Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([NH:20][C@@H:21]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:25][N:24]=2)[CH3:22])(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16].O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([N:20]([C@@H:21]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[N:25][N:24]=2)[CH3:22])[CH3:1])(=[O:18])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](C)N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
K2CO3 (78 mg) and MeI (0.022 ml) were added at room temperature to a solution of Compound 12 (150 mg) of Example 1 in dimethylformamide (2.0 ml), and the mixture was stirred at room temperature for three hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4). The resulting organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and evaporated under reduced pressure to remove the solvent. After eluting the residue with a mixed solvent of ethyl acetate and hexane, the resulting elute was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-10%) and then recrystallized (ethyl acetate-hexane) to give 111 mg of the titled compound as a colorless powdered compound.
Reaction SMILES: C([NH:14][CH:15]([PH:23](=[O:25])[OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C1C=CC=CC=1)C1C=CC=CC=1>Br>[NH2:14][CH:15]([PH:23](=[O:24])[OH:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[PH](O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Agent: Br
Product: NC(Cc1ccccc1)[PH](=O)O

Procedure:
181.1 g of the compound of Step A above in 500 ml of hydrobromic acid are heated at 110-120° C. for 2 hours. The mixture is then concentrated under reduced pressure, and the residue is diluted with water and extracted with diethyl ether. The aqueous phase is concentrated and 600 ml of absolute ethanol are added to the residue. 60 ml of previously cooled propylene oxide are slowly added to the reaction mixture, which is held at 0° C. The expected product which precipitates out on cooling is filtered off, washed with diethyl ether and then dried.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(C(F)(F)F)c1
Yield: 85 %

Procedure:
A solution of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (91 mg, 0.153 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 8 mL of ethanol was stirred for 17 h at 25° C. The ethanol was removed in vacuo. The resultant white precipitate was collected by filtration, washed with small amounts of EtOH and diethyl ether, then dried in vacuo to afford 75 mg (81%) of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.65 (s, 1H), 7.6 (m, 4H), 7.45 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.3 (t, 1H, J=8 Hz), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 1665 and 1618. MS (ES) m/e 441, 443.
Reaction SMILES: Cl[CH2:2][C:3]([O:7][C:8](=[O:12])[N:9]([CH3:11])[CH3:10])=[N:4][O:5][CH3:6].[CH3:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[CH2:16][P:17](=[O:22])([O-:21])[O:18][CH2:19][CH3:20].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[CH2:16][P:17](=[O:21])([O:18][CH2:19][CH3:20])[O:22][CH2:2][C:3]([O:7][C:8](=[O:12])[N:9]([CH3:11])[CH3:10])=[N:4][O:5][CH3:6]
Reactant: CON=C(CCl)OC(=O)N(C)C
Reactant: CCOP(=O)([O-])Cc1ccc(Cl)cc1C
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1ccc(Cl)cc1C)OCC(=NOC)OC(=O)N(C)C
Temperature: 25 °C

Procedure:
1-Chloro-2-(N,N-dimethylcarbamoyloxy)-2-methoxyiminoethane (10grams; 0.05 mole), methyl ethyl ketone (60ml), potassium O-ethyl 2-methyl-4-chlorobenzylphosphonate (15.6 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 4 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvent in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N,,N-dimethylcarbamoyloxy)-2-methoxyiminoethyl] O-ethyl 2-methyl-4-chlorobenzylphosphonate.
Reaction SMILES: O[C:2]1([C:10]#[N:11])[CH:6]([CH3:7])[CH2:5][CH2:4][C:3]1([CH3:9])[CH3:8]>S(Cl)(Cl)=O>[CH3:7][C:6]1[CH2:5][CH2:4][C:3]([CH3:9])([CH3:8])[C:2]=1[C:10]#[N:11]
Reactant: CC1CCC(C)(C)C1(O)C#N
Solvent: O=S(Cl)Cl
Product: CC1=C(C#N)C(C)(C)CC1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A solution of the product of Example 8f (1.54 g, 10.0 mmol) in thionyl chloride (6 mL) was heated to 84° C. overnight in a sealed vessel. The reaction mixture was cooled and then poured into ice-water (100 mL). The organics were extracted with diethyl ether (80 mL×4). The combined organic phase was washed with saturated aqueous sodium bicarbonate (160 mL×2) and brine (160 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a brown oil (1.20 g, Yield: 89%). 1H NMR (400 MHz, CDCl3) δ 2.45 (t, J=7.4 Hz, 2H), 1.96 (s, 3H), 1.80 (t, J=7.4 Hz, 2H), 1.17 (s, 6H) ppm.
Reaction SMILES: CCN=C=NCCCN(C)C.C(OC([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:32]([OH:34])=O)[N:29]([CH3:31])[CH:30]=2)=[CH:22][CH:21]=1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][C:36]3[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=3)=[O:34])[N:29]([CH3:31])[CH:30]=2)=[CH:24][CH:25]=1
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Reactant: COC(=O)c1cc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
Two eq of EDCI and 2.5 eq of DMAP were added to a stirred solution of 6 (0.45 gm, 1.2 eq) in DMF (8 mL) and the mixture was allowed to stir for 30 minutes after which commercially available methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.18 g, 1.18 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hour at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, yield 90.6%) was used for the boc deprotection step to afford 9 without further purification. For boc deprotection, 0.29 gm of 9a was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (9). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 9. Yield 0.21 gm, 95%.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29](I)[N:24]3[N:23]=2)[CH2:21][CH2:20]1>[Cu](I)I.CC(O)C>[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]3[N:23]=2)[CH2:21][CH2:20]1
Reactant: COc1ccc(I)n2nc(C3CC3)nc12
Reactant: C1CCNCC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(N2CCCCC2)n2nc(C3CC3)nc12
Temperature: 80 °C

Procedure:
Copper iodide (1.0 mg, 0.005 mmol) and potassium phosphate (42.5 mg, 0.200 mmol), kept under argon, was added 2-propanol (200 μL), ethylene glycol (12.4 mg, 0.200 mmol), piperidine (10.1 mg, 0.12 mmol) and 2-cyclopropyl-5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (31.5 mg, 0.100 mmol). The resulting suspension was heated to 80° C. for 4 days. The mixture was allowed to reach room temperature before it was extracted with dichloromethane (3 mL). The organic phase was washed with brine, dried (Na2SO4) and filtered before it was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene to 40% EtOAc in toluene) to give 2-cyclopropyl-8-methoxy-5-piperidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine (2.2 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC>ClCCl>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC[n+]1ccccc1Br
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a stirred solution of 5-chloro-2-(4-fluorophenoxy)nicotinic acid (150 mg, 0.56 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (136 mg, 0.67 mmol), and triethylamine (0.31 mL, 2.24 mmol) in dichloromethane (8 mL) was added 2-bromo-1-ethylpyridinium tetrafluoroborate (230 mg, 0.84 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with 1N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 155 mg (67%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.59 (1H, dd, J=2.6, 0.9 Hz), 8.26–8.17 (1H, m), 8.13 (1H, dd, J=2.8, 0.9 Hz), 8.00 (2H, d, J=8.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.15–7.07 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 415 (M+H)+, 413 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13].C[Si]([C:18]#[N:19])(C)C.CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:18]#[N:19])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(F)(F)F)c[n+]([O-])c1Cl
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)c(C#N)nc1Cl
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of 6-chloro-5-methyl-3-trifluoromethyl-pyridine-1-oxide (1.03 g, 5.30 mmol), trimethylsilyl cyanide (1.57 g, 16.0 mmol) and Et3N (1.34 g, 13.3 mmol) in dry CH3CN (30 mL) was heated at reflux for 64 h. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (6:1 hexanes/EtOAc) to afford 6-chloro-5-methyl-3-trifluoromethyl-pyridine-2-carbonitrile as a colorless oil (0.660 g, 56%). 1H NMR (CDCl3) δ 2.56 (s, 3H), 7.95 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CC(=O)O)c1ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.5 %

Procedure:
2-(1′-(Tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (200 mg, 0.58 mmol) was added to a solution of 20% trifluoroacetic acid in anhydrous CH2Cl2 (3 mL) at 0° C. The reaction solution was stirred at rt for 2 h until the starting material had been consumed. The solution was concentrated to give crude 2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (160 mg) which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.I[CH:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].CCCCCC>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][N:5]([CH:16]([CH3:18])[CH3:17])[N:6]=1
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2cn(C(C)C)nc2I)n1
Yield: 47.2 %

Procedure:
A mixture of 4-(5-iodo-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (A) (31.8 g, 0.1 mol), 2-iodo-propane (85 g, 50 mL, 0.5 mol) and K2CO3 (16.5 g, 0.12 mol) in DMF (500 mL) was heated at 40˜50° C. overnight. When TLC (hexane: EtOAc=15:1) showed the reaction was complete, DMF was evaporated under reduced pressure. The residue was taken up with EtOAc (400 mL). The mixture was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to give crude product, which was purified via prep. HPLC to give pure 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine B-1-1 (17 g, 47.2%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[Cl-].[IH2+:14].C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: [IH2+]
Reactant: COC(=O)c1cccc(N)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(I)c(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 3-aminobenzoate (5.0 g, 33.1 mmol) and benzyltrimethylammonium iodonium dichloride (11.51 g, 33.1 mmols) in acetic acid (20 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated, then poured into ethyl acetate and extracted with aq. NaOH until washes remained basic. The washes were back-extracted with ethyl acetate and the combined ethyl acetate layers were dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of 0-40% heptane/ethyl acetate to afford methyl 3-amino-4-iodobenzoate.
Reaction SMILES: [CH:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][C:9]([CH3:42])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[N:32][CH:33]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:42])([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:32][CH:33]=3)=[O:27])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:43][CH:44]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cc3)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(C(=O)NCCOc3ccc(CC(C)(Oc4ccc(C(C)C)cc4)C(=O)O)cc3)cn2)cc1
Yield: 44.3 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino]ethoxy]phenyl]-2-methylpropionate (341 mg), which is the product of Example 148, was reacted with aqueous sodium hydroxide solution (1N, 1.14 ml) and the reaction mixture was treated to give the title compound (144 mg) as colorless crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:27][C:28]1[N:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Br:27][C:28]1[N:33]=[CH:32][C:31]([O:1][C@H:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])=[CH:30][CH:29]=1
Reactant: O=C1OCC[C@H]1O
Reactant: Oc1ccc(Br)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1OCC[C@@H]1Oc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a suspension of (R)-3-hydroxydihydrofuran-2(3H)-one (500 mg, 4.9 mmol) in toluene (15 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) and 6-bromopyridin-3-ol (1.02 g, 5.88 mmol). The solution was cooled to 0° C. and degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-1,2-dicarboxylate was dissolved in toluene (5 mL) and added over a 5 minute period. The reaction was allowed to stir for 12 hours with warming to ambient temperature. The reaction was concentrated in vacuo and the resulting material purified by silica gel chromatography eluting 1:1 hexanes/EtOAc to yield (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 79%) as an off white solid.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:12]=1[NH2:13].[Br:21][CH2:22][C:23](Br)=[O:24]>C1COCC1>[Br:21][CH2:22][C:23]([NH:13][C:12]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])=[O:24]
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc([N+](=O)[O-])c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a flask was added sodium hydride (60% dispersion in mineral oil, 610 mg, 15 mmol) and hexane (2 mL) at 0° C. The supernatant liquid was decanted and the residue was dried under reduced pressure. To this was added THF (20 mL) and a solution of 2-methoxy-6-nitroaniline (2 g, 12 mmol, Kubo, K. et al. J. Med. Chem. 1993, 36, 1772-1784) in THF (20 mL) at 0° C. and stirred at rt for 2 h. To this mixture was added bromoacetyl bromide (1.2 mL, 14 mmol) at 0° C. and stirred at rt for 3 h. Then the reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 2.9 g (85%) of the title compound.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=[O:11].[Na+]>O>[OH:11][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSCC[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
D-Methionine (100 g, 0.67 mol) was dissolved in 600 ml of 10% H 2SO4 and cooled to 0°-5° C. A solution of NaNO2 (58 g, 0.84 mol) in 100 ml of H2O, also chilled to 0°-5° C., was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture at 10° C. or less by means of an ice water bath. After stirring for 18 hours at room temperature, the mixture was extracted 9×200 ml ethyl acetate. The organic extracts were combined, dried over MgSO4, and stripped to yield 10.1 g of title product as oil; tlc Rf 0.15 (ethyl acetate), 0.08 (1:1 hexane:ethyl acetate).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH:15]=O>C(O)C>[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14]/[CH:15]=[N:11]/[NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)NN
Reactant: CC(CC=O)CC(C)(C)C
Solvent: CCO
Product: CCCCCCCC(=O)N/N=C/CC(C)CC(C)(C)C
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of 12a (3.00 g, 19.0 mmol) and 3,5,5-trimethylhexanal (4.05 g, 28.4 mmol) in ethanol (48 ml) was heated under reflux for 2 h. After cooling to room temperature, the product was concentrated and washed with ethanol. Drying under high vacuum (0.33 mbar) gave a total of 4.69 g (88%) of a colorless oil consisting of two isomers with respect to the amide bond conformation (E:Z ca. 56:44).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[C:6]1([C:2]2([CH2:3][C:4]#[N:5])[O:14][CH2:13][CH2:12][O:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CCC1(c2ccccc2)OCCO1
Temperature: 150 °C
Yield: 76.6 %

Procedure:
To a solution of 3-oxo-3-phenylpropanenitrile (10 g, 69 mmol) and PTSA (27 mg, 1.37 mmol) in toluene (120 mL) is added ethylene glycol (120 mL, 2057 mmol). The azeotropic mixture is heated at 150° C. for 14 h. The solvent is evaporated under reduced pressure and the residue is washed with 10% aqueous NaOH solution. The aqueous layer is extracted with diethyl ether (2×100 mL) and the combined organic layers are dried (Na2SO4) and evaporated to provide the crude compound. The crude material is purified over neutral alumina eluting with 1% of ethyl acetate/hexane to afford the title compound as an off-white solid (10 g, 77%).
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH3:16])[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=C3C=2OC2C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=2C3(C)C)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[CH3:16])=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(C)c1nc(Cl)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(=O)N(C)c2cnc(Cl)nc21
Yield: 13.5 %

Procedure:
3-[(5-Bromo-2-chloro-pyrimidin-4-yl)-methyl-amino]-N-methyl-propanamide (Intermediate 15; 2.09 g, 6.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (171 mg, 0.19 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (288 mg, 0.50 mmol) and Cs2CO3 (2930 mg, 8.99 mmol) in 1,4-dioxane (50 mL) were heated at reflux for 16 h under an atmosphere of nitrogen. The reaction mixture was evaporated then suspended in DCM (20 mL) and filtered through a layer of celite washing with DCM (40 mL). Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (190 mg, 19%) as a foam.