Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(-c2cccc(N)c2)c1
Yield: 67.2 %

Procedure:
Iron (35 g, 625.00 mmol, 5.02 equiv.) was added to a solution of methyl 3′-nitrobiphenyl-3-carboxylate (32 g, 124.40 mmol, 1.00 equiv.) in ethanol (300 mL) and water (50 mL). At about 50° C., acetic acid (38 g, 633.33 mmol, 5.09 equiv.) was added dropwise to the stirred solution. The solution was heated at reflux for about 60 minutes. After filtering the solution, the filtrate was concentrated in vacuo, and then water (250 mL) and ethyl acetate (250 mL) was added. The organic phase was separated and the mother liquid was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:7)) to give the title product as a light yellow solid (19 g, yield=67%). 1H NMR (300 MHz, CDCl3) δ: 8.28 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.29 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](O)=[O:9])[CH2:6][CH2:5]1)[CH3:3]>S(Cl)(Cl)=O>[ClH:1].[CH2:2]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:1])=[O:9])[CH2:6][CH2:5]1)[CH3:3]
Reactant: CCN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCN1CCC(C(=O)Cl)CC1

Procedure:
1-Ethyl-isonipecotic acid hydrochloride (0.95 g) was suspended in thionyl chloride (8 ml) and the mixture was stirred and heated under reflux for 3 hours to give a clear yellow solution. The thionyl chloride was removed by evaporation under reduced pressure and the resulting residue was suspended in toluene (5 ml) and the toluene was removed by evaporation under reduced pressure to give 1-ethyl-isonipecotoyl chloride hydrochloride as a white solid. The acid chloride was suspended in dry dichloromethane (20 ml) and silver cyanate (1.5 g) was added. The mixture was stirred and heated under reflux for 1 hour. The mixture was cooled to room temperature and (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1 g) and triethylamine (0.5 g) were added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 ml) and the solid was removed by filtration. The filtrate was washed with saturated sodium bicarbonate and saturated sodium chloride. The solution was dried (sodium sulphate), and the solvent was removed by evaporation under reduced pressure to give a yellow gum. The gum was chromatographed on silica gel using 1:3 ethyl acetate/chloroform and 1:9:90 ammonia solution (35%)/methanol/dichloromethane to give the title compound as a colourless gum (134 mg); 1H NMR (CDCl3) inter alia 2.88 (2H, q, J 6.5 Hz), 3.08 (3H, m), 3.22 (3H, s), 3.42 (1H, m), 5.04 (1H, d, J 17.5 Hz), 5.33 (1H, d, J 10.7 Hz), 5.74 (1H, d, J 9.9 Hz), 6.63 (1H, dd, J 17.5, 10.7 Hz), 7.47 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=O)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1ncccc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1C(C)NCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B, 1-(3-methylpyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668), (4-aminobutyl)-carbamic acid tert-butyl ester and NaBH(OAc)3 were reacted in CH2Cl2 to obtain {4-[1-(3-methylpyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[Cl:30].Cl>O1CCCC1>[Cl:30][C:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]#[N:29])[CH:20]=[CH:21][C:16]=1[CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1Cl)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.40 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.13 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-3′-chlorobiphenyl-2-carbonitrile (2.06 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (2.55 g), 28% sodium methoxide (7.80 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (0.64 g, 73%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[NH4+:13]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-cyanophenyl isocyanate (1.0 g, 6.90 mmol) in THF (5 mL), ammonium hydroxide (1.7 mL, 13.8 mmol) was added. The reaction was stirred for 2 h at rt. The solvent was evaporated and the crude residue was redissolved in ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by flash column chromatography to 41A (0.37 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(OC(=O)C)(=[O:18])C>>[C:1]1([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Product: O=c1cc(-c2ccccc2)cc[nH]1
Reaction time: 2 h

Procedure:
A solution of 4-phenylpyridine-N-oxide (8.55 g, 50 mmol) in acetic anhydride (250 ml) was heated under reflux for sixteen hours. Acetic anhydride was then removed under vacuum and the residue was dissolved in absolute ethanol (200 ml) and 80% sodium hydride (1.5 g, 50 mmol) was added in small portions. The mixture was stirred for 2 hours under nitrogen, then evaporated and the residue was dissolved in ethyl acetate and dilute hydrochloric acid. The phases were separated and the aqueous phase was basified (sodium bicarbonate) and re-extracted (ethyl acetate). The aqueous phase was filtered to give the solid product which was recrystallised from ethyl acetate/methanol to give pure product, 3.76 g, Mp 226°-230° C. The combined organic extracts were evaporated to give a further quantity (1.58 g) of impure product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred mixture of sodium hydride (0.45 g, 15 mmol, 80% oil dispersion) in anhydrous tetrahydrofuran is treated with a solution of 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline (3.30 g, 13.47 mmol) in anhydrous tetrahydrofuran dropwise over the course of 40 minutes. After addition is complete and the initial effervescence subsides, ethyl bromoacetate (2.30 g, 13.50 mmol) is added to the reaction mixture. After 24 hours stirring at room temperature under nitrogen, the reaction mixture is partitioned between water and ether. The layers are separated, and the organic layer is dried over magnesium sulfate, vacuum filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. The residue is purified by flash chromatography (2:1 hexanes/ethyl acetate eluent) to give the title product as a pale yellow oil.
Reaction SMILES: [C:1](=[O:40])([O:18][CH2:19]/[C:20](/[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[C:21](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)\[CH2:22][OH:23])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:4]=1.C[C:42](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:43].[O-]Cl=O.[Na+].CC(=CC)C.[N+](=C)=[N-]>C(Cl)Cl.CC(O)(C)C.O>[Si:11]([O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[O:2][C:1]([O:18][CH2:19]/[C:20](/[C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1)=[C:21](/[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)\[C:22]([O:43][CH3:42])=[O:23])=[O:40])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(OC(=O)OC/C(=C(\CO)c2ccccc2)c2ccc(S(C)(=O)=O)cc2)c1
Agent: C=[N+]=[N-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C(=C(\COC(=O)Oc1cccc(CO[Si](C)(C)C(C)(C)C)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 1.26 g of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl carbonate in 35 mL of CH2Cl2 cooled at −78° C. was added 1.05 g of Dess-Martin reagent. After 1 h of stirring at rt, the reaction was quenched with aqueous NaHCO3, extracted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered through a pad of silica gel by eluting with EtOAc and evaporated. The crude material obtained was dissolved in a solvents mixture of 175 mL of t-BuOH and 75 mL of H2O, and treated with 6.07 g of NaH2PO4 mono hydrated and 6.07 g of NaClO2 for 30 min in the presence of 30 mL of 2-methyl-2-butene. The organic solvents were removed under vacuum. The crude material was diluted with EtOAc, washed with aqueous 1N HCl and brine, dried over Na2SO4, and evaporated. The crude acid obtained was diluted with THE and esterified with diazomethane (excess). The reaction mixture was concentrated and the residue was purified by flash chromatography (10–50% EtOAc/hexane) to afford 1.02 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:28])=[CH:25][CH:24]=4)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:36][CH:37]=4)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Methyl 3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoate (82.1 mg, 0.165 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1N Sodium hydroxide (0.33 mL) was added and the reaction was stirred at room temperature for 24 hours. The reaction was then concentrated. The crude residue was taken up in water and acidified with 1N hydrochloric acid to pH=3. A white precipitate formed. The solids were filtered off and dried under vacuum to give (+/−)-3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid (61.6 mg, 77%) as an off-white solid. 1H NMR (400 MHz, CD3OD, δ): 8.57 (d, J=1.0 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.78-7.69 (m, 3H), 7.61-7.50 (m, 3H), 7.47 (d, J=8.4 Hz, 2H), 7.38-7.31 (m, 2H), 7.24-7.16 (m, 1H), 7.05 (dd, J=8.9, 3.0 Hz, 1H), 4.48-4.41 (m, 1H), 3.63-3.55 (m, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.94-1.69 (m, 2H), 1.58-1.33 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 484.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15]
Reactant: OCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 3,3,3-trifluoropropan-1-ol (618 ml) and pyridine (224 ml). Cool to between 0° C. and 10° C. and add portion-wise p-toluenesulfonylchloride (147 g). Allow to warm to ambient temperature and stir overnight. Add HCl 0.5N (1.6 L), extract with ethyl acetate, combine the organic layers, dry over MgSO4, filter, and evaporate to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K2CO3 (2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]-butoxyl-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:12]([NH:20][C:21]1[S:22][C:23]([C:27](Cl)=[O:28])=[C:24]([CH3:26])[N:25]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.ClCCl>[CH:1]1([CH2:4][NH:5][C:27]([C:23]2[S:22][C:21]([NH:20][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:25][C:24]=2[CH3:26])=[O:28])[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a cooled mixture of cyclopropylmethylamine (0.033 g, 0.46 mmol), pyridine (0.090 g, 1.14 mmol) and 4-dimethylaminoyridine (0.010 mg) in anhydrous tetrahydrofuran was added 2-benzoylamino-4-methylthiazole-5-carbonyl chloride (0.079 g, 0.038 mmol) in anhydrous dichloromethane (1 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 h, then diluted with dichloromethane (10 mL), washed with 1 N hydrochloric acid (5 mL), saturated aqueous sodium bisulfate (2×5 mL), and brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrate in vacuo and the residue was purified by column chromatography to afford the title compound as a white solid in 45% yield (45 mg); m.p. 163-166° C.; 1H NMR (CDCl3, 300 MHz) δ 7.89 (d, J=7.9 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 5.84 (s, 1H), 3.23 (dd, J=5.4, 7.1 Hz, 2H), 2.23 (s, 3H), 1.00-0.98 (m, 1H), 0.53 (q, J=5.8 Hz, 2H), 0.22 (q, J=5.0 Hz, 2H); MS (ES+) m/z 316.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:29])[C:27]=1[OH:28])[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([Cl:20])[C:27]([OH:28])=[C:26]([Cl:29])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Oc1c(Cl)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.50 (bs, 1H), 9.26 (bd, 2H, J=7.5 Hz), 8.06 (d, 1H, J=3.9 Hz), 7.65 (s, 2H), 7.18-7.13 (m, 2H), 6.80 (d, 1H, J=9.0 Hz), 4.20 (s, 4H); LCMS: purity: 100%; MS (m/e): 424(MH+).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH3:35][C:36]([CH3:54])([CH3:53])[C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41][N:42]([CH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O)[CH3:43]>C1C=CC=CC=1>[CH3:35][C:36]([CH3:54])([CH3:53])[C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41][N:42]([CH2:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:47]([CH:48]=[C:2]([CH3:4])[CH3:3])[CH:46]=1)[CH3:43]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(C=O)c1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(C)=Cc1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
Isopropyltriphenylphosphonium iodide (1.18 g; 2.73 mmol) was added to benzene (35 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.8 ml; 2.73 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 8 (0.49 g; 1.82 mmol) in benzene (35 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.13 g of the target compound as pale yellow oily matter (yield: 24.2%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C:33]1([S:47]([C:50]2[CH:55]=[CH:54][C:53]([CH:56]=O)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[CH2:38][CH2:37][CH:36]([NH:39][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])[CH2:35][CH2:34]1.C(#[N:60])C>O>[C:56]([C:53]1[CH:54]=[CH:55][C:50]([S:47]([C:33]2([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[F:25])[CH2:38][CH2:37][CH:36]([NH:39][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])[CH2:35][CH2:34]2)(=[O:49])=[O:48])=[CH:51][CH:52]=1)#[N:60]
Reactant: O=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Reactant: CC#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Triphenyl phosphine (0.32 g, 1.2 mmol), followed by carbon tetrachloride (0.06 ml, 0.60 mmol), were added to a solution of the product from Example 80 (0.16 g, 0.30 mmol) in acetonitrile (1.5 ml). The mixture was stirred for 1.5 hours, additional carbon tetrachloride (0.18 ml, 0.18 mmol) was added, and the mixture was stirred for 0.5 hours, diluted with water (10 ml) and extracted with diethyl ether (2×10 ml). The combined organic phases were washed with brine (sat. 20 ml), dried (magnesium sulfate) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with 20% ethyl acetate/isohexane to give the nitrile (0.11 g, 71%). 1H NMR (CDCl3, 360 MHz): 1.63-1.69 (2H, m), 2.04-2.09 (2H, m), 2.48 (2H, bt, J=13.0), 2.59-2.64 (2H, m), 3.81 (1H, m), 5.66 (1H, d, J=7.3), 6.79-6.86 (1H, m), 7.07-7.13 (2H, m), 7.52 (2H, d, J=8.5), 7.70 (2H, d, J=8.5)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1B(O)O>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[C:13]([O:16][CH:17]([CH3:18])[CH3:19])[CH:12]=[CH:11][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1
Reactant: Brc1ccc(Br)nc1
Product: CC(C)Oc1ccc(F)c(-c2ccc(Br)cn2)c1
Yield: 45 %

Procedure:
Obtained (0.600 g, yield 45%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (4.22 mmol, 1.0 g), 2-fluoro-5-isopropoxyphenylboronic acid (4.22 mmol, 0.836 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][C@@H:32]([C:34]4[CH:45]=[CH:44][C:37]5[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=5[CH:35]=4)[O:31][C:30]3=[O:46])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:43][C:39]1([CH3:42])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@H:32]3[O:31][C:30](=[O:46])[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][C:14]4[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:3]=[C:2]([NH:1][C:48]([C:49]6[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=6)=[O:55])[CH:7]=[CH:6][CH:5]=5)=[O:10])[CH:17]=[CH:16][CH:15]=4)[CH2:33]3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(N)c5)c4)C(=O)O3)ccc2O1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(NC(=O)c6cccnc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 5.5 h
Yield: 89.6 %

Procedure:
A solution of N-(3-aminophenyl)-N′[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-urea (0.20 g) in pyridine (4 ml) was treated under nitrogen at 20° with nicotinoyl chloride hydrochloride (0.118 g) and the mixture stirred for 5.5 h. Sat. sodium bicarbonate solution (25 ml) was added and the product was extracted with dichloromethane (3×20 ml). The combined organic layer was dried (Na2SO4) and the solvent removed in vacuo to give a residue that was purified by SPE. Elution with dichloromethane-EtOAc (1:0, 1:1, then 0:1), then MeOH-EtOAc (1:50), followed by solvent evaporation in vacuo gave the title compound (0.209 g). LCMS RT=3.54 min, ES+ve 738 (MH)+.