Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:27]([F:30])([F:29])[F:28])[C:20]3[CH:19]=[C:18](C(O)=O)[CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10](C(O)=O)=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]1([C:7]2([C:27]([F:30])([F:28])[F:29])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2c(c1)C(c1ccccc1)(C(F)(F)F)c1cc(C(=O)O)ccc1O2
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)C1(c2ccccc2)c2ccccc2Oc2ccccc21
Reaction time: 8 h
Yield: 66 %

Procedure:
A 6 g sample of 9-phenyl-9-trifluoromethylxanthene-2,7-dicarboxylic acid (XX) was stirred and refluxed in 100 ml quinoline along with 11 g of copper powder, the emanating gas being measured by a wet-test meter. The theoretical amount of CO2 was evolved in two hours. The reaction mixture was cooled, filtered through a bed of Celite into 800 ml of water,acidified with 100 ml of concentrated hydrochloric acid, and left standing overnight. The supernantant liquid was decanted, and the residue was takenup in methylene chloride, and filtered through a bed of alumina. The solvent was stripped, the residue was stirred with methanol, and was filtered, yielding 3.1 g (66%) of a white solid. It was recrystallized from methanol; m.p. 89-90°. The IR spectrum was sharp with no OH orCO bands. The NMR spectrum was confirmatory, with the following peaks: d 7.42; m 7.3-7.4; d 7.19, td 6.96, d 6.87 in 2:5:2:2:2 ratio. The compound was analyzed by mass spectrometry which showed the parent ion at 326, along with other peaks, the strongest being at 257 (parent minus trifluoromethyl), and also at 249 (parent minus phenyl), and 199 (parent minus phenyl and minus difluorocarbene). The mass spectrum confirmed the molecular formula as C2H13F3O.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[CH2:11][CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[CH2:11][CH2:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCC1=COc2ccccc2O1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NCCC1=COc2ccccc2O1

Procedure:
0.837 g (2.37 mmol) of the phthalimide obtained in Step E and 0.358 g (7.16 mmol) of hydrazine monohydrate are dissolved in 20 ml of tetrahydrofuran; the mixture is then heated at reflux for 5 hours. After filtering off the solid, the filtrate is concentrated in vacuo; the residue is then taken up in dichloromethane and dried over magnesium sulphate. The filtered organic phase is concentrated in vacuo to yield the amine in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:17])=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][Br:18])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 4-methyl-2-phenyl-thiazole-5-carboxylic acid ethyl ester (5.04 g, 0.02 mol), N-bromosuccinimide (3.8 g, 0.02 mol) and benzoyl peroxide (247 mg, 1 mmol) in carbon tetrachloride (60 mL) was refluxed for 17 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (6.55 g): 1H NMR (CDCl3, 200 MHz): δ=7.94 (m, 2H), 7.44 (m, 3H), 7.03 (m, 1H), 4.98 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H); MS: (+) m/z 326.0, 328.0 (M+1, 79Br/81Br).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1cc(C(F)(F)F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 50 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxy-4-trifluoromethyl-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 185 mg, 50%) which was obtained as a white solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(Cl)cc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-chlorophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -20° C. was added a solution of 1.7 mmol chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 0.3 g of the title compound as a pale yellow foam (65% of the theoretical yield).
Reaction SMILES: Cl.Cl.[CH:3]([NH:6][CH:7]([CH3:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].[Cl-].[Na+]>C(Cl)Cl>[CH:3]([NH:6][CH:7]([CH3:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:11][N:10]=1)([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC(C)Cc1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)NC(C)Cc1ccc(OS(C)(=O)=O)cn1
Reaction time: 0.5 h

Procedure:
To the mixture of 26.7 g of 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride, 200 ml of methylene chloride and 100 ml of saturated aqueous sodium carbonate, 16 ml of methanesulfonyl chloride are added dropwise while stirring at 0°-10° and adding more sodium carbonate to maintain basicity. Stirring is continued for 30 minutes at pH=9.5-10 and the mixture is combined with half of its volume of saturated aqueous sodium chloride. It is separated, the aqueous layer extracted with methylene chloride, the combined organic solutions washed with saturated aqueous sodium carbonate, dried and evaporated, to yield the 2-(2-isopropylaminopropyl)-5-methanesulfonyloxypyridine as an oil.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].CCN(CC)CC.[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20](Br)[N:19]=1)=[O:17].COC(C1C(N)=NC(NCCOC)=C(Cl)N=1)=O>C1COCC1.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.[Cu]I>[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[N:19]=1)=[O:17]
Reactant: COCCNc1nc(N)c(C(=O)OC)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COCCNc1nc(N)c(C(=O)OC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNc1nc(N)c(C(=O)OC)nc1C#C[Si](C)(C)C
Temperature: 80 °C

Procedure:
To a solution of ethynyl-trimethyl-silane (1.05 g, 10.7 mmol), bis(triphenylphosphine)palladium(II) chloride (150 mg, 0.214 mmol), Copper(I) iodide (41 mg, 0.214 mmol) and NEt3 (2.09 ml, 14.98 mmol) in THF (17 ml) was added under an argon atmosphere a mixture (about 1:1) of 3-amino-6-bromo-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester and 3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester (651 mg, 2.14 mmol) and the mixture was heated to 80° C. for 17 h. The reaction mixture was filtered through Hyflo and the solvent evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 60:40) to provide the title compound as brown solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([O:23]C)[CH:16]=2)=[N:10][C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([OH:23])[CH:16]=2)=[N:10][C:9]=1[C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3cc(OC)cc(OC)c3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1cc(O)cc(O)c1
Yield: 48.2 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,5-dimethoxy-benzamide prepared in Example 43 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 48.2%, mp: 262-263 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.21 (2H, s, CH2), 6.44 (1H, t, J=2.12 Hz, ArH), 6.83 (2H, d, J=8.40 Hz, ArH), 6.88 (2H, d, J=2.24 Hz, ArH), 7.22˜7.26 (3H, m, ArH), 7.32˜7.35 (2H, m, ArH), 7.46 (2H, d, J=8.68 Hz, ArH), 9.52 (2H, br, OH), 12.39 (1H, br, CONH); EI-MS m/e (%): 418.1 (M+, 82), 282.1 (66), 137.0 (100); HREI-MS Calcd. for C23H18N2O4S: 418.0987. found: 418.0981.
Reaction SMILES: BrC1C=CC2N(N=C(N3CCCC3)N=2)C=1.[N:16]1([C:22]2[N:31]=[C:25]3[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][N:24]3[N:23]=2)[CH2:21][CH2:20]O[CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:31]=[C:25]3[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][N:24]3[N:23]=2)[CH2:21][CH2:20][CH2:18][CH2:17]1
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: Brc1ccc2nc(N3CCCC3)nn2c1
Product: Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using 6-Bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine, this compound was prepared following the same method as for the synthesis of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine. Brown solid (1.1 g, 81%). MS: m/z=204 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:7][CH:8]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(C#N)n1-c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-hydroxymethylphenyl)-5-methylpyrrole-2-carbonitrile (890 mg) in dichloromethane (9 ml) was added triethylamine (794 μl) and methanesulfonyl chloride (343 μl) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for an hour and then dichloromethane was added therein. The mixture was stirred and washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (1.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Br)cc1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80° C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83% yield) of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC=C(c2ccc(Cl)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Yield: 99.2 %

Procedure:
Reduce a solution of the product of STEP 2 (1.36 g) in EtOAc (50 mL) over 10% Pd/C under H2 (50 psi) for 14 h. Filter the catalyst and concentrate the solution to give the title compound (1.36 g).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10]OC(OC)N(C)C>C1C=CC=CC=1>[N:1]12[CH:10]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9]1)[CH2:3][CH2:2]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCNCCN1
Solvent: c1ccccc1
Product: C1CN2CCN3CCN1C23

Procedure:
A reaction mixture of 4.00 g (31 mmol) of 1,4,7-triazacyclononane (perhydro-1,4,7-triazonine), 3.70 g (31 mmol) of dimethylformamide dimethyl acetal and 50 ml of dry benzene was distilled through a spinning band column until the by-products and solvent were removed (dimethylamine, benzene-methanol azeotrope, bp 58°, and benzene, bp 80° ). The residue was then distilled through a short-path apparatus giving 3.68 g (86%) of clear, colorless liquid, bp 80°-82° (2.5 mm), nD24 = 1.5175. Redistillation of a small sample in a molecular still at 80° (0.4 mm) gave an analytical sample of 1,4,7-triazatricyclo[5.2.1.04,10 ]decane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([C:7]([N:9](C(=O)C2C=CC(OC)=CC=2)[C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]([CH3:32])[CH3:31])[CH:16]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]([CH3:31])[CH3:32])[CH:16]=3)[N:11]=2)=[O:8])=[CH:43][CH:44]=1
Reactant: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccccc3)c2C#N)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2nc3ccc(N(C)C)cc3c(NCc3ccccc3)c2C#N)cc1

Procedure:
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 20 mL of acetonitrile, 5 mL of 1N methanolic potassium hydroxide solution is added. The reaction mixture is heated under reflux conditions for 10 minutes, 1.5 mL of glacial acetic acid is added to it, then it is neutralized with 15 mL of 1M sodium hydrogen carbonate solution. The precipitate is filtered off, the yellow crystalline material is recrystallized from the mixture of 5 ml of dimethylformamide and 40 mL of ethanol. After drying 1.3 g of the title compound is obtained, m.p.: 185° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[N:4]1)[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl.C(OCC)(=O)C>[Cl:21][CH2:22][C:23]([N:8]([C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)[CH:9]([CH3:10])[CH3:11])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CCn1nccc1NC(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1nccc1N(C(=O)CCl)C(C)C
Yield: 53.1 %

Procedure:
1-Ethyl-N-isopropyl-1H-pyrazol-5-amine (0.49 g, 3.2 mmol) was dissolved in dichloromethane (11 ml) and stirred in an ice bath. N,N-diisopropylethylamine (1.14 ml, 6.4 mmol) was added followed by slow addition of chloroacetyl chloride (0.51 ml, 6.4 mmol). The reaction was stirred to 25° C. over 16 h. Water (100 ml) and ethyl acetate (100 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases were washed with a saturated aqueous sodium chloride solution (25 ml). After drying over sodium sulfate and evaporation the residue was purified by silica gel chromatography (5-80% ethyl acetate/hexanes) to give 0.39 g (53%) of 2-chloro-N-(1-ethyl-1H-pyrazol-5-yl)-N-isopropylacetamide as a brownish solid. MS (ESI) m/z 230 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[I:17]I.O>CN(C)C=O>[I:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: II
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccccc2C1=O

Procedure:
1.06 g (5 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one are stirred at 90° for 40 hours together with 1.26 g of iodine in 20 ml of dimethylformamide. The mixture is poured into water and extracted three times with chloroform. The chloroform extracts are washed five times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 174°-176°.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC(=CC(=O)OCC)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.85 g (5.4 mmol) Ethyl 3-oxohexanoate, 1.0 g (6.21 mmol) 3-trifluoromethylaniline and 5 mg (0.08 mmol) acetic acid are dissolved in 15 ml ethanol, and 0.78 g (6.5 mmol) magnesium sulfate are added. The reaction mixture is stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane as eluent.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[F:73])[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=4[F:73])[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2F)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.052 mmol), 2,5-dimorpholinopyridin-3-amine (0.103 g, 0.39 mmol), 4-chloro-5,7-difluoro-2-(2-fluorophenyl)-3-methylquinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.078 g, 0.81 mmol) in toluene (3.3 mL) at 120° C. for 3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-2-(2-fluorophenyl)-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3-d) δ ppm 7.59-7.68 (3H, m), 7.47-7.54 (1H, m), 7.36 (1H, td, J=7.5, 1.2 Hz), 7.20 (1H, m,), 7.05 (1H, ddd, J=13.6, 8.6, 2.6 Hz), 6.42 (1H, br. s.), 3.93 (4H, br. s.), 3.83 (4H, m), 3.40 (2H, br. s.), 3.08 (4H, br. s.), 3.01 (2H, br s), 2.07 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=536.2 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]([CH3:13])[CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Cl-].[Na+].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>[CH3:12][N:11]([CH3:13])[C:9]1[C:10]2[C:2]([C:28]3[CH:29]=[C:24]([CH2:23][OH:22])[CH:25]=[CH:26][CH:27]=3)=[CH:3][N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CN(C)c1ncnc2c1c(I)cn2COCC[Si](C)(C)C
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: CN(C)c1ncnc2c1c(-c1cccc(CO)c1)cn2COCC[Si](C)(C)C
Temperature: 120 °C

Procedure:
A solution of 5-iodo-N,N-dimethyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C3) (418 mg, 1.00 mmol), [3-(hydroxymethyl)phenyl]boronic acid (228 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.100 mmol), and cesium carbonate (625 mg, 1.92 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was purged with nitrogen, then heated under microwave irradiation at 120° C. for 20 minutes. The reaction mixture was diluted with saturated aqueous sodium chloride solution (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 2% to 17% ethyl acetate in petroleum ether) afforded the product as a brown oil. Yield: 369 mg, 0.926 mmol, 93%. LCMS m/z 399.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28]Cl>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1ccc(CCl)cc1F
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5ccc(OC)c(F)c5)o4)cc23)cc1
Yield: 86 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluoro-4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 86%) was obtained as colorless crystals.