Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.Cl[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>C1COCC1>[F:22][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([S:17][C:24]([O:26][CH3:27])=[O:25])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Sc1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 3.05 g (0.0089 mol) of product of example 1 and 0.094 g (0.01 mol) of methyl chloroformate in 25 mL dry THF was added 1.16 g (0.012 mol) of triethylamine dropwise at room temperature. After stirring for 30 min, the solvent was evaporated under reduced pressure. The residue was diluted with 100 mL of water and extracted with ether (3×50 mL). The combined organic layers were washed with water, dried (MgSO4) and evaporated. Purification of the residue by preparative HPLC (5% ethyl acetate-hexane) gave 2.75 g (77%) of product as a yellow oil: nD25 1.5830.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:25]2[CH:24]=[N:23][C:22]([O:21][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CCCCCCCCCCCCOc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 34.4 %

Procedure:
A reaction of 35 mmol of 2,5-dibromopyrimidine, 27 mmol of 2-dodecyloxypyridine-5-boronic acid, 64 mmol of sodium carbonate and 0.3 mmol of tetrakis(triphenylphosphine)palladium(0) in 210 ml of toluene, 135 ml of ethanol and 70 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 3.9 g (35%) of a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[O:11].[SH:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[N:21]1[CH:20]=[CH:19][N:18]2[C:13]([S:12][CH2:2][CH2:3][CH2:4][N:5]3[C:9](=[O:10])[CH2:8][S:7][C:6]3=[O:11])=[CH:14][CH:15]=[CH:16][C:17]=12
Reactant: Sc1cccc2nccn12
Reactant: O=C1CSC(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a nitrogen atmosphere, 3.87 g (20 mmol) of 3-(3-bromopropyl)thiazolidine-2,4-dione was added to a suspension of 3.0 g (20 mmol) of 5-mercaptoimidazo[1,2-a]pyridine, 2.76 g (20 mmol) of potassium carbonate and 3.00 g (20 mmol) of sodium iodide in 100 ml of N,N-dimethylformamide was added, followed by stirring at room temperature for 64 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 2.44 g (39.7%, light red-purple solid) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:26])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:26]=[C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]1[CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:27])[C:4]([OH:28])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
A solution of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.5 g) in hot methanol (50 mL) was treated with sodium carbonate (0.14 g) in water (1.5 mL), and the reaction was stirred at room temperature for 5 hours. After the methanol was removed in vacuo, dichloromethane and water were added and the rnixmre was acidified with 3N hydrochloric acid. The precipitated solid was faltered off, dried and then crystallized from ethyl acetate-tetrahydrofuran to afford 0.337 g of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid, mp 183°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=O)=[CH:7][CH:6]=1)=[O:4].C[Si]([C:20]#[N:21])(C)C.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[C:20]([C:12]1[C:13]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Agent: [I-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Yield: 47.1 %

Procedure:
A solution of 1-tetralon-7-carboxylic acid methyl ester (3.50 g, 0.017 mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene (20 mL) was stirred at ambient temperature over 15 hours. Then added, sequentially and dropwise, was pyridine (20 mL) and phosphorous oxychloride (4.0 mL, 6.55 g, 0.0425 mol). The reaction mixture was stirred at reflux over 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in chloroform, backwashed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give methyl 8-cyano-5,6-dihydro-2-naphthoate (1.70 g, 0.008 mol, 47%) as a yellow solid. mp=73°-75° C.; 1H NMR (CDCl3) d 8.0-7.9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t, 1H, J=4.8 Hz), 3.95 (s, 3H), 2.9 (t, 2H, J=8.3 Hz), 2.6-2.4 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:28][C:29]([OH:31])=O)[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:32]>C(Cl)Cl>[NH2:32][C:29](=[O:31])[CH2:28][N:8]([C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Reactant: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC(N)=O)[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
N,N′-Carbonyldiimidazole (27 mg, 0.17 mmol) was added to a solution of [(tert-butoxycarbonyl){(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl}amino]acetic acid (50 mg, 0.12 mmol) in dry CH2Cl2 (3 mL) at 0° C. (ice-water bath). The solution was stirred for 40 min at room temperature and cooled again at 0° C.; NH3 (25% aqueous solution, 0.05 mL, 0.60 mmol) was added and the reaction was allowed to reach room temperature and stirred for additional 1.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with brine (10 mL) and HCl (10% aqueous solution, 1 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (5% MeOH/CH2Cl2) affording 38 mg of tert-butyl 2-amino-2-oxoethyl[(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl]carbamate [Rf=0.6 (10% MeOH/CH2Cl2), colorless oil, 76% yield].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([N:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br-].[O:39]=[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42](=[O:49])[N:41]1[CH2:50][CH2:51][CH2:52][CH2:53][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:12]([N:31]1[CH:35]=[C:34]([CH:36]=[CH:53][CH2:52][CH2:51][CH2:50][N:41]2[C:42](=[O:49])[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:40]2=[O:39])[N:33]=[CH:32]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 50.6 %

Procedure:
0.663 ml (4.43 mmol) of DBU and 1.0 g (2.96 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde are added to 2.41 g (4.43 mmol) of [4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]triphenylphosphonium bromide. The reaction medium is refluxed for 18 hours. The reaction is stopped by adding aqueous 5% citric acid solution and the organic compounds are extracted with CH2Cl2. The organic phase is dried over MgSO4, filtered and concentrated. The residue obtained is chromatographed on silica gel (eluent: heptane/EtOAc (6/4)). 785 mg of 2-[5-(1-trityl-1H-imidazol-4-yl)pent-4-enyl]isoindole-1,3-dione are obtained in a yield of 51%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[CH:35]=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cc(F)cc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,5-trifluorophenyl)boronic acid gave 236. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.63 (s, 1H), 8.14-8.04 (m, 1H), 7.83-7.71 (m, 2H), 4.85 (dd, J=10.7, 3.5 Hz, 1H), 4.71-4.46 (m, 1H), 4.36-4.22 (m, 1H), 4.20-3.94 (m, 1H), 3.81 (s, 3H), 3.45-3.31 (m, 1H), 2.16-2.07 (m, 1H), 1.98-1.76 (m, 3H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: Br[CH:2]=[C:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.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>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1/[CH:2]=[C:3]1/[CH:4]=[CH:5][C:6](=[O:8])[O:7]/1
Reactant: OB(O)c1cccs1
Reactant: O=C1C=CC(=CBr)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C/C(=C/c2cccs2)O1

Procedure:
A mixture containing 5-bromomethylene-2(5H)furanone (0.175 g, 1 mmol), 2-thiopheneboronic acid (0.154 g, 1.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.035 g, 0.05 mmol), tetrabutylammonium iodide (0.018 g, 0.05 mmol) and cesium fluoride (0.456 g, 3 mmol) in toluene (10 mL) and water (10 mL) were stirred at reflux for 24 hours under nitrogen. After cooling, brine (50 mL) was added and the product extracted with ethyl acetate (50 mL×3). The organic fractions were combined, washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) giving the desired product 32 as a yellow powder. Yield 0.170 g (95%), m.p. 100-102° C. 1H NMR (CDCl3) δ 7.50 (d, J=4.9 Hz, 1H, H3′), 7.46 (d, J=5.3 Hz, 1H, H4), 7.38 (d, J=3.4 Hz, 1H, H5′), 7.08-7.05 (m, 1H, H4′), 6.31 (s, 1H, H6), 6.17 (d, J=5.3 Hz, 1H, H3). 13C NMR (CDCl3, 75 MHz) δ 169.5 (C), 146.6 (C), 143.8 (CH), 136.0 (C), 131.3 (CH), 130.7 (CH), 127.7 (CH), 118.0 (CH), 107.5 (CH). IR (Nujol) 1777, 1738, 1459, 1417, 1376, 1107, 935, 886, 731 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][OH:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CO)cc2C1
Yield: 93 %

Procedure:
To a solution of 0.245 mmol of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid in 2 ml dry THF were added at room temperature 0.736 mmol borane dimethyl sulphide complex and the mixture was stirred over night. The mixture was diluted with EtOAc and washed with saturated Na2CO3 solution and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. Evaporation of the solvent gave 60 mg of a pale yellow oil (93%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH3:42])[CH2:12]1
Reactant: Nc1ncnc2c1n(-c1ccc(Oc3ccccc3)cc1)c(=O)n2[C@@H]1CCNC1
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
In mixture of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (76 mg, 0.37 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C., HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm up to rt, and stirred for 2 hrs under N2, and purified directly by preparative-HPLC (RP C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (64) (36 mg, 25.9%) as a light yellow solid. LC-MS (ESI): m/z (M/M+2) 518/520. 1H NMR (400 MHz, DMSO) δ 8.11 (d, J=6.0 Hz, 1H), 7.48-7.36 (m, 4H), 7.23-7.07 (m, 5H), 6.69-6.55 (m, 1H), 6.34 (dd, J=35.9, 15.1 Hz, 1H), 5.89-5.67 (m, 2H), 5.18-4.95 (m, 1H), 4.15-3.42 (m, 4H), 2.97 (dd, J=18.6, 6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.73-2.58 (m, 1H), 2.33-2.10 (m, 1H), 1.98 (d, J=12.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.63-1.48 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15][NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19]>C1C=CC=CC=1>[Br:12][CH2:13][CH2:14][CH2:15][N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: COCC(C=O)NCCCBr
Reactant: C=CCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(CCCBr)C(C=O)COC)s1

Procedure:
5-Allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-γ-bromopropylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product 2-[1-γ-bromopropyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of N-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (96 mg, 0.22 mmol, Example 71) in CH2Cl2 (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated and dried in vacuo to yield N-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+): 348 (M+H); (ES−): 346 (M−H). Calc'd. for C20H21N5O—347.17.
Reaction SMILES: Cl.[CH:2]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)=[O:3].C(=O)(O)[O-].[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:3][CH2:2][C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)[CH3:25]
Reactant: CCO
Reactant: O=Cc1ccc(-c2sccc2-c2cccs2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOCc1ccc(-c2sccc2-c2cccs2)s1
Reaction time: 2 h

Procedure:
The yield could be increased to 85% or higher by substituting absolute ethanol for alcohol and concentrated hydrochloric acid for diluted hydrochloric acid. More specifically, 5-formyl terthiophene (0.2 g) was first dissolved in absolute ethanol (15 ml) at room temperature. To the solution, 0.03 ml concentrated hydrochloric acid/absolute ethanol mixture (0.3 ml conc. HCl in 10 ml absolute ethanol) was then added. After stirring for 2 hours, 0.8 g sodium bicarbonate (NaHCO3) was added and the stirring was continued for 0.5 hours followed by filtration. The ethanol was removed under reduced pressure. 5-ethoxymethyl terthiophene thus obtained was purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH:8]1[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N+:13]([O-:15])=[O:14])[C:6]=2[O:10][C:9]1([CH3:12])[CH3:11]
Reactant: CC1(C)Cc2c(Cl)ccc([N+](=O)[O-])c2O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1Br
Yield: 95.4 %

Procedure:
A mixture of 11.82 g (0.052 mole) of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran (Example 1, Step C) and 9.3 g (0.052 mole) of N-bromosuccinimide in 200 mL of carbon tetrachloride was irradiated with a sun lamp for approximately 16 hours. No reaction occurred during this time. To this mixture was then added 0.10 g of benzoyl peroxide, and the reaction mixture was then heated at reflux and irradiated simultaneously for a period of five hours. The sun lamp was turned off, and the mixture was allowed to stir while being heated at reflux for an additional hour. The mixture was then passed through a column of silica gel, and product-containing fractions were combined. The solvent was evaporated from the combined fractions under reduced pressure, leaving 15.2 g of 3-bromo-4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran as a solid, m.p. 103°-104° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].[BH4-].[Na+].[OH-].[Na+]>C(O)(=O)C.C(O)C>[CH2:15]([NH:12][C:6]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][O:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOc1ccc(C)cc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COCOc1ccc(C)cc1NCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-methoxymethoxy-5-methylaniline (see Example 8) (15.6 g, 93.3 mmol), ethanol (100 ml), acetic acid (75 ml), benzaldehyde (19.0 ml, 187 mmol) and sodium acetate (15.5 g, 189 mmol) was added sodium borohydride (7.15 g, 189 mmol) under ice-cooling over a period of 30 minutes. The reaction mixture was stirred at 0° C. to room temperature for 1 hour. The reaction mixture was poured into 1N sodium hydroxide (500 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography on silica gel to give white crystals. The crystals were recrystallized from chloroform/hexane to give the desired benzylaniline compound (1). Yield 25.2 g (86%, a mixture with dibenzyl compound in the ratio of 6:1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[Cl-].[Ca+2].[Cl-].[Br:13]Br>S(=O)(=O)(O)O>[Br:13][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: BrBr
Reactant: Cc1cccnc1C
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a stirred solution of 2,3-dimethyl-pyridine (6.79 mL, 60 mmol) in fuming sulfuric acid (80 mL) held at 150° C. in a round bottom flask fitted with a water cooled reflux condenser and a calcium chloride filled drying tube, was added, dropwise, bromine (3.1 mL, 60 mmol) over 2 hr. The resulting dark red solution was stirred for 16 hr then cooled to room temperature and allowed to stand overnight. This mixture was poured into approximately 400 g of ice. This mixture was brought to pH 12 with cooling in an ice bath. The resulting mixture was extracted with ether and the ether extract washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography (50 g silica, eluted with 2-20% ethyl acetate in hexanes) to give the title compound (8.3 g) as a colorless oil.