Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])=[CH:19][CH:18]=1
Reactant: COC(=O)CCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(CCCCCCCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 2.8 g (6.5 mmol) of 9-[4-chloro-N-(4-methoxyphenyl)-benzamido]-pelargonic acid methyl ester, 0.3 g (7.8 mmol) of sodium hydroxide and 50 cc. of methanol. Reaction time: 42 hours, reaction temperature: 25° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>C1(C)C=CC=CC=1>[CH2:31]([N:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30])[CH2:34][CH3:35])[CH3:32]
Reactant: CCNCC
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Yield: 30.9 %

Procedure:
Compound 5 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and diethyl amine (48 mg, 0.63 mmol) in toluene 10 mL was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 32 mg of 4-(3-(4-((diethylamino)methyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile as brown viscus oil, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.43 min, M+1, 493.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1OC
Product: COc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 1) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.1 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH2:10])[CH2:6][CH:7]([CH3:9])[CH3:8].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:10]1[CH2:25][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][C:17]=2[C:21]([F:24])([F:22])[F:23])[C:14]1=[O:13])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)c1cccc(C(F)(F)F)c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 115 °C
Yield: 55.7 %

Procedure:
A mixture of (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride (Aldrich, 273 mg, 1.5 mmol) and 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (prepared as in Example 1, 445 mg, 1.5 mmol) in acetonitrile (5 mL) and triethylamine (420 μL, 3.0 mmol) was placed in a microwave reaction vessel and sealed. The reaction mixture was then placed in a microwave reactor and heated at 115° C. for 15 min. After this time, the reaction mixture was cooled and concentrated with silica gel (2 g) in vacuo. The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 20% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid methyl ester (275 mg, 56%) as a colorless viscous oil.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[C:14]1([C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17])[OH:15]>C1(C)C=CC=CC=1>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:15][C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[OH:17])=[O:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: Oc1ccccc1O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(C(=O)Oc2ccccc2O)C1

Procedure:
p-Menth-3-oyl chloride (2.0 g.) and pyrocatechol (1.1 g.) were heated under refluxing conditions in toluene (75 ml.) for 4 hours. An oily liquid was recovered which was identified as ortho-hydroxyphenyl p-menthane-3-carboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH2:9][CH2:8]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C=O)C>[CH:7]1([C:10]2[CH:14]=[CH:13][N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:11]=2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)CBr
Reactant: c1cc(C2CC2)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(C2CC2)n1
Reaction time: 0.33 h
Yield: 42 %

Procedure:
Potassium carbonate (7.67 g, 55.56 mmol) was added to 3-cyclopropyl-1H-pyrazole (2.0 g, 18.52 mmol) in dry DMF (20 mL) at 25° C. and the mixture was stirred for 20 minutes. Ethyl bromoacetate (2.06 mL, 18.52 mmol) was added then the mixture was stirred for 2 days at room temperature. The reaction mixture was neutralized with aqueous HCl (1.0 M), extracted with ether (40 mL) and the organic extract was washed with brine (30 mL), dried over sodium sulfate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 42% yield, 1.50 g.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[OH:24]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: COc1ccc(O)c(Cl)c1
Product: COc1ccc(Oc2cn[nH]c(=O)c2)c(Cl)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-4-methoxy-phenol afforded 5-(2-chloro-4-methoxy-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) which afforded the lithium salt of 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid as a white solid (0.19 g); ES+-HRMS m/e calcd for C20H23N2O5Cl [M+H+] 407.1368, found 407.1369. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-1.19 (m, 6H), 1.44-1.65 (m, 4H), 1.65-1.77 (m, 1H), 1.93 (t, J=6.9 Hz, 2H), 3.81 (s, 3H), 5.09 (t, J=7.7 Hz, 1H), 5.52 (d, J=3.0 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.97 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([NH2:25])=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: NC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 90.6 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (1.73 g, 4.37 mmol) in N,N-dimethylformamide (20 mL) was added thionyl chloride (1.05 mL, 14.4 mmol). The resultant mixture was stirred at 50° C. for 1.5 hr and poured into saturated aqueous sodium hydrogen carbonate at 0° C. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound as a pale white solid (1.496 g, 3.96 mmol, 91%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:4]1.S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[NH2:2][CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([O:24][CH2:32][CH3:33])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:4]1
Reactant: CCO
Reactant: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1N
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CC(C)C(N)C3)c(F)cc2c1=O

Procedure:
7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (6.6 g) was suspended in absolute ethanol. Sulfuric acid (7 g) was added to the suspension and the mixture was refluxed for 1 hour with stirring. After evaporation of ethanol (ca. 20 ml), absolute ethanol (20 ml) was added and the mixture was again refluxed. This operation was repeated three times and then the mixture was refluxed for 15 hours with stirring. After evaporation of ethanol, chloroform and 20% aqueous sodium hydroxide solution was added to the residue, and the mixture was adjusted to pH>9. The organic layer was separated, chloroform was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give ethyl 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylate (4.3 g), m.p. 148°-150.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[O:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Cc1oc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (130 mg, 0.63 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (243 mg, 0.63 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.55 ml, 3.15 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (324 mg, 0.69 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (190 mg, 0.23 mmol, 37% yield) as a clear oil: LCMS (ES) m/e 537 (M+H)+.
Reaction SMILES: [N:1]1([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:30])C(=O)C1.O>CN(C=O)C>[Br:30][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
A solution of tert-butyl 3-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (1.86 g, 6.15 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (1.09 g, 6.15 mmol) in 15 mL DMF. The reaction was stirred at 0° C. for 1.5 hours then treated with 100 mL H2O. The suspension was extracted with 2×150 mL EtOAc. The combined organic layer was rinsed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated to give a viscous oil. This residue was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.50 g, 63.8%). 1H-NMR (CDCl3) δ 7.13 (d, J=9.0 Hz, 1H), 7.07 (brs, 1H), 6.55 (d, J=9.0 Hz, 1H), 4.35-4.33 (m, 1H), 3.58-3.18 (m, 6H), 2.71 (t, J=6.3 Hz, 2H), 2.11-2.04 (m, 2H), 1.91-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 325.1 and 327.1 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=1[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:22](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[NH2:22][C:12]([C:11]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
2-{[(Tert-butoxycarbonyl)amino]methyl}-5-fluorobenzoic acid (800 mg, 2.97 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (854 mg, 4.46 mmol), and 1-hydroxy-7-azabenzotriazole (607 mg, 4.46 mmol) were added to dry DMF (10 mL) and stirred for 30 minutes to preform the activated ester. Ammonia gas was bubbled through the solution for 30 seconds and the reaction was allowed to stir for 5 minutes. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ISCO column, 120 g silica) running a gradient of 0-40% acetone/hexane over 35 min. The product fractions were concentrated to afford the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Product: O=C(Nc1ccc(CN2CC(C(=O)O)C2)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and azetidine-3-carboxylic acid (Apollo), the title compound was obtained as a yellow solid after precipitation from DCM/MeOH.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][NH:17][CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC(Cl)(Cl)Cl)n1c2c(c3ccccc31)CCNC2
Yield: 82.1 %

Procedure:
3,4-Dihydro-1H-β-carboline-2,9-dicarboxylic acid 2-tert-butyl ester 9-(2,2,2-trichloro-ethyl) ester (3.53 g) and trifluoroacetic acid (5 ml) in dichloromethane (30 ml) were stirred at room temperature for 1.5 h. The mixture was partitioned between 6N NaOH solution (70 ml) and dichloromethane (50 ml). The dichloromethane was washed with water (50 ml) and dried (MgSO4) then the solvent removed under reduced pressure to give the title compound (2.25 g, 81%) as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:27]([NH2:29])[CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[C:27]([NH:29][C:1](=[O:3])[CH3:2])[CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16 μL (170 μmol) acetic anhydride are added to a solution of 35 mg (84 μmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in 2 mL DCM and the reaction mixture is stirred overnight at RT and then purified by chromatography on silica gel (gradient: EtOAc to EtOAc/MeOH/NH3 7:3:0.3) without any further working up
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:15])=[O:8])[C:5]([Cl:11])=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)cnc1Cl
Yield: 99.4 %

Procedure:
To a slurry of 5-bromo-2-chloronicotinic acid (2.063 g, 8.725 mmol) in methylene chloride (20 mL) was slowly added oxalyl chloride (1.11 g, 8.725 mmol) followed by the addition of dimethylformamide (5 drops). After 4 H the mixture was concentrated in vacuo to provide 2.21 g of 5-bromo-2-chloropyridine-3-carbonyl chloride as a light brown solid, which was used as is in the next reaction.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Br:22][Si](C)(C)C>ClCCl>[Br:22][CH2:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[CH:11][CH:10]=1)=[O:14]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-c2cnco2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,3-Oxazol-5-yl)phenyl]-1-ethanone (2.81 g) and triethylamine (6.27 mL) were dissolved in dichloromethane mL), and bromotrimethylsilane (3.96 mL) was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature overnight under argon. The reaction mixture was washed sequentially with water and saturated saline, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the formed brown oily matter was dissolved in tetrahydrofuran mL). Subsequently, N-bromosuccinimide (2.67 g) was added to the solution, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified through flash column chromatography (dichloromethane), followed by concentration under reduced pressure. The obtained solid was recovered through filtration by use of n-hexane, to thereby yield the title compound (3.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-chloroaniline (10.0 g) and triethylamine (16.4 ml) in acetonitrile (80 ml) was added dropwise pivaloyl chloride (14.5 ml) under ice-cooling. The mixture was allowed to warm to room temperature and stirred for 5 hrs. The obtained reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (1500 ml) and water (1500 ml). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and hexane to give N-(4-chlorophenyl)-2,2-dimethylpropionamide (15.0 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: NC1CCCC1
Product: c1ccc2c(c1)nc(NC1CCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with cyclopentylamine according to a procedure that is similar to that followed in example 3 there is obtained 4-cyclopentylaminoimidazo[1,2-a] quinoxaline. m.p. (DSC)=114.3° C. (onset); IR (KBr): 3419, 2962, 1543 cm-1 ; 1H-NMR (CDCl3):δ7.9 (1H,s), 7.8÷7.0 (5H,m), 6.2 (1H,d), 4.7 (1H, m), 2.3÷2.05 (4H,m), 2.0÷1.3 (4H,m); UV (EtOH): δmax =228, 244, 285, 297, 319, 333 nm.
Reaction SMILES: [K].Br[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1.[CH3:10][CH:11]([OH:13])[CH3:12]>[Cu]>[Br:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:13][CH:11]([CH3:12])[CH3:10])[CH:8]=1
Reactant: CC(C)O
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [K]
Product: CC(C)Oc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Under a nitrogen atmosphere, 2-propanol (30 mL) was added to potassium (2.4 g, 61.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. To the resulting solution was added 3,5-dibromopyridine (4.74 g, 20.0 mmol) and copper powder (250 mg, 3.9 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 70 h. Upon cooling to ambient temperature, the mixture was concentrated under high vacuum to a solid, which was diluted with water (200 mL) and extracted with diethyl ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a dark-brown oil (3.71 g). Purification by column chromatography on silica gel, eluting with 10→20% (v/v) diethyl ether in benzene afforded 1.38 g (31.9%) of 3-bromo-5-isopropoxypyridine as a volatile, colorless oil.