Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH:8]([CH3:10])[CH3:9])[CH3:7])=[O:5].[CH3:15][NH:16][CH:17]([CH3:19])C.C12C(=CC=CC=1)[NH:25][C:24](=O)OC2=O>>[NH:16]1[CH2:15][CH2:24][N:25]=[C:17]1[CH2:19][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH:8]([CH3:10])[CH3:9])[CH3:7])=[O:5]
Reactant: CNC(C)C
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)N(C)C(=O)c1ccccc1N
Product: CC(C)N(C)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-isopropyl-N-methylbenzamide (prepared from N-methylisopropylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-isopropyl-N-methylbenzamide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.[CH3:17][C:18]1[N:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:13]1([N:10]2[CH2:11][CH2:12][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24]([C:21]4[CH:22]=[N:23][C:18]([CH3:17])=[CH:19][CH:20]=4)=[O:25])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:14][CH2:15][CH2:16]1
Reactant: O=C(C1CNC1)N1CCN(C2CCC2)CC1
Reactant: Cc1ccc(C(=O)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCN(C4CCC4)CC3)C2)cn1
Yield: 19.3 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutylpiperazine (60 mg, 0.27 mmol) in dichloromethane (1 mL) at 0° C., was added 6-methylpyridine-3-carbonyl chloride (31 mg, 0.32 mmol) and DIPEA (142 μL, 0.81 mmol). After 4 hours the reaction was quenched by addition of saturated aq. NaHCO3 (1 mL) and the aqueous extracted with dichloromethane (2×5 mL), dried (MgSO4), filtered, and concentrated at reduced pressure. Purification by silica FCC (eluting with 90:9:1 Et2O/MeOH/NH3) followed by capture and release on an SCX-2 cartridge (washing with MeOH and releasing with 7M NH3 in MeOH) gave the title compound (17.8 mg, 19%)
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:41])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH:38]3[CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:53][O:52][CH2:51][CH2:50]1>>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][S:17]5(=[O:22])=[O:21])=[CH:15][C:10]=4[C:9]([N:8]4[CH2:50][CH2:51][O:52][CH2:53][CH2:6]4)=[O:41])=[O:24])[CH2:26][CH2:27]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N2CCOCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (155 mg) described in Example 805 and morpholine (24 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (36 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14](Cl)(=[O:16])[CH3:15].Cl.C(O)(=O)C>[OH-].[Na+]>[C:14]([NH:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: NC(CF)(Cc1cnc[nH]1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(CF)(Cc1cnc[nH]1)C(=O)O
Temperature: 5 °C

Procedure:
A solution of 1.87 g (0.01 mole) of 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid in 10 ml of 2 N sodium hydroxide solution is cooled to 5° C. To this solution, maintained at 5° C., are added simultaneously from two syringes 1.0 g (0.013 mole) of acetyl chloride and 26 ml 2 N sodium hydroxide dropwise. After 2 hours the solution is neutralized by the addition of 8 ml of 5 hydrochloric acid followed by 0.5 ml of acetic acid. The mixture is cooled to 0° C. and the resultant N-acetyl 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid filtered off.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1I.[CH3:22][Si:23]([CH3:40])([CH3:39])/[CH:24]=[CH:25]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1/[CH:25]=[CH:24]/[Si:23]([CH3:40])([CH3:39])[CH3:22]
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 79.5 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate (350 mg, 0.824 mmol), and tetrakis triphenylphosphine palladium(0) (95 mg, 0.082 mmol) were combined in a Biotage microwave reaction vessel that was then sealed and purged with nitrogen. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (417 mg, 1.072 mmol) in dioxane (4122 μl) was added and the reaction mixture was heated in a microwave reactor at 120° C. for 30 min The cooled reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated on to silica. The product was purified by flash chromatography. (SiO2, 0-20% EtOAc:Hex gradient) to provide the title compound as a tan solid (260 mg, 0.655 mmol, 79% yield); 1H NMR (400 MHz, DMSO-d6) d 0.17 (s, 9H), 3.76 (s, 3H), 6.09 (d, J=19.2 Hz, 1H), 6.60 (s, 2H), 6.91 (d, J=19.2 Hz, 1H), 7.75 (dd, J=3.8, 1.9 Hz, 2H), 7.83 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −145.16 , −115.98; ESIMS m/z 398 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>C(O)CCC>[O:24]=[S:21]1(=[O:25])[CH2:22][CH2:23][N:18]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:19][CH2:20]1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=S1(=O)CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCS(=O)(=O)CC2)ncn1
Temperature: 200 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.4 g, 3.09 mmol) were suspended in n-butanol and thiomorpholine 1,1-dioxide (0.417 g, 3.09 mmol) was added. The reaction was stirred at 200° C. for 18 hours, the butanol was evaporated off and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). Yield=2.45 mmol (79%). 1H-NMR (CD3OD): 8.03 ppm (s, 1H); 5.87 ppm (s, 1H); 4.10 ppm (t, 4H); 3.09 ppm (t, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:30][CH2:29]1)=[O:27].CO.[H][H].[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>O1CCCC1.[Pd]>[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[((S)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran and methanol (1:1) (4 ml) under a nitrogen atmosphere. 10% palladium on carbon (60.4 mg) was added, and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 19 hours. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.0991 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (174.9 mg, quant.) as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][N:5]=[C:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[N:16]([O-])=[O:17].[Na+].[S:20]([O-:23])([O-:22])=[O:21].[Na+].[Na+].C([O-])(=O)C.[Na+]>Cl.O>[OH2:17].[NH:5]1[CH2:6][CH2:7][CH2:8][N:3]=[C:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][S:20]([OH:23])(=[O:22])=[O:21])=[CH:11][CH:10]=1.[NH:5]1[CH2:6][CH2:7][CH2:8][N:3]=[C:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][S:20]([OH:23])(=[O:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=S([O-])[O-]
Reactant: Nc1ccc(C2=NCCCN2)cc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)NNc1ccc(C2=NCCCN2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a stirred suspension of the product of Stage (ii) (18.0 g) in 2N hydrochloric acid (36.6 ml) at -5° was added to a solution of sodium nitrite (5.05 g) in water (11 ml) keeping the temperature below 0°. After stirring for a further 15 min, the solution was added to a stirred solution of sodium sulphite (23.05 g) and sodium acetate (9.95 g)in water (220 ml) at -5°. A solid deposited and the mass was stirred at -5° for a further 15 min, then warmed to room temperature over 1 h. Concentrated hydrochloric acid (25 ml) was added, the solution was heated at 75° for 30 min and then allowed to cool. The solid which had deposited was collected by filtration, washed with 2N hydrochloric acid (50 ml) followed by ethanol (50 ml) and dried in vacuo to give the title compound as a powder (18.18 g), m.p. 280°-281°.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: OCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
151 g of potassium t-butoxide were added, whilst ice-cooling and stirring, to a solution of 152 g of salicyl alcohol in 600 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes; 160 ml of benzyl bromide were then added dropwise to the mixture. The reaction mixture was then stirred at a temperature of from 30° to 40° C. for 2 hours, after which it was partitioned between ethyl acetate and water. The organic layer was washed twice, each time with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 228.5 g (yield 87%) of 2-benzyloxybenzyl alcohol as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8].P(Br)(Br)[Br:18]>ClCCl.N1C=CC=CC=1>[Br:18][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8]
Reactant: COc1c(C#N)ccc2oc(CO)c(C)c12
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C#N)ccc2oc(CBr)c(C)c12
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A solution of 2-hydroxymethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.17 g; 0.76 mmol) in dichloromethane (5 mL) was cooled to 0° C. To this solution was added, successively, neat phosphorus tribromide (0.11 mL; 0.32 g; 1.2 mmol; 1.5 eq) and pyridine (2 drops). The ice bath was removed and the reaction was allowed to come to room temperature overnight with stirring. After quenching with ice, the crude product was isolated by ethyl acetate extraction. The organic layer was washed with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-bromomethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.20 g; 95% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 65 °C
Reaction time: 40 h
Yield: 80.5 %

Procedure:
Into a solution of methyl 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.53 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.6 ml), and the resulting mixture was stirred at 65° C. for 40 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (412 mg) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28])O>C(O)CCC.C(O)(=O)C>[Br:15][C:11]1[C:12](=[O:14])[NH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:1][CH:33]3[CH:31]([OH:32])[CH:29]([OH:30])[CH:27]([OH:28])[CH:25]([CH2:24][OH:23])[O:34]3)[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])=[N:9][C:10]=1[CH:16]([CH3:18])[CH3:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCOc1ccc(NC2OC(CO)C(O)C(O)C2O)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 20.6 %

Procedure:
The compound of example 34 (200 mg, 0.55 mmol) was dissolved in n-butanol (10 ml), and added with glucose (200 mg, 1 mmol) and one drop of glacial acetic acid. The reaction mixture was heated under nitrogen protection to reflux for 12 h. The cooled reaction mixture was concentrated to dryness, and added with dichloromethane. The organic layer was washed with saturated saline (20 ml×3), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was passed through a silica gel column to give the title compound (60 mg, yield: 21%). 1H NMR (DMSO-d6) δ: 7.47 (1H, d), 7.21 (1H, dd), 7.09 (1H, d), 4.31 (1H, d), 4.01 (3H, t), 3.63 (1H, d), 3.46 (1H, d), 3.09-3.29 (4H, m), 2.57 (2H, q), 2.46 (2H, q), 1.72 (2H, m), 1.18 (6H, d), 0.95 (3H, t).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][CH:12]=1)C.[BH4-].[Li+].O>C1COCC1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2F)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(-c2ccccc2F)nc1

Procedure:
Under argon, 400 mg (1.46 mmol) of 3-(6-(2-fluorophenyl)pyridin-3-yl)propionic acid ethyl ester and 63.8 mg (2.93 mmol) of lithium borohydride were stirred in 20 ml of THF at 40° C. for 3 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and water and methylene chloride were added to the filtrate. The organic phase was separated, washed with water and concentrated. Yield: 241 mg (71%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19].[NH3:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([NH:19][C:5]([NH2:24])=[O:11])[CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N
Solvent: Cc1ccccc1
Product: NC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of triphosgene (3.613 g, 12.175 mmol) in toluene (15 ml) was added a solution of 5-chloro-2-nitroaniline (2.100 g, 12.175 mmol) in toluene (15 ml) over 0.5 h and then the reaction was heated at 80° C. for 24 h. The reaction was then cooled and carefully poured onto aqueous NH3. This mixture was stirred for 1 h, filtered, washed with water (100 ml), MeOH (50 ml) and ethyl acetate (50 ml) to leave the desired product as a yellow solid (1.558 g, 60%).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13].O[CH:23]1[C:28]2=[CH:29][C:30]3[CH:31]=[CH:32][C:33]4[C:42]5[C:41]=3[C:40]([CH:39]=[CH:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[C:27]2[CH:26](N2C3C(=O)NC(N)=NC=3N=C2)[CH:25](O)[CH:24]1O>>[CH:36]1[C:37]2=[C:42]3[C:41]4[C:40]([CH:39]=[CH:38]2)=[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:28]2=[C:29]([C:17]2[NH:18][C:19]5[C:20](=[O:21])[NH:11][C:12]([NH2:13])=[N:14][C:15]=5[N:16]=2)[C:30]=4[CH:31]=[CH:32][C:33]3=[CH:34][CH:35]=1
Reactant: Nc1nc2ncn(C3c4c(cc5ccc6cccc7ccc4c5c67)C(O)C(O)C3O)c2c(=O)[nH]1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: Nc1ncnc2nc[nH]c12
Product: Nc1nc2nc(-c3c4ccccc4c4ccc5cccc6ccc3c4c65)[nH]c2c(=O)[nH]1

Procedure:
##STR3## wherein R is adenine or guanine. The following compounds are exemplary: 7-(7,8,9-trihydroxy-7,8,9,10tetrahydrobenzo[a]pyren-10-yl)guanine, and
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:10]([C:20]2[CH:25]=[C:24](C#N)[CH:23]=[CH:22][N:21]=2)[N:9]=1)(C)(C)C.[C:29]([OH:35])(C(F)(F)F)=[O:30]>>[NH2:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[C:24]([C:29]([OH:35])=[O:30])[CH:23]=[CH:22][N:21]=2)[N:9]=1
Reactant: Cc1ccc(-c2cc(NC(=O)OC(C)(C)C)nn2-c2cc(C#N)ccn2)cc1
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(N)nn2-c2cc(C(=O)O)ccn2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of tert-butyl[1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazol-3-yl]carbamate (150 mg, 0.4 mmol) in TFA (2 mL) was heated to 50° C. for 30 min and evaporated to an oily residue. To the residue was added 10 N NaOH (2 mL) followed by MeOH (2 mL). The solution was stirred at 70° C. for 4 h and then cooled to rt. Solvent was evaporated, and the pH of the resulting aqueous phase was carefully adjusted to pH=5.5 using conc. HCl and then 1N HCl. The resulting mixture was extracted with EtOAc (2×20 mL). The organic layers were dried (MgSO4), filtered, concentrated to an oil, and purified by flash column chromatography (MeOH/EtOAc=5:95) to give the title compound (56 mg, 48%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 2.28 (3H, s), 5.73 (1H, s), 5.82 (1H, s), 7.05˜7.18 (4H, m), 7.51 (1H, d, J=5.2 Hz), 8.02 (1H, s), 8.22 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H14N4O2, 295; Found, 295.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN1CCCC1=O>[C:18]1([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]23)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1CCC2N1CC(=O)N2c1ccccc1
Yield: 11.7 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol; prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.2 g, 1.05 mmol), K2CO3 (1 g, 7.14 mmol) and iodobenzene (5 g, 24.5 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp=185-188° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:17][C:18](=[O:29])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[C:33]([F:39])[CH:32]=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[CH:19]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][C:33]=1[F:39])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a stirred solution of diisopropyl amine (1.3 mL, 9.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M solution in hexanes, 5.6 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then cooled to −78° C. A solution of 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 2 hours. A solution of 4-Bromo-1-bromomethyl-2-fluoro-benzene (1.3 g, 4.9 mmol) in THF (4 mL) was added dropwise. After completion, the dry-ice bath was removed and the reaction was warmed to 0° C. in an ice bath. After stirring at 0° C. for 30 minutes, the reaction was poured into saturated NH4Cl aqueous solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 20:1 to 5:1) to give 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.35 g, 77%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, J=8.0 Hz, 2H), 7.08 (t, J=8.0 Hz, 1H), 4.86 (m, 1H), 3.28 (m, 2H), 2.92 (m, 3H), 1.43 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 85 °C
Yield: 90.7 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5 g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to 4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96 ml, 6.96 mmol) at 0° C. The reaction mixture was heated to 85° C. for 3 hours, poured onto ice, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over flash silica chromatography eluting with petroleum ether to ethyl acetate/petroleum ether (5:95) to afford the desired product (1.91 g, 91% yield). LC/MS: (PS-A2) Rt 3.78 [M+H]+ 391.93.