Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C1C=CC(C(Cl)=O)=CC=1)#[N:2].Cl[C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1>>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[C:25]1[C:20]([C:14]2[CH:15]=[CH:16][C:17]([C:1]#[N:2])=[CH:18][CH:13]=2)=[N:21][C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)=[N:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(-c2nc(NCCNc3ccc([N+](=O)[O-])cn3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-[5-imidazol-2-yl-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-4-yl]benzenecarbonitrile was prepared from 4-cyanobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[C:21]2[CH2:33][CH3:34])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[C:21]2[CH2:33][CH3:34])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To the methanolic (15 mL) solution of (±) ethyl-2-ethoxy-3-[4-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate (420 mg, 0.909 mmol) obtained in example 1 was added NaOH (365 mg, 9.125 mmol) in H2O (10 mL), the mixture was stirred at 25° C. for 1 hr, evaporated the solvent under reduced pressure. The residue was added to 50 mL of cold water and washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water, brine, dried (Na2SO4) and evaporated the solvent, to give a stick compound, which was solidified by either long drying under vacuum or trituration with dry ether to give a white solid (380 mg, 96%) mp: 138-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[CH:34][C:35](/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Product: O=C(O)/C=C/c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-(4-formyl-phenyl)-acrylic acid according to the procedure of Example 66. MS (ESI) m/z 553.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:15]=[CH:14]2
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 4-fluorobenzyl bromide and 5-bromoindole in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a white solid; mp: 57-58° C. Mass spectrum (APCI, [M+H]+) m/z 304. 1 HNMR (400 MHz, DMSO-d6): δ 7.73 (d, 1H, J=1.8 Hz), 7.55 (d, 1H, J=3.2 Hz), 7.43 (d, 1H, J=8.9 Hz), 7.24-7.19 (m, 3H), 7.12 (t, 2H, J=8.9 Hz), 6.47 (d, 1H, J=3.6 Hz), 5.40 (s, 2H), and 2.22 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:13]([NH:14][C:15]([NH2:17])=[O:16])=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([F:18])[CH:3]=1.[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:13]([NH:14][C:15]([NH:17][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:16])=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Br)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2Br)CCC1

Procedure:
using isopropyl 4-bromo-2-fluoro-5-ureidobenzoate and ethyl cyclopentanon-2-carboxylate is toluene there is obtained isopropyl 4-bromo-2-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 166°-168° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12](O)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:37]>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([NH2:37])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(N)=O)n1Cc1ccccc1[N+](=O)[O-]

Procedure:
(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5yl]-2-benzyl-2-propenoic acid, prepared in Example 58, is treated with thionyl chloride and then ammonium hydroxide, as described in Example 57, to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15].[OH:30]O>C(O)(=O)C.O>[OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15])=[O:30]
Reactant: OO
Reactant: CC(CO)(CCCCSCCCCC(C)(CO)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(CO)(CCCCS(=O)CCCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.2 %

Procedure:
To a solution of 6-(6-hydroxy-5-methyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexan-1-ol (3.0 g, 7.0 mmol) in glacial acetic acid (20 mL) was added hydrogen peroxide (50 wt. % in water; 0.5 mL, 7.0 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (100 mL), and extracted with chloroform (3×80 mL). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×80 mL) and saturated NaCl solution (80 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude 6-(6-hydroxy-5-methyl-5-phenylhexylsulfinyl)-2-methyl-2-phenylhexan-1-ol (2.63 g 88%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.42-7.12 (m, 10 H), 3.78-3.58 (m, 2 H), 3.58-3.45 (m, 2 H), 2.90-2.70 (m, 2 H), 2.68-2.39 (m, 2 H), 1.95-1.50 (m, 8 H), 1.50-1.00 (m, 10 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.5, 144.4, 128.4, 128.3, 126.5, 126.2, 126.1, 72.2, 72.1, 71.9, 52.4, 52.0, 43.2, 37.8, 37.7, 23.2, 22.9, 22.4, 21.7, 21.5. HRMS (LSIMS, nba): Calcd. for C26H39O3S1 (MH+): 431.2620, found: 431.2611.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:29]([OH:41])[C:30]2[NH:34][C:33]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].[OH-].[K+]>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([CH:29]([OH:41])[C:30]2[NH:34][C:33]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1cc(C)c2[nH]cc(-c3ccccc3)c2c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of (±)-2-((5-ethyl-7-methyl-3-phenyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.036 mmol) and KOH (10 mg, 0.178 mmol) was stirred at 100° C. for 0.5 h under microwave irradiation. The reaction mixture was diluted with CH2Cl2. The mixture was filtered through silica gel. The silica gel cake was washed with CH2Cl2/MeOH (c.a. 9/1). After concentration, the filtrate was purified by silica gel flash column chromatography [CH2Cl2/(5% 2,2,2-trifluoroethanol in CH2Cl2)=95/5 to 40/60] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.54 (br. s., 1H), 7.93 (s, 1H), 7.70 (dd, J=1.30, 8.60 Hz, 1H), 7.63 (d, J=8.60 Hz, 1H), 7.03-7.38 (m, 6H), 6.99 (s, 1H), 6.59 (s, 1H), 2.53-2.54 (m, 5H), 0.98 (t, J=7.33 Hz, 3H). HRMS calcd. for C26H22N4O (M+H)+ 407.1872. found 407.1868.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 84%), MS (ISP) m/z=331.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([CH2:24][C:9]2[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:26][C:27]=1[F:33])#[N:30]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: N#Cc1ccc(CCl)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(C#N)c(F)c2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.07 g), 4-(chloromethyl)-2-fluorobenzonitrile (0.89 g), 2 mol/L aqueous sodium carbonate solution (3.50 mL) and DME (20.0 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.14 g) under argon atmosphere, and the mixture was stirred overnight at 80° C., and then at room temperature for weekend. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]3[C:27]([CH:28]=2)=[C:26]([Cl:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)=O)[CH:4]=1.Cl>O1CCCC1>[CH2:31]([N:21]1[C:22]2[C:27](=[C:26]([Cl:29])[CH:25]=[C:24]([Cl:30])[CH:23]=2)[CH:28]=[C:20]1[CH2:18][NH:17][CH2:16][CH2:15][CH2:14][NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(NCCCNC(=O)c2cc3c(Cl)cc(Cl)cc3n2Cc2ccccc2)nc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(NCCCNCc2cc3c(Cl)cc(Cl)cc3n2Cc2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-benzyl-4,6-dichloro-1H-indole-2-carboxylic acid [3-(4-methoxy-quinolin-2-ylamino)-propyl]-amide (200 mg, 0.37 mmol) [from example 12] in anhydrous tetrahydrofuran (15 ml) was treated with 1 N borane-tetrahydrofuran complex (1.1 ml, 1.1 mmol). The solution was heated a reflux for 24 hours then cooled to ambient temperature. Treated with the dropwise addition of concentrated hydrochloric acid (1 ml) then stirred for 1 hour. Evaporated under reduced pressure to a residue and taken into a system of saturated aqueous sodium chloride (20 ml) and 10% sodium hydroxide (20 ml). Extracted into ethyl acetate. The extracts were dried (sodium sulfate) then evaporated to an oil. Column chromatography on silica (95/5 methylene chloride/methanolic ammonia) gave N-(1-benzyl-4,6-dichloro-1H-indol-2-ylmethyl)-N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine as a colorless resin. This was taken into chloroform (5 ml) then treated with 4N hydrogen chloride in 1,4-dioxane (300 μl). Evaporation under reduced pressure gave N-(1-benzyl-4,6-dichloro-1H-indol-2-ylmethyl)-N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine dihydrochloride (102 mg, 42%) as a white solid. [M+H]+ 519.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([C:17]([O:19]C)=O)=[CH:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1.[C:21]([Li])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[C:17](=[O:19])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(F)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cc(CO)ccc1-c1cc(F)ccc1F
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
To a stirred solution of 83.27C (0.485 g, 2 mmol) in THF (17 mL) at −78° C. was added tert butyl lithium (3 mL, 5 mmol, 1.7 M). The reaction was then stirred for 1.5 hours and then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 83.27D as a colorless oil (0.450 g, 85% yield).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH2:24][OH:25])=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:25][CH2:24][CH2:23][C:20]1[N:18]2[CH2:19][C@H:13]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([F:12])[C:6]=3[F:5])[CH2:14][CH2:15][C@@H:16]([NH:26][C:27]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:33])[C:17]2=[N:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CCO)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
Acetyl chloride (24 μL, 0.344 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (70 mg, 0.172 mmol) and triethylamine (48 μL, 0.344 mmol) in dichloromethane (6 mL) at 0° C. After 1.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (64 mg). MS 450.2 (M+1).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[S:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:36])(=[O:35])=[O:34]>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:40]3[CH2:41][CH2:42][N:37]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:38][CH2:39]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(S(C)(=O)=O)CC4)n(CC4CC4)c3n2)cn1
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (140.5 mg, 0.29 mmol) and N-mesylpiperazine (190.2 mg, 1.16 mmol) was heated at 140° C. and stirred for 3 hours. N-Mesylpiperazine (190.2 mg, 1.16 mmol) was added, the resulting mixture was further stirred for 5.5 hours and left standing to cool followed by the addition of dichloromethane-methanol (10:1), and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the reaction mixture was filtrated, then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=20:1) to give the title compound (120.5 mg, 79%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)C1Cc2cc(Br)ccc2O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2Cc3cc(Br)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243 g, 1.00 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.464 g, 1.05 mmol), 1-methyl-piperazine (116 μL, 1.05 mmol) and N,N-diisopropylethylamine (696 μL, 4.00 mmol) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.325 g, 95%). LCMS (M+H)+=324.9/327.0.
Reaction SMILES: Br[C:2]1[C:3]([O:14][C@H:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].CCOC(C)=O.O>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH:31]=[CH2:32])[C:3]([O:14][C@H:15]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]3)=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3cc2Br)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C=Cc1cc2ccc(OC)cc2nc1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
TEA (0.87 mL, 6.23 mmol) was added to a solution of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-bromo-7-methoxyquinolin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate (2.0 g, 4.2 mmol) in EtOH (30 mL). Potassium vinyltrifluoroborate (0.84 g, 6.23 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.17 g, 0.21 mmol) were then added, and the reaction mixture was stirred at 100° C. for 2 h. The reaction mixture was worked up with EtOAc and water, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on silica (gradient elution, 0-40% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H-tBu)+=373.3.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][NH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][N:15]2[CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: C=CC#N
Solvent: Cc1ccccc1
Product: N#CCCN1CC2CC1CN2Cc1ccccc1
Yield: 89.2 %

Procedure:
Freshly distilled acrylonitrile (2.5 g) is added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous toluene and refluxed with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 120°–130° C. at 0.01 mbar) resulted in 3.43 g of 142 as a colorless oil (88% of the theoretical yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH2:12])[CH:2]=[CH2:3].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]2[N:21]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[N:23]=[C:16]2[N:15]=1.[OH-].[Na+].C>N1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]2[N:21]=[C:22]([S:24](=[O:25])(=[O:26])[NH:12][C:6]3[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:1][CH:2]=[CH2:3])[N:23]=[C:16]2[N:15]=1
Reactant: C=CCOc1cccc(Cl)c1N
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: C=CCOc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
0.77g of 2-amino-3-chlorophenyl allyl ether in 12ml of dry pyridine were treated with 1.03g of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulphonyl chloride and stirred at ambient temperature overnight. The pyridine was removed by evaporation with final traces eliminated by means of a vacuum pump. An oily brown product was obtained which was stirred with 30ml of 1M sodium hydroxide for 20 minutes to give a brown solution. Charcoal (20-30mg) was added and the mixture stirred for 10 minutes and then filtered through Celite ("Celite" is a trade mark). The filtrate was cooled, acidified with 10% hydrochloric acid to pH 1-2 to produce a solid which was then filtered off, washed with water and dried in vacuo to give 1.2g (a yield of 73%) of 5,7-dimethyl-2-(N-[2-allyloxy-6-chlorophenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (Compound No. 1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:1]([N:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
6 mL benzyl bromide was added to 5 g azepane-4-one hydrochloride and 18.5 g potassium carbonate in 50 mL THF and 25 mL water. The mixture was stirred 5 h at 50° C., evaporated, diluted with water and extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (petrolether/ethyl acetate:8/2) to give 5 g of the desired product. Rf: 0.40 (hexane/ethyl acetate=1/1), (M+H)+=204