetate) and drying as a foam. Analysis: calculated for C24H35N3O8 : C, 58.40; H, 7.15; N,8.52. Pound: C, 58.20; H, 7.19; N, 8.48. [Rf : 0.52 from chloroform: methanol (20:1)]. The yield was 4.50 g (95 %).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH:3]=1.[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccnc2[nH]cc(I)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A solution of 3-iodo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (0.30 g, 1.08 mmol) in dimethylformamide (10 mL) at 0° C. was treated with sodium hydroxide (0.056 g, 1.41 mmol) for 15 minutes. To the material was added benzenesulfonyl chloride (0.25 g, 1.41 mmol) dropwise and stirred at room temperature for 3 hours. The material was diluted with water (40 mL), filtered, and dried in vacuo at 50° C. to afford 0.35 g of the title compound. MS (ESI) m/z 414.9 (M+H)+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>CS(C)=O>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:4]2[C:5](=[O:17])[C:6](=[O:16])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: Cc1cc(Br)ccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 4-bromo-2-methylaniline (40 mg, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 373 (M+).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.S(Cl)([Cl:34])=O>ClCCl>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([Cl:34])=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.19 g, 3.49 mmol), prepared as described in Example 10, in dichloromethane (50 mL) was added a catalytic amount of dimethylformamide (100 μL) and thionyl chloride (1.50 mL, 20.6 mmol), and the resulting mixture was stirred at rt overnight. The solid was filtered, washed with hexanes, and dried under reduced pressure (high vacuum) to give the product (4-(4-phenylquinazolin-2-ylamino)benzoyl chloride) as a yellow solid (1.21 g, 97%). This material was then added portionwise to a solution of commercially available 3-amino-4-methylbenzyl alcohol (600 mg, 4.37 mmol), and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (50 mL) that had been cooled to 0° C. in an ice bath. The mixture was allowed to warm to rt overnight, then the solid was collected by filtration, washed with saturated sodium bicarbonate and water and dried under reduced pressure to give N-(5-hydroxymethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide as a pure yellow solid (1.33 g, 86%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([I:14])=[CH:12][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])[C:9]=2[N:10]=1>C1COCC1.O>[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([I:14])=[CH:12][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])[C:9]=2[N:10]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cnc(Cl)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)n1cc(I)c2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Lithium hydroxide monohydrate (4.08 g, 97.5 mmol) was added to methyl 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (18.5 g, 48.7 mmol) (see Preparation 41) in THF (185 mL) and water (45 mL). The mixture was stirred at 60° C. for 3 hours then the reaction mixture volume was reduced to one third by evaporation in vacuo. The aqueous residue was acidified using aqueous HCl (2.0 M) then extracted with EtOAc (4×200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with hexane (100 mL) to afford the title compound as a white solid in 90% yield, 16.0 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCOCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: FC(C(C1C=CC=CC=1)=O)(F)F.[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[C:13]1([CH:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccccc1
Agent: O=C(c1ccccc1)C(F)(F)F
Solvent: c1ccccc1
Product: CC(N)c1ccccc1
Yield: 82 %

Procedure:
Trifluoromethylphenyl ketone (348 mq, 2 mmol) and (S)-1-phenylethylamine (242 mg, 2 mmol) were metered out into a 50-mL round-bottom flask, 20 mL benzene was added, a Dean-Stark trap was mounted, and the system was refluxed. The solvent was removed with the aid of an evaporator, and 1a was produced at a yield of 82%. Rf 0.45 (hex/AcOEt=4:1) 1H NMR d 1.44 (d, 3H, J=6.6 Hz), 4.54 (q,1H, J=6.6 Hz), 7.17-7.35 (m, 8H), 7.47-7.50 (m, 2H); 19F NMR d -71.63(s). 13C NMR d 24.53(s), 61.38(s), 119.77(q, JCF =278.8 Hz), 126.45(s), 127.24(s), 127.60(s), 128.61(s). 128.77(s), 130.02(s), 130.56(s), 143.76(s), 156.58(q, JCF =33.2 Hz). MS 277 (M, 7.6), 262 (M-Me, 2.1), 105(100). Anal. Calcd for C16H14F3N: C, 69.31; H, 5.09; N, 5.05; F, 20.55. Found: C, 69.43; H, 5.19; N, 5.05; F, 20.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:8])[CH:6]=1
Reactant: [Br-]
Reactant: COc1ccn(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: COc1nn(C)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=2.29 min (polar—5 min, ZQ3).
Reaction SMILES: C(OC(C1CCC2C(=CC=CC=2)C1=O)=O)C.C(OC(C1CCC2C(=CC=C(Cl)C=2)C1=O)=O)C.[OH:34][NH:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47](Cl)[CH:48]=2)[C:43]1=[O:53]>>[OH:34][NH:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]1=[O:53]
Reactant: O=C(CCCCCC1CCc2cc(Cl)ccc2C1=O)NO
Agent: CCOC(=O)C1CCc2cc(Cl)ccc2C1=O
Agent: CCOC(=O)C1CCc2ccccc2C1=O
Product: O=C(CCCCCC1CCc2ccccc2C1=O)NO

Procedure:
6-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-hexanoic acid hydroxyamide (5a) is prepared from 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (1a) in an analogous manner to that described for the conversion of 3a to 3c in example 3. Yield in the last step is 10%, MS (APCI): 274.1 (M−1).