Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:4]([O:10][CH3:11])=[N:5][CH:6]=[C:7]([CH:2]=1)[C:8]#[N:9]
Reactant: COc1ncc(C#N)c(C)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(C#N)cc1CBr
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-cyano-2-methoxy-3-methyl-pyridine (36) (0.25 g, 1.7 mmol) in CCl4 (10 mL) was added N-bromosuccinimide (346 mg, 1.7 mmol) and 2′,2-azobisisobutyronitrile (13.0 mg, 0.085 mmol). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated to afford 5-(bromomethyl)-6-methoxy nicotinonitrile (37) as a yellow solid; (180 mg, 46.9%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:11][C:12]([N:14]1[CH2:17][C:16]([N:19]([C:21]2[CH:22]=[C:23]3[C:32](=[CH:33][C:34]=2Br)[O:31][CH2:30][C:29]2[N:24]3[C@H:25]([CH3:37])[C:26](=[O:36])[NH:27][N:28]=2)[CH3:20])([CH3:18])[CH2:15]1)=[O:13])(C)(C)C.C(OC(N1CC(NC2C=C3C(=CC=2Br)OCC2N3[C@H](C)C(=O)NN=2)(C)C1)=O)(C)(C)C.[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1B(O)O>O1CCOCC1.O.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>[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[C:34]1[CH:33]=[C:32]2[C:23]([N:24]3[C:29]([CH2:30][O:31]2)=[N:28][NH:27][C:26](=[O:36])[C@H:25]3[CH3:37])=[CH:22][C:21]=1[N:19]([CH3:20])[C:16]1([CH3:18])[CH2:17][N:14]([C:12]([OH:11])=[O:13])[CH2:15]1
Reactant: OB(O)c1ccccc1F
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N(C)C4(C)CN(C(=O)O)C4)cc3N21
Temperature: 90 °C

Procedure:
A degassed solution of potassium carbonate (0.432 g, 3.13 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.255 g, 0.313 mmol), 3-[((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (prepared from 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step G) using the similar procedure detailed in Example #102, Step A), 0.618 g, 1.25 mmol) and (2-fluorophenyl)boronic acid (0.262 g, 1.875 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were heated at 90° C. for 4 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to afford 3-{[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-methyl-amino}-3-methyl-azetidine-1-carboxylic acid ten-butyl ester (0.540 g, 85%). 1H NMR (CDCl3, 400 MHz): δ 8.14 (s, 1H), 7.35-7.26 (m, 2H), 7.19-7.10 (m, 2H), 6.94 (s, 1H), 6.54 (s, 1H), 4.71-4.56 (m, 3H), 3.86-3.78 (m, 2H), 3.48 (m, 2H), 2.41 (s, 3H). 1.54 (d, J=6.8 Hz, 3H), 1.42 (s, 9H), 1.26 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.913 min., MS m/z: 510 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccc(Br)cc2)CCCC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (20 g, 60.01 mmol) in dimethyl sulfoxide (100 mL) were added KI (0.99 g, 6.00 mmol) and NaCN (4.41 g, 90.02 mmol). The reaction mixture was then stirred at 140° C. for 5 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×250 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4, and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (13.9 g, 87%) as a colorless thick liquid.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:15]C(=O)OC(C)(C)C)[CH:9]([OH:14])[C:10]([NH:12][NH2:13])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>C(O)C>[NH2:15][C@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:9]([OH:14])[C:10]([NH:12]/[N:13]=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NN
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: N[C@H](CC1CCCCC1)C(O)C(=O)N/N=C/c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A solution of Example 14A (0.064 g, 0.20 mmol) in ethanol (3 mL) was treated with pyridine (2 mL) and 4-chlorobenzaldehyde (0.033 mL, 0.23 mmol), heated to 85° C., stirred for 16 hours, and concentrated. The concentrate was purified by flash column chormatography on silica gel with ethyl acetate in hexanes, and the purified concntrate was treated with 4N HCl in dioxane, stirred for 4 hours, concentrated, precipitated from diethyl ether, and collected by filtration to provide the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:27]>C1COCC1.CO.[Pd]>[ClH:27].[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccc(CN)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 6.5 h

Procedure:
A mixture of 10% Pd-C 50% wet (100 mg) and ethyl 5-(4-cyanophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1 g) in THF (10 ml), MeOH (5 ml), and 1M HCl (2.9 ml) was hydrogenated under H2 latmat ambient temperature for 6.5 hours. The catalyst was filtered off through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was dissolved in EtOH and concentrated in vacuo. The residue was crystallized from AcOEt to give ethyl 5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate hydrochloride (984 mg) as a powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)c(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(Br)cc1F
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of DMF. To the stirred solvent were added 4-Bromo-2,5-difluorophenol (2.0 g, 9.6 mmol), K2CO3 (3.98 g, 28.8 mmol) and methyl iodide (1.63 g, 11.53 mmol), stirred at 45° C. for 15 minutes under nitrogen atmosphere. The RM was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (1.2 g, yield: 56.07%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1ccc(C=CCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C=CCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Compound 102-3 (550 mg) was dissolved in ethanol (18 ml), concentrated hydrochloric acid (3.5 ml) was added, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether and methanol to give the object product (180 mg) as a white powder.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOCC>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14])[CH2:11]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 980 mg (4.87 mmol) of boc-azetidine-3-carboxylic acid, 951 mg (9.75 mmol) of N,O-dimethylhydroxylamine hydrochloride, 329 mg (2.435 mmol) of HOBT and 1.87 g (9.75 mmol) of 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 30 mL of CH2Cl2 was added 2.54 mL 44.61 mmol) of N,N-diisopropylethylamine at 0° C. and it was stirred for 6 h at rt. Then the reaction mixture was poured into 100 mL of ether and washed with 20 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford the title compound. 1NMR(CDCl3) δ 1.46 (s, 9H), 3.23 (s, 3H), 3.62 (m, 1H), 3.68 (s, 3H), 4.07 (m, 2H), 4.09 (m, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[N:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:8])[CH3:7]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1.C(OCC)C>[CH3:4][C:5]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[N:33][C:32]([C:35]([OH:37])([CH3:1])[CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(OCc4ncccn4)cn3)C(C)C)cc2)nn1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(-c2ccc(C(C)(C)O)nn2)cc1)c1ccc(OCc2ncccn2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (30.9 mL of a 1.4 M solution in THF:toluene (25:75)) was added to a stirred solution of 7c (14.0 g, 30.9 mmol) in a mixture of THF (130 mL) and diethyl ether (260 mL) at 0° C. After approximately 1 h at 0° C., the reaction was quenched by the addition of saturated aqueous ammonium chloride, and the resulting mixture stirred for 15 min. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% acetone/DCM as eluent) to furnish the title compound 7d. m/z (ES) 470 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.01 (d, 1H, J=9.1 Hz), 8.88 (d, 2H, J=5.0 Hz), 8.73 (d, 1H, J=9.2 Hz), 8.52 (d, 1H, J=2.7 Hz), 8.34 (dd, 1H, J=3.0, 9.4 Hz), 8.25 (d, 2H, J=8.5 Hz), 8.17 (d, 1H, J=9.1 Hz), 7.65 (d, 2H, J=8.5 Hz), 7.53 (t, 1H, J=5.0 Hz), 5.62 (s, 2H), 3.05 (m, 1H, J=6.7 Hz), 1.91 (s, 3H), 1.75 (s, 6H), 1.00 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.4 Hz).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([Cl:26])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The title compound, white solid, MS: m/e=395.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dichloro-4-trifluoromethyl-benzoic acid (intermediate Y).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].NC(N)=O.[C:9]([C:12]([CH2:19]O)([C:16]([OH:18])=[O:17])[C:13]([OH:15])=[O:14])([OH:11])=[O:10].OS(O)(=O)=O>O>[C:16]([C:12]([CH2:19][O:2][N+:1]([O-:4])=[O:3])([C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])([OH:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C(CO)(C(=O)O)C(=O)O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(CO[N+](=O)[O-])(C(=O)O)C(=O)O
Yield: 30 %

Procedure:
To a mixture cooled to 0° C. of 2.5 g of 95 (%) strength HNO3, a spatula-full of urea and 10 ml of water is added with stirring and ice-cooling, 1.0 g (0.004 mol) of carboxy-2-hydroxymethylmalonic acid. After 10 min 2.5 g of 94% strength H2SO4 are added dropwise with stirring and stirring is continued for another hour at 0° C. The organic layer is isolated and evaporated down. 2-carboxy-2-nitryloxymethylmalonic acid is obtained as the residue as a viscous oil which is purified column chromatographically.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>N1C=CC=CC=1>[O:1]1[CH2:4][CH:3]([O:5][S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of oxetan-3-ol (1.0 g, 13.0 mmol) in anhydrous pyridine (25 mL) at room temperature was added 4-toluene sulfonyl chloride (3.09 g, 16.2 mmol). After stirring the reaction mixture for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 1.9 g (62% yield) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][C@@H:10]([NH:25][C:26](=[O:40])[NH:27][C:28]2[CH:29]=[C:30]([C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:43]>CO>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:11][C@@H:10]([NH:25][C:26](=[O:40])[NH:27][C:28]2[CH:29]=[C:30]([C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:2])[CH3:3].[Na+:43]
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(C)(C)C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(C)(C)C(=O)[O-])c2)CN(C2CCCCC2)c2ccccc21

Procedure:
To a solution of (R)-(−)-2-[3-[3-(1 -tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenyl]-2-methylpropionic acid (960 mg) in methanol (10 mL), 1 N sodium hydroxide (1.79 mL) was added. The solution was concentrated under reduced pressure. The residue was purified through HP-20 (“Diaion”, product of Mitsubishi Chemical Corporation) by means of water and methanol. The thus-purified residue was lyophilized, whereby the title compound (900 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH2:16]Cl)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(COC)OC>[CH2:12]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH2:16][NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: Cc1nc2cccc(N)c2[nH]1
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1cccc(C)c1CNc1cccc2nc(C)[nH]c12
Yield: 27.8 %

Procedure:
4-amino-2-methylbenzimidazole (0.4 g, 2.7 mmol) and 2-ethyl-6-methylbenzylchloride (0.46 g, 2.7 mmol) were dissolved in 10 ml dimethoxyethane. Sodium carbonate (0.5 g, 4.7 mmol) and (0.2 g, 4.7 mmol) of potassium iodide were added to the solution. The reaction mixture was refluxed to for 2 h. Inorganic salts were removed by filtration and washed with dimethoxyethane. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel. The product was eluted with a 50:50 mixture of methylene chloride and ethyl acetate. There was obtained 0.21 g of the title compound. (1H-NMR, 400 MHz, CDCl3): 1.1 (t, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 2.70 (q, 2H), 4.35 (s, 2H), 4.45 (bs, 1H), 6.55 (d, 1H), 6.75 (d, 1H), 6.95-7.20 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([Cl:11])=[N:8]2)=[C:4]([Cl:12])[N:3]=1.[CH3:13][C:14]1([CH3:24])[O:21][C:20](=[O:22])[C:17]2([CH2:19][CH2:18]2)[C:16](=[O:23])[O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:11])[N:8]2[CH2:19][CH2:18][CH:17]2[C:16](=[O:23])[O:15][C:14]([CH3:24])([CH3:13])[O:21][C:20]2=[O:22])=[C:4]([Cl:12])[N:3]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CCn2c(Cl)nc3c(Cl)nc(N)nc32)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
A mixture of 2-amino-6,8-dichloropurine (2.04 g), 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (1.73 g) and anhydrous potassium carbonate (2.12 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 18 hours under dry nitrogen. The solvent was evaporated and the residue dissolved in water (60 ml) and acidified from pH 10 to pH 4 with dilute hydrochloric acid. The yellow precipitate was filtered off, washed with water and dried to give 2-amino-6,8-dichloro-9-[1-(2,2-dimethyl-1,3-dioxane4,6-dione-5-yl)eth-2-yl]purine (2.2 g, 50%). T.1.c. r.f. 0.65 (25% methanol-dichloromethane).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1.O.[OH-].[Na+]>C(O)(=O)C.[Zn]>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][CH:2]=[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1cccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)c1
Temperature: 120 °C
Yield: 53.1 %

Procedure:
To the solution of 3-[5-bromo-4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.50 g, 1.10 mmol) in the 10 ml of acetic acid was added Zn dust (0.50 g, w/w). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (50 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×100 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.22 g, 53%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:16])[CH2:12][C:13](O)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:31][C:32]1[C:33]([NH:47][CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)=[CH:34][C:35]([NH:38][C:39]2[CH:44]=[N:43][C:42]([C:45]#[N:46])=[CH:41][N:40]=2)=[N:36][CH:37]=1>CN(C=O)C>[C:45]([C:42]1[N:43]=[CH:44][C:39]([NH:38][C:35]2[N:36]=[CH:37][C:32]([NH:31][C:13](=[O:14])[CH2:12][N:11]([CH3:16])[CH3:10])=[C:33]([NH:47][CH2:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:34]=2)=[N:40][CH:41]=1)#[N:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CN(C)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diisopropylethylamine (16 μL, 0.092 mmol), N,N-dimethylglycine (7 mg, 0.067 mmol), HOBt (12 mg, 0.092 mmol) and EDC (17 mg, 0.092 mmol) were added to tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (26 mg, 0.061 mmol) in DMF (1.5 mL). The mixture was stirred at room temperature for 6 hours and then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried and concentrated. Preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(1-boc-piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide as a white solid. The solid was dissolved in 20% trifluoroacetic acid in dichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOH SPE cartridge and eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated to give N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide (7.52 mg, 30%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.[H-].[Na+].Cl.CCO>C1COCC1>[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH:32][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:26][CH:25]=1
Reactant: ICCCCCCc1ccccc1
Reactant: NCCOCc1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: c1ccc(CCCCCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-phenyl-1-hexyl iodide (0.63 g; 2.2 mmol) in THF (12 ml) is added 2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine hydrochloride (0.6 g ; 2 mmol) followed by NaH (60% suspension; 0.11 g). The reaction mixture is stirred for 1 hour at room temperature and then heated for 1 1/2 hours at reflux. The mixture is next cooled, acidified with HCl/EtOH, concentrated and purified by column chromatography using 10% MeOH/CH2Cl2 as eluant. The resultant product is treated with HCl/EtOH and recrystallized from EtOH to give pure N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-6-phenyl-1-hexanamine hydrochloride. (m.p. 163°-165° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[CH:24][N:23]=1>>[CH:28]1([C:27]2[C:22]([O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Clc1nccnc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCCC3)cc2)nc1
Temperature: 120 °C

Procedure:
A mixture of 4-(pyridin-2-ylamino)phenol (0.30 g, 1.60 mmol), cesium carbonate (1.56 g, 4.80 mmol), and 2-chloro-3-cyclopentylpyrazine (0.29 g, 1.60 mmol) under argon was heated to 120° C. for 20 h. The mixture was cooled to RT and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with aqueous 1N sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give N-(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 333.3 (M+1). IC50 (uM) 0.012.