Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[Cl-].[Li+].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:12]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH:10]=[CH2:11]
Reactant: CC(C)[Mg]Cl
Reactant: Cc1cc(Br)ccc1I
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1ccc(Br)cc1C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methylbenzene (8.41 mL, 58.9 mmol) in THF (200 mL) in a 1.0 L flask under Ar at −20° C., was added isopropylmagnesium chloride (2M, THF) (52.5 mL, 105 mmol) though a dropping funnel. The reaction was stirred for 20 min at −20° C. A solution of lithium chloride (6.00 g, 141 mmol) and copper(I) cyanide (6.33 g, 70.7 mmol) in THF (140 mL) (stirred 15 min at rt to dissolve the LiCl) was cannulated to the above solution. The pale green solution was stirred for 10 min at −10° C., then allyl bromide (15.30 mL, 177 mmol) was added. The mixture was stirred at −10° C. for 30 min. The reaction was quenched with 0.5 N HCl and the solvent was evaporated. The residue was redissolved in diethyl ether/ethylacetate and organic phase was washed with 1N HCl, H2O, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was purified by flash chromatography (0% to 15% EtOAc in hexanes). The desired fractions were combined and concentrated to give 16A (12.10 g, 97% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.15-7.25 (m, 2H) 6.92 (d, J=8.24 Hz, 1H) 5.83 (dddd, J=16.97, 10.37, 6.18, 6.05 Hz, 1H) 5.00 (d, J=9.89 Hz, 1H) 4.85-4.94 (m, 1H) 3.23 (d, J=6.60 Hz, 2H) 2.18 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>O1CCCC1.ClCCl.C(O)(=O)C>[CH3:22][O:21][C:19](=[O:20])[CH:18]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[Cl:12])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1Cl)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of 4.25 g of 4-tert.-butyl-2-chlorophenol, 30 ml of tetrahydrofuran and 0.88 g of sodium hydride (60% dispersion in oil) is stirred at room temperature for 1 hour. To the mixture is added 3.48 g of potassium iodide and then a solution of 8.28 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 30 ml of tetrahydrofuran is added dropwise. After stirring and heating in an oil bath at 60° C. for 18 hours, the mixture is poured into ice-water containing 3 ml of acetic acid. The mixture is extracted with ethyl acetate and the combined extracts washed with sodium bicarbonate solution, 10% sodium bisulfite and saturated sodium chloride solution. The dried (MgSO4) extract is concentrated under reduced pressure to give an amber gum. The gum is dissolved in dichloromethane and the solution passed through a column of silica gel with dichloromethane as eluent. From the main cuts there is obtained 10 g of product as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Br)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
To a round bottom flask containing 3-bromo-4-chlorobenzoic acid (5.0 g, 21.2 mmol) (commercially available from Aldrich, CAS No. 42860-10-6) was added a cold solution of MeOH (60 mL) and sulfuric acid (1.4 mL). The mixture was heated to 80° C. and monitored with TLC. After 17 hours, the reaction was cooled to room temperature and diluted with water. The aqueous phase was extracted with diethyl ether (3×50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate. After filtration, the organic solvent was removed in vacuo to yield white solid 13.1 (5.0 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (1H, d, J=2.0 Hz), 7.93 (1H, m), 7.52 (1H, d, J=8.2 Hz), 3.93 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
0.25 g (0.94 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]), 0.15 g (1.03 mmol) of phthalimide and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0° C. and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl azodicarboxylate in 2 ml of THF was added drop by drop. Then, the reaction was warmed up to ambient temperature. After 1 hour, the solvent was evaporated and the residue purified by crystallization from MeCl2 and n-heptane to give 0.32 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7](=O)[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:3](=O)[CH3:4].C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([C:7]2[O:6][C:2]([CH3:1])=[C:3]([CH3:4])[N:23]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)OC(C)C(C)=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nc(C)c(C)o2)cc1
Temperature: 90 °C

Procedure:
To a solution of terephthalic acid 1-methyl ester 4-(1-methyl-2-oxo-propyl) ester (0.5 g, 2 mmol) in acetic acid (20 mL) was added ammonium acetate (0.308 g 4 mmol) and the mixture was stirred at 90° C. over night. Acetic acid was removed under reduced pressure and ice cold water (10 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (50 mL×2), the combined organic layers were washed with water (25 mL×2) and with brine, dried over anhydrous sodium sulphate and concentrated to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:32]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.053 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.6 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.93 (s, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.97 (t, J=7.2 Hz, 1H), 6.84 (s, 1H), 6.58 (dd, J=8.2, 1.5 Hz, 1H), 4.42 (s, 2H), 3.29-3.25 (m, 4H), 2.88 (s, 3H), 2.83 (s, 3H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
The mixture of 3,5-dimethylbromobenzene (80.25 g, 0.43M), NBS (77 g, 0.43M), and benzoyl peroxide (5.2 g, 0.021M) in carbon tetrachloride (400 ml) was refluxed for 3 hr. under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a white solid, which was purified by silica gel column chromatography (eluent, hexane) to afford 82 g (72%) of a white solid; m.p. 46-47° C.; 1H NMR (200 MHz, CDCl3) δδ 2.32 (3H, s), 4.38 (2H, s), 7.12 (1H, s), 7.25 (1H, s), 7.33 (1H, s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]=[CH:10][CH:9]=[C:8]3[O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(C(F)(F)F)cc4)ccnc23)c1F
Yield: 11.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-46, 126 mg, 0.44 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 142 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) in CH2Cl2 (5 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 8.80-8.75 (m, 2H), 8.16 (t, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 6.96 (d, J=5.1 Hz, 1H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 574.26 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1CCOCC1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and benzyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O.C(=O)=O>CO.C(O)C>[C:1]1([C:7](=[O:17])[C:8](=[O:10])[CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reaction time: 0.03 h
Yield: 65 %

Procedure:
To a boiling solution of 30 g 1,3-diphenyl-2,3-epoxy-1-propanone in 500 ml methanol was rapidly added a hot solution of 30 g potassium t-butoxide in 500 ml ethanol. The mixture was kept boiling on a steambath for 2 minutes. It was then diluted with 3 l. water. The aqueous solution was saturated with carbon dioxide by the addition of small pieces of dry ice. The resulting emulsion was extracted with ether. The ether extracts were diluted with benzene, dried over sodium sulfate and evaporated under reduced pressure. The remaining dark oil was distilled in high vacuum to afford 19.5 g 1,3-diphenyl-1,2-propanedione; b.p. 136°-138° /0.1 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][C:13]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(N)sc2cc(-c3ccc(F)cc3)ccc12
Yield: 89.9 %

Procedure:
To a solution of 1d (200 mg, 0.67 mmol) in 1,4-dioxane/water (40 mL, 3:1) was added 4-fluorophenylboronic acid (209 mg, 1.34 mmol), NaHCO3 (225 mg, 2.68 mmol) and Pd(PPh3)4 (9% Pd, 79 mg, 0.067 mmol). The resultant mixture was heated at 110° C. for 1 h, diluted with brine solution (50 mL) and extracted with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then provided the title compound (190 mg, 90%) as a pink sticky oil: MS (ES) m/z 316 (M+H)+; 1H NMR (400 MHz, CDCl3) δ8.16 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.62 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.15 (m, 2H), 6.58 (brs, 2H), 4.46 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([N:25]6[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(N3CCCCC3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Yield: 81 %

Procedure:
3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.28 g, 0.8 mmol) was heated to 110° C. for 2 1/4 h in a mixture of 20 ml of dimethylformamide and 1 ml of piperidine. The reaction mixture was then evaporated in vacuo and the residue triturated with 5 ml of water, filtered off and dried to give 0.26 g (81%) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl -5-oxo- 6-(1-piperidyl)-4,5-dihydro-imidazo(1,5-a)quinazoline, M.p. 185°-192° C..
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](O)[CH2:20][CH2:21]C>>[CH2:1]([O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCO
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1cc(Cl)ccc1N
Reaction time: 6 h
Yield: 93 %

Procedure:
186 parts of 5-chloroanthranilic acid methyl ester, 150 parts of n-butanol and 10 parts of potassium carbonate are refluxed for half an hour. The separated methanol is then distilled off over a column. Distillation is continued until the boiling point of n-butanol is reached, then after addition of 4 parts each of bleaching earth and of active charcoal the hot mixture is filtered and agitated with 100 parts of acetone and 200 parts of ice. The reaction lasts for about 6 hours. The precipitate is filtered off, washed with ice-cold water and dried in vacuo at room temperature. There are obtained 211 parts of 5-chloroanthranilic acid-n-butyl ester, melting point 37°-39° C. The yield is 93% of the theory.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[NH2:14])([O-])=O.[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:4]1([NH2:1])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cccc2c(N)cccc12
Yield: 97.5 %

Procedure:
8.20 g of 5-nitro-1-naphthylamine (43.6 mmol) in 35 ml of toluene are placed in a 0.1 liter autoclave with 0.5 g of palladium on carbon (5%) and hydrogenated at 50° C. and 40 bar hydrogen pressure for 5 h, stirring. On completion of the reaction, the cooled autoclave is depressurised and the catalyst is filtered off. With a quantitative conversion, 6.72 g of 1,5-naphthalenediamine (42.5 mmol, 97.5%) are formed.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>CO.CN(C)C=O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][O:13][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([NH2:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: Nc1ccc2ccc(O)cc2c1
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a suspension of 40.0 g 7-amino-2-naphthol hydrochloride (205 mmol) in 250 mL methanol under nitrogen is added 451 mL of 0.91N sodium methoxide (410 mmol) in methanol. After 1 hour of stirring, the solvent is removed and the residue is taken up in 500 mL dimethylformamide and cooled to 10° C. under nitrogen. A solution of 36.3 g 2-(chloromethyl)quinoline (205 mmol) in 200 mL dimethylformamide is added. After stirring overnight at ambient temperature, the reaction is stripped of solvent, water is added and the precipitate is filtered off, dried and recrystallized from toluene to afford 31.1 g (62%) of white crystals, which is further purified by filtration through Florisil. Recrystallization from toluene affords white crystals, m.p. 164.5°-166.0° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][NH2:20])=[O:18])[CH:15]=2)[C:10]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:9]1[CH:33]([CH3:35])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36](OCC)(OCC)OCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH:36]=[N:20][N:19]=3)[CH:15]=2)[C:10]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:9]1[CH:33]([CH3:35])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NN)cc2n1Cc1ccccc1
Reactant: CCOC(OCC)OCC
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3nnco3)cc2n1Cc1ccccc1

Procedure:
1-benzyl-N-(3,4-difluorobenzyl)-6-(hydrazinecarbonyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 88, 21 mg, 0.044 mmol) in triethyl orthoformate (5 ml) was heated to 145° C. for 5 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>O.CN(C)C=O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:2]=[O:1])[CH:11]=[CH:10][C:8]=1[O:9][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)O
Yield: 90.7 %

Procedure:
Vanillin (16.3 g, 0.107 mole), ethyl bromoacetate (21.6 g, 0.128 mole), potassium carbonate (17.8 g, 0.128 mole) and N,N-dimethyl-formamide (75 ml) were united, stirred and heated at 50°-55° C. for 35 minutes. Then a 10% aqueous sodium hydroxide solution (100 ml) and water (300 ml) was added and the mixture stirred on a steam bath for one hour. The solution was cooled and acidified with hydrochloric acid. The solid that separated was removed by filtration, washed with water and dried to give 20.4 g of the desired product, m.p. 177°-178° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:55]([SH:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:55]([S:62][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: SCc1ccccc1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1[nH]cnc2cc(SCc3ccccc3)ccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 7-bromoquinazolin-4(3H)-one (10 g, 44.4 mmol), Xantphos (1.286 g, 2.222 mmol), and Pd2(dba)3 (1.017 g, 1.111 mmol). The flask was flushed with Ar (g), then dioxane (89 ml), benzyl mercaptan (5.52 ml, 46.7 mmol), and n,n-diisopropylethylamine (15.52 ml, 89 mmol) were added in sequence. The reaction was fitted with a reflux condenser, heated to 90° C., and stirred for one hour. The reaction was diluted with water and filtered. The solids were washed thoroughly with water, then air dried for several hours and triturated with ethyl acetate. After stirring overnight, the solids were filtered, washed with ethyl acetate, and vacuum dried over a nitrogen blanket overnight to afford 7-(benzylthio)quinazolin-4(3H)-one as a light yellow solid. (ESI) 269.1 (M+H)+.