Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21]C(=O)C)[CH:16]=1)([CH3:3])[CH3:2].C[O-].[Na+].O.C(OCC)(=O)C>CO>[CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2cc3cc[nH]c3cc2OC(C)C)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
N-(4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 17-5 (116 mg, 0.357 mmol) was dissolved in methanol (2.5 mL), 28% sodium methoxide (0.728 mL) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and then water and ethyl acetate were added for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off and the resultant was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-9:1), then the target fraction was concentrated under vacuum to obtain the title compound (66.3 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]([S:13]([CH3:15])=O)[C:5]2=[O:16].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:15][S:13][C:6]1[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]([CH3:12])[N:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1nc(S(C)=O)c(=O)c2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCSc1nn(C)c2ccc(Cl)cc2c1=O
Reaction time: 8 h

Procedure:
A mixture of 8 g of 6-chloro-1-methyl-3-(methylsulfinyl)-4(1H) cinnolinone and 30 ml of acetic anhydride was refluxed for 21/2 hrs. The resulting solution was allowed to stand at room temperature overnight. The crystalline precipitate was filtered off, washed with Skelly B, and recrystallized from CH3CN, mp. 191°-92°; yield 6 g (65%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH2:15]([SH:17])[CH3:16].C(N(CC)CC)C>O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([S:17][CH2:15][CH3:16])[C:10]=2[CH:11]=1
Reactant: CCS
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC1=CCC(C)(C)c2ccc(Br)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 1.03 g (4.1 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2 H)-one (Compound G) in 30.0 mL of tetrahydrofuran, was added dropwise 0.49 g (0.85 mL, 7.8 mmol) of titaniumtetrachloride and the resulting solution stirred for 10 min. A solution of 35 mg (0.50 mL, 6.7 mmol) of ethanethiol and 0.54 g (0.75 mL, 5.4 mmol) of triethylamine in 10.0 mL of tetrahydrofuran was added and the reaction stirred at room temperature for 13 h. The mixture was diluted with water and extracted with ether (2×). The organic phase was washed with brine, dried over Na2SO4 and then concentrated in vacuo. Purification by flash chromatography (silica, 100% hexane) gave the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][CH:31]1[CH2:34][NH:33][CH2:32]1.O(C(C)(C)C)[Na].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[F:1][C:2]1[CH:7]=[C:6]([N:33]2[CH2:34][CH:31]([F:30])[CH2:32]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1CNC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CC(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 40.4 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3-fluoroazetidine hydrochloride (66.9 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 13 h under N2. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (88 mg, 40% yield) as a pale yellow solid: mp 162-163° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 3.86-4.04 (2H, m), 4.12-4.29 (2H, m), 5.36-5.64 (1H, m), 6.25 (1H, dd, J=8.5, 2.1 Hz), 6.48 (1H, dd, J=12.8, 2.3 Hz), 6.81-6.95 (2H, m), 7.25-7.48 (5H, m), 7.77 (1H, d, J=1.9 Hz), 8.36 (1H, d, J=1.9 Hz). Anal. Calcd for C23H19F2N5O2: C, 63.44: H, 4.40: N, 16.08. Found: C, 63.62: H, 4.44: N, 15.92.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(Cl)Cl>[Cl:39][CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSc1nccc(C(O)c2cccc(C#N)c2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1nccc(C(Cl)c2cccc(C#N)c2)n1
Reaction time: 4 h

Procedure:
To the solution of 3-{hydroxy[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile (1.65 g, 6.41 mmol) in CCl4 (10 mL) and CH2Cl2(10 mL) was added triphenylphophine (2.36 g, 8.98 mmol) and stirred for 4 h. The mixture was concentrated and the residue was purified by silica gel chromatography (20% EtOAc in hexane) to give 3-{chloro[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=5.1), 7.79 (s, 1H), 7.70 (d, 1H, J=8.1), 7.62 (d, 1H, J=7.8), 7.49 (t, 1H, J=7.8), 7.25 (d, 1H, J=4.9), 5.92 (s, 1H), 2.51 (s, 3H). LRMS m/z (M+H) Calcd: 276.8, found: 276.0.
Reaction SMILES: [CH:1]([C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:27](=[O:29])[NH2:28])[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([CH2:22][C:23](O)=[O:24])[C:6]1=[O:26])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:1]([C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:27](=[O:29])[NH2:28])[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([CH2:22][C:23]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:24])[C:6]1=[O:26])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)O)N=C(c3ccccc3)c3ccccc32)cc1
Reactant: Nc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)Nc3ccccc3)N=C(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
According to Process F, a mixture of {1-[Isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl}-acetic acid (200 mg, 0.400 mmol), prepared as in Intermediate 29, aniline (0.033 mL, 0.356 mmol), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (167 mg, 0.356 mmol) in anhydrous DCM (3 mL) is treated with diisopropylethylamine (0.170 mL, 0.978 mmol) and stirred at ambient temperature under nitrogen. After 1.5 hrs., the solvent is removed in vacuo and the residue is purified by chromatography on flash grade silica gel using 60% ethyl acetate in n-hexane. Fractions containing the product are combined, concentrated in vacuo and triturated with n-hexane. After removing the solvent in vacuo, the product is dried overnight at ambient temperature under high vacuum to provide the title compound (123 mg, 0.214 mmol) as a white solid. The product is lyophilized from acetonitrile/water. 1H NMR (300 MHz, d6-DMSO) δ=0.86-0.96 (m, 6H); 3.14 (d, J=6.9 Hz, 2H); 3.77 (S, 3H); 4.03-6.12 (M, 2H); 4.23 (D, J=16.8 HZ, 1H); 4.59-6.73 (M, 1H); 6.97-7.08 (M, 3H); 7.15-7.32 (M, 6H); 7.36-7.66 (M, 9H); 10.15 (S, 1H). MS (FAB): [M+H]+ =575.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:15][O:16][C:17]1[CH:57]=[CH:56][C:20]([CH2:21][N:22]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]3[C:31]([NH:38][C:39]4[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=4)=[N:32][CH:33]=[C:34]([CH:37]=3)[CH:35]=[O:36])[N:24]=2)=[CH:19][CH:18]=1>>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:57][CH:56]=2)[C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]3[CH:37]=[C:34]([CH:35]([OH:36])[C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:14])[CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=4)[CH:33]=[N:32][C:31]=3[NH:38][C:39]3[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[N:24]=2)=[CH:53][CH:52]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CN(C)S(=O)(=O)c1ccc([Mg]Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 16 h
Yield: 73.8 %

Procedure:
(4-(N,N-Dimethylsulfamoyl)phenyl)magnesium bromide (0.48 M in THF) (2545 μL, 1.222 mmol) was added to 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (176.4 mg, 0.305 mmol) to give a deep orange solution. The solution was stirred for 16 h and then quenched with MeOH (1.0 mL). The product was extracted into DCM from water, dried (MgSO4), and purified by flash chromatography (0 to 10% to 20% to 30% EtOAc/DCM) to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (171.5 mg, 0.225 mmol, 73.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.51 (s, 1H); 8.74 (s, 1H); 8.30 (dd, J=4.11, 2.54 Hz, 2H); 7.85 (d, J=2.35 Hz, 1H); 7.55-7.72 (m, 4H); 7.26 (d, J=8.22 Hz, 2H); 7.19 (d, J=8.41 Hz, 2H); 6.90 (d, J=8.41 Hz, 2H); 6.83 (d, J=8.61 Hz, 2H); 6.74 (d, J=9.00 Hz, 1H); 6.19 (d, J=3.91 Hz, 1H); 5.86 (d, J=4.11 Hz, 1H); 4.68-4.91 (m, 4H); 3.82 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.56 (s, 6H); 2.54 (s, 3H). m/z (ESI, +ve ion) 763.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]([O:18][CH3:19])=[O:17])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:26]([C:25]3[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][C:24]=3[CH3:29])[CH2:14][CH2:13][CH2:12][N:7]21
Reactant: COc1ccc(N)c(C)c1
Reactant: COC(=O)c1ccc(Br)c2nc(Cl)n(CCCCl)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(OC)cc1C
Temperature: 120 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A mixture of methyl 4-bromo-2-chloro-1-(3-chloropropyl)-1H-benzimidazole-7-carboxylate (429 mg, 1.17 mmol), 4-methoxy-2-methylaniline (0.301 mL, 2.34 mmol) and p-toluenesulfonic acid monohydrate (0.0223, 0.117 mmol) in o-xylene (2.4 mL) was stirred at 120° C. for 3 days, and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown solid (301 mg, 0.700 mmol, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[H-].[Na+].[CH3:26]I.Cl>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:26])[C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1
Reactant: CI
Reactant: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Reaction time: 0.5 h

Procedure:
A mixture of 0.254 g (0.65 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one from Example 429, and 50.0 mg (1.25 mmol) of 60% sodium hydride dispersion in mineral oil in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide was stirred for 20 min. 0.062 ml (1.00 mmol) of methyl iodide was added in one portion to the above mixture. The mixture was stirred for 30 min and poured into 10 ml of 1 N aq hydrochloric acid. The mixture was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over manesium sulfate and concentrated in vacuum. The residue was triturated with hexane and the resulting precipitate was filtered and washed with hexane. Yield 260 mg (98%). MS (ESI+): 408.1
Reaction SMILES: [N:1]1[C:6]2[C:7](=[O:11])O[C:9](=[O:10])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C1COCC1>[OH:11][C:7]1[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9](=[O:10])[NH:12][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C1OC(=O)c2ncccc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(=O)c2cccnc2c1O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared as described in M. Suzuki et.al., Synthetic Communications, 1978, pg. 461. To a solution of furo[3,4]pyridine-5,7-dione (130 g, 872 mmol) in anhydrous DMF (250 ml) was added 1 liter of dry THF and methyl isocyanoacetate (86.4 g, 872 mmol). This was stirred for 15 minutes at 40° C. under nitrogen, followed by dropwise addition of DBU (132.8 g, 130.4 ml, 872 mmol) which was dissolved in THF (300 ml). After one hour the solvent was removed under reduced pressure and the resultant crude 2-[4-(methoxycarbonyl)-1,3-oxazol-5-yl]nicotinic acid and regioisomeric 3-[4-(methoxycarbonyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid products were taken up into MeOH (1 liter). Concentrated HCl (12 M, 291 ml) was then added dropwise while the solution stirred at 55° C. This was stirred for 0.5 hours at which time the crude solids were collected by vacuum filtration. The desired regioisomer was purified by successive recrystallizations in methanol. This provided pure yellow solids. TLC (silica, 90:10:3, dichloromethane, methanol, acetic acid), R f (desired regioisomer)=0.23, R f (undesired regioisomer)=0.62.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(F)cc2)n1
Yield: 36 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol), using 4-fluorobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (22 mg, 36%) which was obtained as a yellow gum. MS: m/e=485.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH3:2]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 5 by alkaline saponification of ethyl 3-[-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionate and subsequent purification by column chromatography (chloroform/methanol=9/1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:20][C:19]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:18]=3[O:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:25][C:22]1[CH:23]=[CH:24][C:18]2[O:17][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:20][C:19]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1Cc2cc(F)ccc2O1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 100 ml round-bottomed flask was added 4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.8 g, 5.1 mmol), 50 ml of dichloromethane, and 2 ml of trifluoroacetic acid. The solution was stirred at room temperature overnight. The solution was made basic with the addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with 4×50 ml of dichloromethane. The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 1.2 grams of the desired amine as a brown oil (94%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:8]([F:18])[CH:7]=2)[CH2:2]1.[C:19]1([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:8]1[CH:7]=[C:6]([CH:17]=[CH:16][C:9]=1[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[O:5][CH:3]1[CH2:4][N:1]([C:30]([C:28]2[O:29][C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:26][N:27]=2)=[O:31])[CH2:2]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: Fc1cc(OC2CNC2)ccc1CN1CCCC1
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC3)c(F)c2)C1
Yield: 69.9 %

Procedure:
Using a similar protocol as described in Example 16 employing 31C (0.11 g, 0.44 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.10 g, 0.48 mmol) as starting materials afforded 130 mg (71%) of 31 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.80 (s, 4H), 2.50 (s, 4H), 3.65 (s, 2H), 4.30 (m, 1H), 4.65 (m, 1H), 4.75 (m, 1H), 5.05 (m, 1H), 5.15 (m, 1H), 6.50 (m, 2H), 7.30 (t, 1H), 7.55 (m, 3H), 8.20 (d, 2H), MS (APCI+) m/z 423 [M+H]+, LC purity: 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.S(Cl)([Cl:30])(=O)=O>ClCCl>[Cl:30][C:13]1[C:14](=[O:16])[O:15][C:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([O:25][CH3:26])=[CH:4][C:5]=2[O:23][CH3:24])([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][C:12]=1[OH:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: ClCCl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by chlorination of 6-[2-(5-chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from step 6 of example B(15) with sulfuryl chloride in dichloromethane at room temperature. 1H NMR (CDCl3) δ 1.51 (m, 8H), 1.79 (m, 1H), 2.06, (m, 2H), 2.45 (m, 2H), 2.60 (m, 1H), 2.67 (d, J=17.75, 1H), 2.92 (d, J=17.75, 1H), 3.82 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 7.06 (s, 1H). HRMS calcd for C20H24O5Cl2 (M+H+) 415.1079, found 415.1063.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (10.0 g, 45.5 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.6 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (15.8 mL, 49.6 mmol) and 2-benzyl-4,5-dimethyl-furan (10.1 g, 54.3 mmol) in CH2Cl2 to give 18.8 g (crude) of the title compound. 1H NMR (DMSO-d6) consistent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[Cl:12][CH2:13][C:14](Cl)=[O:15].Cl>C(OCC)(=O)C>[Cl:12][CH2:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCNC(=O)CCl
Reaction time: 0.5 h

Procedure:
20 g (153 mMol) 6-Amino-hexanoic acid was mixed with 80 ml of 2N Sodium Hydroxide (NaOH). 18 ml (221 mMol) of Chloro-acetylchloride and 6N NaOH were added to the mixture at Room Temperature (RT). The pH of the reaction mixture was maintained between 10 and 11 during the addition of Chloro-acetylchloride and 6N NaOH by using a burette to control the addition. The mixture was stirred for 30 mins at this constant pH. Ethyl acetate (EtOAc) was then added to the reaction mixture and the pH was adjusted to 2 with 2N Hydrochloric Acid (HCl). To work up the product, the EtOAc-layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were dried and the solvent was evaporated. The residue was then re-crystallized from diisopropylether/EtOAc (1:1, v:v).