Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=O)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(CC(=O)O)c1
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1

Procedure:
(3-Amino-phenyl)-acetic acid methyl ester was prepared by reacting 3-aminophenylacetic acid with acetyl chloride in MeOH to afford the corresponding methyl ester, HCl salt, (3.09 g, 15.324 mmol). The ester was dissolved in DMF (5 ml) with DIEA (2.67 ml, 15.324 mmol) and cooled to 0° C. To this solution was added dropwise a 0° C. solution of DMF (5 ml) containing 2,4-dichloro-1,3,5-triazine (2.297 g, 15.324 mmol) and DIEA (2.67 ml, 15.324 mmol). The reaction was stirred at ODC for 15 min and then at RT for 1 h. The reaction mix was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed 4 times with brine and dried over Na2SO4. The crude was concentrated down and dried under reduced pressure, giving [3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetic acid methyl ester (4.3 g, 100%).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:14]([F:19])[C:15](OC)=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:13]=[C:14]([F:19])[CH2:15][OH:16])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 90.7 %

Procedure:
The method of Example 9 was repeated using 1-(4-difluoromethoxyphenyl)-1-(2-fluoro-2(methoxycarbonyl)-ethenyl)cyclopropane (Example 8) (0.77 g), diethyl ether (10 ml) and lithium aluminium hydride (0.2 g) to yield the title compound (0.63 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][OH:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][CH2:18][CH:15]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[O:16]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(F)cccc4F)c3O2)cc1
Yield: 63 %

Procedure:
Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.5 g, 13.35 mmol) with p-toluenesulfonyl chloride (3.05 g, 16.01 mol) generally according to the procedure described for Intermediate 10 gave 3.5 g (64%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.20 mmol) with sodium azide (1.87 g, 28.8 mmol) generally according to the procedure described for Intermediate 98 gave (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.20 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.69 g (90%) of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 219-222° C.; Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.87; N, 4.58.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12](=[S:22])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=1>C1COCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12]([S:22][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=3)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Reactant: CS(=O)c1ccc(CCl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(CSc2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)c3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (55-65%; 0.1 g; about 2 mmol) was introduced into a solution of 24a (0.31 g; 1.0 mmol) in absolute THF (15 ml). The initial charge was stirred at room temperature for 5 min, and 4-methylsulfinylbenzyl chloride (3, 0.19 g; 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The yellow-brown solution was diluted with H2O and neutralized with 10% strength citric acid. The THF was removed and the aqueous solution was extracted with ethyl acetate (2×). The combined organic extract was washed with saturated NaCl solution (2×), dried over Na2SO4 and concentrated. The solids residue was purified by column chromatography (SiO2 60, CH2Cl2/EtOH 9.5+0.5). M.p. 179° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.[CH3:15]O>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:15])=[O:12])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Agent: Cl
Product: COC(=O)c1ccnc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To 2-(acetamido)pyridine-4-carboxylic acid (25 g, 139 mmol) was added a saturated solution of anhydrous hydrogen chloride in methanol (600 mL). The cloudy suspension was stirred for 16 h at RT and refluxed for 24 h. The resulting solution was concentrated, dissolved in chloroform, washed with saturated sodium bicarbonate, brine, dried (magnesium sulfate) and concentrated to give the title compound as a white solid (17.86 g, 84%). TLC Rf 0.55 (5% methanol/chloroform); 1H NMR (CDCl3) δ3.96 (3H, s), 4.80 (2H, s),7.12 (1H, J=5 Hz, d), 7.19 (1H, s), 8.10 (1H, d, J=5 Hz).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][OH:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][O:28][C:30](=[O:32])[CH3:31])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 92 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(2-hydroxyethylthio)pentanamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2O[C:10]([NH2:12])=[N:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:15][NH2:16]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:15]([NH2:16])[C:10]([NH2:12])=[N:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)o1
Reactant: NN
Solvent: O
Product: Nc1nnc(Cc2ccc(F)cc2)n1N
Temperature: 195 °C

Procedure:
A mixture of 5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-ylamine 10.182 g (52.7 mmol), water 80 mL and anhydrous hydrazine 20 mL was refluxed under nitrogen on an oil bath (190-200° C.) for 23 hours. The mixture was cooled and allowed to crystallize at room temperature under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 mL) and dried on high vacuum. The crude product was re-crystallized from water 60 mL (reflux under nitrogen, than to +4° C. in a refrigerator overnight). The product was filtered, washed with ice-cold water and dried on high vacuum.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1>COCCOCCOC>[CH3:10][N:11]1[CH:15]=[C:14]([NH:16][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:13]=[N:12]1
Reactant: Cn1cc(N)cn1
Reactant: CSc1nccc(=O)[nH]1
Solvent: COCCOCCOC
Product: Cn1cc(Nc2nccc(=O)[nH]2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 2-(methylsulfanyl)pyrimidin-4(3H)-one (5.2 g) obtained in Step A in diethylene glycol dimethyl ether (50 mL) was added 1-methyl-1H-pyrazol-4-amine (4.1 g), the mixture was stirred overnight at 150° C., and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (5.4 g).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][N:3]=[CH:2]1.[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]>C(Cl)Cl>[N:10]1([C:8]([O:7][CH2:6][C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[O:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cnco1
Solvent: ClCCl
Product: O=C(OCc1cnco1)n1ccnc1
Reaction time: 2 h

Procedure:
Oxazol-5-ylmethanol (0.15 g, 1.51 mmol) in anhydrous CH2Cl2 (5 mL) under a dry N2 atmosphere was treated with 1,1′-carbonyldiimidazole (0.20 g, 1.23 mmol) at ambient temperature and stirred for 2 hours to provide the title compound in a solution of CH2Cl2 which was used in subsequent Examples without further manipulation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2ccccn2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccccn2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-C), the title compound was prepared as a solid having a melting point of 100° C.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21]([CH2:24][NH:25][OH:26])=[CH:20][C:19]=3[CH:27]=2)[CH:9]=1>O1CCCC1>[OH:26][N:25]([CH2:24][C:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:10]3[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=3)=[CH:27][C:19]=2[CH:20]=1)[C:6]([NH2:5])=[O:7]
Reactant: ONCC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)N(O)CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
1.84 ml of trimethylsilyl isocyanate was added dropwise to a solution of 3.03 g (11.3 mmol) of N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3-ylmethyl]hydroxylamine in tetrahydrofuran (30 ml) at 0° C. over 5 minutes, followed by stirring overnight at room temperature. Then, the solvent was evaporated in vacuo, the residue was purified by silica gel chromatography (chloroform:methanol:concentrated ammonia water=300:9:1−100:9:1), followed by recrystallization in a mixed solvent of chloroform-methanol-ethyl acetate to obtain 2.41 g (yield=68.5%) of the desired compound as white columnar crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2cc[nH]c(=O)c12
Agent: [Pd]
Solvent: CO
Product: Cc1cccc2c1C(=O)NCC2
Reaction time: 48 h
Yield: 98.6 %

Procedure:
A mixture of 8-methylisoquinolin-1(2H)-one (76a, 1 g, 6.29 mmol) and 10% Pd/C (0.5 g) in MeOH (20 mL) was hydrogenated under H2 (60 psi) at 80° C. for 48 hours. The reaction mixture was filtered and the solids were washed with MeOH (2×20 mL). The filtrate was concentrated under vacuum to give 8-methyl-3,4-dihydroisoquinolin-1(2H)-one (76b, 1 g, ˜100%) as a gray solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13](Cl)=[N:12][C:11]=1[Cl:18])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([S:3][CH2:1][CH3:2])=[N:12][C:11]=1[Cl:18])[CH3:7]
Reactant: CCS
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Ethanethiol (15.08 mL, 204 mmol) was added slowly to a stirred suspension of NaH (60% in Mineral oil, 8.15 g, 204 mmol) in THF and stirred for 30 min at room temperature to yield a white thick suspension. This suspension was diluted by cold THF, cooled to 0° C. and transferred to an already cooled solution of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) (48.5 g, 204 mmol) in THF at −20° C. under argon by maintaining the temperature below −10° C. The solution was stirred at −20° C. for 15 min and allowed to come at room temperature slowly. The solution was poured into water and extracted by ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure to yield 53 g (98%) of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester (66) as brown liquid. 1H-NMR (DMSO-d6): δ 1.33 (m, 6H), 3.19 (q, J=7.2 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 8.10 (d, J=9.6 Hz, 1H); EIMS m/z 264 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1([C:8]2[CH:32]=[CH:31][C:11](/[CH:12]=[C:13]3\[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]5[CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[O:16][C:17]\3=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>C(O)C>[CH:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([C:15]([NH:14]/[C:13](/[C:17]([NH:1][CH2:2][CH2:3][OH:4])=[O:18])=[CH:12]\[C:11]3[CH:31]=[CH:32][C:8]([CH:5]4[CH2:6][CH2:7]4)=[CH:9][CH:10]=3)=[O:16])=[CH:20][CH:21]=2)[CH2:30][CH2:29]1
Reactant: NCCO
Reactant: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Solvent: CCO
Product: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
2-Aminoethanol (20 μL, 0.33 mmol) was added to a solution of ethanol (1.6 mL) containing (4Z)-4-(4-cyclopropylbenzylidene)-2-[4-(2-cyclopropylethoxy)phenyl]-1,3-oxazol-5(4H)-one (95 mg, 0.25 mmol) prepared in Example 9 (9c). The mixture was stirred at 60° C. for 1 hour, and then the solvent was removed. The residue was washed with hexane:ethyl acetate (3:1, v/v). The precipitate was collected by filtration and dried under reduced pressure to give 95 mg of the title compound (white powder, yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.[OH-].[Na+]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: C#Cc1ccnc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(CNCCc2ccnc(Cl)c2)cc1
Temperature: 105 °C
Yield: 55.4 %

Procedure:
A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65 ml of 4-tert-butyl-benzylamine (15.11 mmol), 0.58 ml of acetic acid (10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07 mmol) in ethanol (12 ml) were heated to 105° C. in a sealed tube for 2 d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOH solution and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. After column chromatography (heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound were isolated as a brown liquid. MS (ISP) 303.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl.CO>[C:1]1([CH2:7][S:8]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CSc2nc3cnccc3[nH]2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1)c1nc2cnccc2[nH]1
Reaction time: 0.75 h

Procedure:
To a chilled (0°-5° C.) solution of 3.3 g (0.014 mol) of 2-[[(phenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine in 50 mL of chloroform and 5 mL of methanol was added dropwise a solution containing 2.78 g (0.014 mol) of m- chloroperoxybenzoic acid in 50 mL of chloroform. The reaction mixture was then stirred at room temperture for 45 minutes. Approximately one half of the chloroform was removed in a rotary evaporator and the reaction mixture was then poured into 200 mL of ether. The reaction mixture was cooled in ice. The precipitate that formed was collected and amounted to 1.78 g. The product was suspended in aqueous 10% sodium bicarbonate solution, filtered and was air dried overnight. The product amounted to 1.39 g. An analytical sample (m.p. 190°-193° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[C:22]1([NH:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)Nc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)c1ccccc1N1CCNCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a vial containing 4-(2-phenylcarbamoyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.438 g, 1.150 mmol) is added 2 mL of CH2Cl2 and 2 mL of TFA. The mixture stirred for 1 h and then concentrated to dryness to give 0.454 g of 4-(2-phenylcarbamoyl-phenyl)-piperazine trifluroacetate in 100% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:30]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: OCCCN1CCCC1
Reactant: OC1(c2ccccc2)C=CC=CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(OCCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
A mixture of 1-(3-hydroxypropyl)pyrrolidine (400 mg), triphenylphosphine (812 mg) in toluene (18 mL) is stirred for five minutes at room temperature, 1-hydroxybiphenyl (493 mg) is then added. The mixture is cooled and diisopropyl azodicarboxylate (609 μL) is added. The mixture is stirred for 48 hours room temperature, concentrated under reduced pressure and diluted with ethyl acetate. The organic layer is washed with water and extracted with an aqueous 1N hydrochloric solution. The aqueous phase is washed with ethyl acetate, then made alkaline with an aqueous 5N sodium hydroxide solution and extracted twice with ethyl acetate. These extracts are pooled, dried over magnesium sulphate, concentrated under reduced pressure, diluted with diethyl oxide and mixed with a solution of oxalic acid (169 mg) dissolved in acetone. The precipitate is filtered, washed with diethyl oxide and dried to give 480 mg of 1-{3-[(biphenyl-4-yl)oxy]propyl}pyrrolidine, oxalate as a white solid melting at 201° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1C.Cl[CH2:27][C@H:28]1[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]1>CN(C=O)C>[CH3:33][C:30]1([CH3:34])[O:29][C@@H:28]([CH2:27][N:19]2[C:20](=[O:22])[C:21]3[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=4[F:3])=[CH:13][C:14](=[O:24])[N:15]([CH3:23])[C:16]=3[N:17]=[CH:18]2)[CH2:32][O:31]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H]3COC(C)(C)O3)cnc21
Reaction time: 0.17 h

Procedure:
Sodium hydride (89 mg, 4.7 mmol, 5 eq) was stirred in anhydrous DMF (1 mL) for 10 minutes. 5-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (400 mg, 0.94 mmol, 1 eq) in anhydrous DMF (400 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (260 μl, 1.88 mmol, 2 eq) was added and the mixture subjected to microwave irradiation at 150° C. for 35 minutes. The solvent was removed in vacuo and the residue purified by HPLC. 1H NMR (400 MHz, MeOD) δ ppm 1.37 (s, 3H) 1.47 (s, 3H) 3.70 (s, 3H) 3.85 (dd, J=8.97, 5.68 Hz, 1H) 4.13 (dd, J=13.89, 7.07 Hz, 1H) 4.20 (dd, J=8.72, 6.69 Hz, 1H) 4.38 (dd, J=13.89, 3.03 Hz, 1H) 4.50-4.59 (m, 1H) 5.81 (s, 1H) 7.36 (t, J=8.21 Hz, 1H) 7.62-7.74 (m, 2H) 8.49 (s, 1H). [M+H] calc'd for C20H20FIN4O4, 527; found, 527.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[C:38](=[O:40])[CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH:41]([CH3:42])[CH3:43])[C:38](=[O:40])[CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N1Cc2cc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)nn2CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1Cc2cc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nn2CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 25-mL single-neck round-bottomed flask was charged with 151h (90 mg, 0.14 mmol), NaBH4 (18 mg, 0.42 mmol), and methanol (5 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. To the resulting residue was added water (10 mL) and the mixture was extracted with dichloromethane (3×15 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 151 (50 mg, 55%). MS-ESI: [M+H]+ 626.8. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.59-7.58 (m, 3H), 7.55-7.52 (m, 2H), 5.90 (s, 1H), 5.07-5.05 (m, 1H), 4.74 (s, 2H), 4.50-4.47 (m, 4H), 4.09-4.06 (m, 1H), 3.73 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(=O)C(OCC)=O)[CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([O:18]C)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([OH:18])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(C(=O)OC(C)(C)C)C1CC2CC(C(=O)OC)C1C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC2CC(C(=O)O)C1C2
Reaction time: 8 h

Procedure:
To a solution of methyl 6-[tert-butoxycarbonyl-(2-ethoxy-2-oxo-acetyl)amino]norbornane-2-carboxylate, 72f, (0.80 g, 2.17 mmol) in methanol (20 mL) was added NaOH (4.33 mL of 2N solution, 8.66 mmol) at room temperature. The reaction mixture was stirred overnight. The mixture was diluted into 0.5 N HCl in ice, and extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to afford 600 mg of desired product that was used without further purification.