Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>C(#N)C>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)=[O:26])[CH2:29][CH2:30]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCn2ccnc2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (218 mg, 0.5 mmol) obtained in Example 1201a), potassium carbonate (83 mg, 0.6 mmol, 1.2 eq.) and imidazole (41 mg, 0.6 mmol, 1.2 eq.) were suspended in acetonitrile (5.0 ml) and the mixture was stirred at 80° C. for 10 hr. The mixture was concentrated to dryness, and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (42 mg, 21%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:34]1[N:38]=[N:37][C:36]([CH3:39])=[N:35]1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:67])(=O)=O)CCCCCCCCCCCCCCC>>[I:67][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:34]1[N:38]=[N:37][C:36]([CH3:39])=[N:35]1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)n1nnc(C)n1

Procedure:
3-(3-Chloropropylsulfonylamino)-2-(5-methyl-2H-tetrazol-2-yl)-1-octadecylcarbamoyloxypropane IIIh3 is allowed to react and worked up by the same procedure as described in (5). m.p. 53.5°-54° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(F)cc23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Yield: 15 %

Procedure:
To a solution of (S)-tert-butyl 3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (0.45 g, 1.12 mmol) in dioxane (10 mL) was added CDI (0.72 g, 2.24 mmol) under N2. The mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (70 mg, 40%). ESI-MS m/z [M+H-Boc]+ 316.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.Cl.[N:23]1([C:28]2[N:33]=[CH:32][C:31]([NH2:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>>[N:23]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc(N2CCCC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc(N2CCCC2)cc1C(F)(F)F)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in step 5.3, using 0.3 g (1.04 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1), and of 0.363 g (1.36 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-aminopyridine hydrochloride, prepared in step 11.4, in the presence of 0.22 ml (1.57 mmol) of triethylamine.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[CH:27]([N-]C(C)C)(C)C.[Li+].CI.NCCC(CN)O.S(=O)(=O)(O)O>C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C:10]([CH3:27])([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)[N-]C(C)C
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: NCCC(O)CN
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)C(=O)N1C(=O)C(C)(C)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
10 g (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-a, R1=Piv) is added to THF (100 ml). The mixture is cooled to −30° C. Lithium diisopropylamide (17.16 ml, 2 M) is added and the mixture is stirred for 1 h. Methyl iodide (5.4 ml) is added and the mixture is stirred for 3 h. Aminoethylethanolamine (6.1 ml) is added and the mixture is warmed to 40° C. and stirred for 15 min. Sulphuric acid (12 g) is then added. The mixture is concentrated in vacuo and the residue taken up in toluene. The phases are separated. The organic phase is concentrated in vacuo and taken up in methanol (300 ml) at reflux. On cooling, the precipitate is collected by filtration to give (R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one. 1H NMR (DMSO): 1.04 (3H), 1.15 (3H), 1.28 (9H), 1.72 (1H), 1.38 (1H), 2.59 (1H), 3.14 (1H), 4.37 (1H), 7.31 (3H), 7.45 (2H), 7.62 (4H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH3:9])[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH:3]([CH3:9])[C:4]([NH:6][C:7](=[O:8])[O:19][CH:10]([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[O:5]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CC(CCl)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Product: CC(CCl)C(=O)NC(=O)OC(C(F)(F)F)C(F)(F)F

Procedure:
To a solution of beta-chloroisobutyryl isocyanate (7.38 g; 50 mmol) in chloroform (50 ml), a solution of 1,1,1,3,3,3-hexafluoroisopropanol (8.4 g; 50 mmol) in chloroform (10 ml) was dropwise added at 10° C. under ice-cooling. After completion of the addition, the resultant mixture was stirred for 1 hour, whereby hexafluoroisopropyl beta-chloroisobutyrylcarbamate was produced. A solution of triethylamine (5.05 g; 50 mmol) in chloroform (50 ml) was added to the reaction mixture in 30 minutes under ice-cooling. The reaction mixture was stirred for 1 hour, and precipitated triethylamine hydrochloride (6.87 g) was eliminated by filtration. The filtrate was concentrated under reduced pressure to give hexafluoroisopropyl N-methacryloylcarbamate (13.4 g), which was recrystallized from benzene to give colorless prisms. M.P., 112.5°-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([N:17]1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]1[NH:17][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)nc(N)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n(NC(=S)n2ccnc2)c(=N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldiimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C([O:9][C:10]1[C:21](=[O:22])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19](Br)[C:13]2=[N:12][C:11]=1[C:23]([O:25][CH3:26])=[O:24])(=O)C1C=CC=CC=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.CO.O>[OH:9][C:10]1[C:21](=[O:22])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:35][C@@H:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:34])[C:13]2=[N:12][C:11]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCCC2Br
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1nc2n(c(=O)c1O)CCCCC2N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate (1.0 eq.) was added to a solution of (1R)-1-phenylethylamine (2.2 eq.) and triethylamine (1 eq) dissolved in N,N-dimethylformamide. The mixture was stirred vigorously for 2 hours at room temperature and then at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the title crude product (a mixture 1:1 of diasteroiesomers) for use without further purification. In an alternative procedure (Step 5A), solid methyl 3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate (1.0 eq.) was added to a solution of (1R)-1-phenylethylamine (4.5 eq.) dissolved in a 7:3 methanol/water mixture at −30° C. The reaction was carried out over night, then the temperature was raised to room temperature and the solvent concentrated to obtain a white solid that was filtered off and discarded. The title compound (as a mixture 7:3 of diasteroisomers) was extracted in dichloromethane from the mother liquid for use in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C

Procedure:
3-Hydroxy-4-nitro-benzoic acid 1a (3.17 g, 17.32 mmol) was dissolved in 40 mL of anhydrous methanol. The reaction solution was cooled down to 0° C. and added dropwise with thionyl chloride (3.09 g, 25.98 mmol) with stirring. Upon the completion of the addition, the resulting solution was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (100 mL×3), saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound methyl 3-hydroxy-4-nitro-benzoate 1b (3.30 g as a yellow solid) yield: 96.7%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8]C(=O)[C:5]2=[CH:11][C:12]=1[F:13].FC1C=C(C(O)=O)C(=CC=1F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]=1[F:13])[C:9]([OH:10])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: O=C(O)c1cc(F)c(F)cc1C(=O)O
Product: O=C(O)c1ccc(F)c(F)c1

Procedure:
4,5-Difluorphthalic anhydride and 4,5-difluorophthalic acid may be decarboxylated in high yield to 3,4-difluorobenzoic acid by heating in N-methyl-2-pyrrolidone or dimethyl acetamide using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:9])=O)[C:3]=1[CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]#[N:9])[C:3]=1[CH3:10]
Reactant: Cc1c(C(N)=O)n[nH]c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C#N)n[nH]c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-iodo-4-methyl-1H-pyrazole-3-carboxamide (compound 258.2, 800 mg, 3.19 mmol) in dichloromethane (10 mL). The solution was cooled to 0° C., then trifluoroacetic anhydride (1.32 mL, 9.5 mmol) and triethylamine (3.16 mL, 22.7 mmol) were each added carefully drop-wise. The mixture was stirred for 2 h at 0° C., then the pH was carefully adjusted to 7-8 with aqueous sodium bicarbonate (10%). The aqueous phase was extracted with ethyl acetate (2×40 mL) and the combined organic layers were washed with 2×10 mL of brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a white solid (280 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:9]=[O:10])=[C:4]([CH3:18])[CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23]Br>C1COCC1>[Br:21][CH2:22][CH2:23][O:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1C(C=O)c1ccc(F)cc1C
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluoro-2-methylphenyl)-(2-methylphenyl)acetaldehyde (3.5 g, 0.0144 mol) was dissolved in dry THF (20 ml) and added dropwise to a suspension of sodium hydride (60% oil dispersion) (0.63 g, 0.0158 mol) in dry tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1 h and heated at reflux for 0.5 h. After cooling 1,2-dibromoethane (12.4 ml, 10 equiv.) was added, and the reaction mixture was allowed to stand at room temperature for 192 h. The reaction mixture was filtered and evaporated. The residue was pumped in vacuo, but still contained ca. 30% starting aldehyde, so the above procedure was repeated.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[C:12]([O:39]CC3C=CC(OC)=CC=3)=[N:13][C:14]([CH:17]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:29][CH:28]=3)[O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:16]=2)[CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[CH:8]1([C:11]2[C:12](=[O:39])[NH:13][C:14]([CH:17]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:31][CH:32]=3)[O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COc1ccc(COc2nc(C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Trifluoroacetic acid (50 mg) was added to a solution of 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine (90 mg) in chloroform (5 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=88:12→0:100) to give the title compound as a yellow powder (53 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1>CN(C)CCN.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH:9][CH2:8][CH2:16][N:11]([CH3:12])[CH3:10])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Agent: CN(C)CCN
Solvent: CCOC(C)=O
Product: CN(C)CCNc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Temperature: 95 °C

Procedure:
A mixture of 100 mg of 2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine (0.282 mmol, 1 eq) in 1 mL of N,N-dimethylethane-1,2-diamine (excess) in a sealed tube was heated to 95° C. for 2 h. The solution was then diluted with EtOAc, washed with water, dried on MgSO4, filtered and concentrated. The crude was purified by silica gel chromatography (MeOH:NH4OH (95:5)/EtOAc, 0 to 15%). The product was finally washed with ether (33 mg, 29%) m/e+=407 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.55 (s, 1H), 7.90 (d, 1H, D, J=6.6 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.67 (d, 1H, D, J=9.2 Hz), 7.42 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.7 Hz), 6.81 (t, 1H, D, 7.7 Hz), 5.86 (s, 1H), 4.38 (s, 2H), 2.43 (m, 2H), 2.17 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:11].[C:12]([O:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17]([NH:11][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:10][C:17](=[O:18])[CH2:16][O:15][C:12](=[O:14])[CH3:13])[C:2]=1[Cl:1])[C:6]#[N:7])=[O:18])(=[O:14])[CH3:13]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cc(C#N)cc(NC(=O)COC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzonitrile (6.7 g) in pyridine (150 ml) is added dropwise acetoxyacetyl chloride (9.5 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and dissolved in chloroform, and the insoluble substance is filtered off. The filtrate is washed with water and then with aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting solid substance is recrystallized from ethanol to give the title compound (4.3 g) having the following physical properties.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](B(O)O)=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:11][NH:10][C:8]([C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]([CH3:23])=[C:2]([C:36]2[N:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[N:33]=[CH:34][CH:35]=2)[N:7]=1)=[O:9]
Reactant: N#Cc1ccc(-n2nccc2B(O)O)cc1
Reactant: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CNC(=O)c1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 19.6 %

Procedure:
6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (SM2, 0.05 g, 0.128 mmol), 1-(4-cyanophenyl)-1H-pyrazol-5-boronic acid (SM4, 0.062 g, 0.256 mmol), Cs2CO3 (0.125 g, 0.384 mmol) and DME (3 ml) were added to a glass tube for microwave synthesis. The mixture was degassed with nitrogen and Pd(PBut3)2 (0.010 g) was added. The tube was sealed and heated with stirring at 110° C. (150 W) in a microwave heater for 10 minutes. The mixture was diluted with EtOAc (5 ml), and filtered. The solution was concentrated in vacuo and was purified by chromatography on silica to give a reasonably pure material that was further purified by preparative HPLC to give 0.012 g (20%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.O[N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]>>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)(C)OC(=O)N1CCC(CON2C(=O)c3ccccc3C2=O)CC1
Yield: 80 %

Procedure:
The title compound was prepared from t-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 2-hydroxyisoindoline-1,3-dione in 80% yield using the same procedure as described in the synthesis of intermediate B. LCMS (method B): [MNa]+=383, tR=2.64 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25][CH2:24][CH2:23][CH2:22]C[C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.N1N2C(N=C3C(=C2C2C=CC(O)=CC=2)CCCC3)=CC=1.BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]3[N:18]=[C:19]3[C:20]=2[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:10][CH:11]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: ClCCCBr
Agent: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1

Procedure:
Using the method described for the preparation of 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 4-(5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazolin-9-yl)-phenol and 1-bromo-3-chloropropane provided the title compound.