Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH3:19])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 18 h
Yield: 68 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (1.00 g, 4.13 mmol), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (Japan Tobacco Inc WO 9518125) (0.84 g, 4.13 mmol), and triphenylphosphine (1.41 g, 5.37 mmol) in THF (17 mL) was treated dropwise at ambient temperature with diisopropyl azodicarboxylate (0.96 mL, 5.0 mmol). After 18 h, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine (40 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using 10-15% ethyl acetate in hexanes to give the product (1.2 g, 68%). 1H. NMR (400 MHz, CDCl3) δ 7.98 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.30 (m, 8H), 6.78-6.69 (m, 3H), 4.99 (s, 2H), 4.19 (t, J=6.6 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.53 (q, J=7 Hz, 2H), 0.88 (t, J=7 Hz, 3H); MS (FIA) m/e 42.8 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Br)ccc1N
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 2-tert-butylaniline (50 g, 335 mmol) in THF (500 mL) was added tetrabutylammonium tribromide (234.5 g, 335 mmol) at 0° C. After the solution was stirred for 30 minutes at that temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated Na2S2O3 solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=100:0 to 20:80) to provide 4-bromo-2-tert-butylaniline (74.6 g, 98%) as a pink oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([NH:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21])=[O:16])[CH2:7][CH2:6]2.[OH-].[Na+]>CO.C1COCC1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH2:7][C:8]([C:15]([NH:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([OH:22])=[O:21])=[O:16])=[CH:9]2
Reactant: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)CCC(C(=O)Nc1ccccc1C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred solution of methyl 2-(6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxamido)benzoate (440 mg, 1.2 mmol) in MeOH (6 mL) and THF (3 mL) was added 2N NaOH (3 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours, then quenched with 1N HCl and diluted with water. The resulting suspension was filtered and the solid was dried under vacuum to give 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoic acid (350 mg, 83%). 1H-NMR (400 MHz, DMSO-d6) δ 2.59 (t, J=8.4 Hz, 2H), 2.83 (t, J=8.4 Hz, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 6.90 (s, 1H), 6.97 (s, 1H), 7.15 (app t, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.62 (m, 1H), 8.03 (dd, J=8.0, 1.6 Hz, 1H), 8.69 (d, J=8.4 Hz, 1H), 11.89 (s, 1H); LC-MS (ES-API); rt 9.22 min; m/z calculated for C20H19NO5 [M+Na]+ 376.1, found 376.1.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCCN1CCCC1=O
Product: COc1cc(NCCN2CCCC2=O)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 89 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-amino-ethyl) -pyrrolidin-2-one instead of thiomorpholine to the title compound (231 mg, 89%) which was obtained as an off-white solid. MS: m/e=478.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O>C1COCC1.S(=O)(=O)(O)O.[Cl-].[NH4+].C(OCC)(=O)C>[Br:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1c[nH]c2ncccc12
Yield: 74.6 %

Procedure:
To a solution of 7-azaindole (5 g, 42.2 mmol) in THF (400 mL) were added first the solid N-bromosuccinimide (8 g, 45.0 mmol) then 20 drops of conc. sulfuric acid at room temperature. While stirring some suspension was formed during 2 days. The mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (4×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude yellow solid. This solid was dissolved in ethyl acetate (˜100 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with ethyl acetate. After drying in air, 6.2 g (75% yield) of 3-bromo-1H-pyrrolo[2,3-b]pyridine was isolated as an yellow solid: EI-HRMS m/e calcd for C7H5BrN2 (M+) 195.9636. found 195.9636.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:37][NH2:38]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:38][CH3:37])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CN
Reactant: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 65 °C

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-1-piperidyl]propan-1-one and Na2CO3 (114 mg, 1.1 mmol) in tetrahydrofuran was treated with a solution of methylamine (1.3 mL of 2 M, 2.5 mmol) in THF and heated at 65° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via reverse phase HPLC (1-50% CH3CN/5 mM HCl) to provide 1-(4-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)piperidin-1-yl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[F:19][C:20]([F:31])([F:30])[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:26][CH2:25][N:24]([S:21]([C:20]([F:30])([F:31])[F:19])(=[O:22])=[O:23])[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(N1CCNCC1)C(F)(F)F
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=S(=O)(N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1)C(F)(F)F

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-trifluoromethanesulfonyl-piperazine using procedure C yielded 2-chloro-4-morpholin-4-yl-6-(4-trifluoromethanesulfonyl-piperazin-1-ylmethyl)-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography
Reaction SMILES: [K].[OH-].[K+].O.[CH:5]#[CH:6].[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([O:13][CH:5]=[CH2:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C#C
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: OC1CCCCC1
Product: C=COC1CCCCC1
Temperature: 159 °C

Procedure:
A jet loop reactor having an internal volume of about 10.5 l and equipped with a jet nozzle fitted at the head of the reactor and an external circulation pump was charged with about 10.5 kg of a mixture of 5% by weight of potassium cyclohexoxide in cyclohexanol, which was prepared by reaction of cyclohexanol with potassium hydroxide and subsequent distillative removal of the water formed in the reaction. After heating to 159° C., the system was pressurized with ethyne to 2.0 MPa absolute. The reaction mixture was circulated through the jet nozzle by means of a circulation pump and the reacted ethyne was replaced while the total pressure was held constant. Any excess product was removed by a pressure control. The reactor was operated in the absence of a continuous gas phase. After the uptake of ethyne fell to zero, a sample was taken and analyzed by gas chromatography. 91.7% by weight of vinyl cyclohexyl ether and about 0.4% by weight of unconverted cyclohexanol were obtained. The residue was about 6% by weight, consisted predominantly of the potassium cyclohexoxide catalyst and was predominantly undissolved. The remainder is attributable to quantitatively insignificant materials, such as ethyne and ethyl vinyl ether. The conversion of cyclohexanol was 99.6%, based on the cyclohexanol used. The productivity rate was 0.10 kg of vinyl cyclohexyl ether per liter of reaction volume per hour.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20](=[O:45])[C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:31]3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17]1)(C)(C)C>>[NH2:14][CH2:15][CH:16]1[CH2:17][N:18]([C:20]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([N:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:31]3)(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[O:45])[CH2:19]1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Yield: 95.5 %

Procedure:
Add trifluoroacetic acid (5 mL) to [1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-carbamic acid tert-butyl ester (853 mg, 1.56 mmol) causing much gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 2× with MeOH). Dissolve the resultant yellow oil in MeOH (10 mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 5 g) to free-base the amine. Filter the mixture and rotary evaporate the filtrate (40° C.; azeotroped 3× with CH2Cl2) to yield 664 mg (95.3%) of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as an off-white foam. MS (m/e): 446.02 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.NN>C(O)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH2:11])=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(N3C(=O)c4ccccc4C3=O)nc21
Agent: NN
Solvent: CCO
Product: Cn1ccc2ccc(N)nc21
Reaction time: 16 h
Yield: 98.5 %

Procedure:
2-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (220 mg, 0.793 mmol) was dissolved in ethanol (4 mL), then hydrazine (0.5 mL, 15.9 mmol) was added. After 16 h, the mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate, then the combined organic extracts were washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by chromatography (silica, 10 to 50% ethyl acetate in hexanes) gave 1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamine (115 mg, 98%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.67 (d, J=8.3 Hz, 1H) 6.87 (d, J=3.4 Hz, 1H) 6.35 (d, J=8.3 Hz, 1H) 6.30 (d, J=3.4 Hz, 1H) 4.38 (br. s., 2H) 3.76 (s, 3H); LCMS (EI/CI) m/z: 148 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine (0.175M, 20 mL, 3.5 mmol) in anhydrous N,N-dimethylformamide was added to (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone, followed by diisopropylethylamine (1.3 mL, 7.0 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via preparative HPLC to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidine-3-yl)(pyrrolidin-1-yl)methanone (1.0 g, 89.6%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([OH:26])=[C:7]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:8]=1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(CCc2ccccc2N)cc(C(C)(C)C)c1O
Reaction time: 3 h
Yield: 199.1 %

Procedure:
To a suspension of 2,6-di-tert-butyl-4-(2-nitrostyryl)phenol (16.4 g, 23.3 mmol) in ethanol (150 ml) was added a catalytic amount of 10% palladium carbon and the suspension was subjected to catalytic reduction at room temperature at 1-2.5 atms for 8 hrs and at 40° C. for 3 hrs. After filtering the catalyst, distilling off the solvent gave 4-(2-aminophenethyl)-2,6-di-tert-butylphenol (15.1 g, 100%) as a viscous oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:25])[N:18]3[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:23][C:21]1[N:20]=[C:19]2[C:15]([NH:16][C:17](=[O:25])[N:18]2[CH3:24])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:22]=1
Reactant: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c2c(N3CCNCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-Chloro-9-methyl-8-oxo-8,9-dihydro-7H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (compound 18d) (8 mg) was dissolved in trifluoroacetic acid. This reaction solution was stirred at room temperature for five minutes, and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (5.08 mg).
Reaction SMILES: Br[C:2]1(Br)[C:6]2[N:7]=[C:8]([Cl:17])[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[N:4]([CH3:18])[C:3]1=[O:19].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl.[Zn]>[Cl:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:4]([CH3:18])[C:3](=[O:19])[CH2:2][C:6]=2[N:7]=1
Reactant: CN1C(=O)C(Br)(Br)c2nc(Cl)nc(N3CCOCC3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C(=O)Cc2nc(Cl)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To 7,7-dibromo-2-chloro-5-methyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one (1.70 g, 3.99 mmol) in 2M aqueous ammonium chloride solution (9.96 mL, 19.9 mmol) and THF (40 mL) at 0° C. was added zinc dust (573.4 mg, 8.775 mmol). The reaction mixture was stirred at RT for 30 min and then diluted with DCM (40 mL). The reaction mixture was filtered through a pad of Celite. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 679 mg (63.4%) of 2-chloro-5-methyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one a solid. MS(ESI) m/z: 269.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-:3])=[O:2].C1C(=O)N([Br:18])C(=O)C1.O>CC(O)=O>[Br:18][C:8]1[CH:7]=[CH:6][C:5]([NH2:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Yield: 93.4 %

Procedure:
To a solution of 2-nitro-phenylamine (13.8 g, 100 mmol) in HOAc (150 mL) was added NBS (18 g, 101 mmol). The reaction mixture was stirred and heated to reflux over 1 hour. The cooled reaction mixture was poured into H2O (1000 mL) and stirred for 15 minutes. The resulting orange slurry was filtered and washed with H2O (300 mL) affording a 20.26 g (93%) of the title compound as a bright orange solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](I)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH2:33][O:32][C:31](=[O:34])[CH:30]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([C:29]3[CH2:33][O:32][C:31](=[O:34])[CH:30]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(I)c2cccnc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C=C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CO1

Procedure:
The iodide from step 2 (4.37 g, 10.32 mmol) was dissolved in anhydrous toluene (40 ml) in an oven dried flask that was purged with nitrogen. Dichlorobis(triphenylphospine)palladium (II) (660 mgs., 0.94 mmol) and 4-(tributylstannyl)furan-2(5H)-one, (3.85 g, 10.32 mmol) (prepared as described by Gregory J. Hollingworth, Gemma Perkins, and Joseph Sweeney, J. Chem. Soc., Perkins 1. 1996, 1913) were then added to the reaction. After four hours at reflux the reaction was cooled and the solids that precipitated from the solution were collected by vacuum filtration. The product contained 17% of an impurity: N,N′-bis(4-fluorobenzyl)-8,8′-dihydroxy-5,5′-bi-1,6-naphthyridine-7,7′-dicarboxamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH3:2].ClC1C=C(C=CC=1)C(O)=O.C(NCC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>>[Cl:11][C:7]1[C:6]([Si:31]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(Cl)c1[Si](C)(C)C
Yield: 94.4 %

Procedure:
N,N-diethyl-3-chlorobenzamide (10.45 g, 50 mmol) (prepared from 3-chlorobenzoic acid and diethylamine using the procedures described above) was reacted with TMSCl (16.30 g, 150 mmol) using General Method A to afford 13.4 g of the title compound as an orange oil in 95% yield.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[C:1]([Cl:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(=O)Cl
Reaction time: 16 h
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.027 mole) of undecanoic acid in 75 mL of methylene chloride was stirred and 2.8 ml (0.032 mole) of oxalyl chloride and 5 drops of N,N-dimethylformamide were added. Upon completion of addition, the reaction mixture was stirred for about 16 hours, then it was concentrated under reduced pressure, yielding 2.2 grams of undecanoyl chloride.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][N:21]1[C:26]2[CH:27]=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]5[N:21]([CH3:20])[CH2:22][CH2:23][O:24][C:25]=5[CH:30]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1CCOc2cc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)ccc21

Procedure:
(1-Methyl-cyclohexyl)-[2-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazine following general procedures as described in these Examples. MP 243-244° C., M+H=391.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3[CH2:56]C[C@@H:54]([N:57]([CH3:59])[CH3:58])[CH2:53]3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C[N:61](C)[C@@H:62]1CCN[CH2:63]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3[CH2:53][CH2:54][N:57]([CH2:58][CH2:63][C:62]#[N:61])[CH2:59][CH2:56]3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CC[C@@H](N(C)C)C5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CCN(CCC#N)CC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to (R)-3-dimethylamino-pyrrolidine-1-carboxylic acid {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-amide trifluoroacetate (Example 134) by replacing dimethyl-(R)-pyrrolidin-3-yl-amine with the appropriate amine. (MH+ 697.4)