Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][C:3]=1[F:30].[C:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[C:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[N:11]=[C:10]([C:20]([C:22]([F:25])([F:24])[F:23])([C:26]([F:29])([F:28])[F:27])[OH:21])[CH2:9]3)=[CH:4][C:3]=2[F:30])[CH:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1)(C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
5-(4-bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (30.0 mg, 0.056 mmol) prepared in Step 5 of Preparation 21, 3-acetylphenylboronic acid (10.4 mg, 0.064 mmol), Pd(PPh3)4 (6.7 mg, 0.006 mmol), and a 2N sodium carbonate solution (145.0 uL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 3 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.O.[C:14](OCC)(=O)C>CO.Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][CH:5]=1
Reactant: COCc1ccc(C(=O)O)cc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COCc1ccc(C(=O)OC)cc1
Reaction time: 2.5 h

Procedure:
Methyl 4-(methoxymethyl)benzenecarboxylate (MMBC) was prepared from 4-(methoxymethyl)benzoic acid (Sigma-Aldrich) by esterification in methanol using HCl as catalyst. The reaction was conducted under reflux conditions for 2.5 hours. Following the reaction, water and ethyl acetate was added and the MMBC product was separated using liquid extraction into the ethyl acetate phase. The ethyl acetate was then removed by rotary evaporation to obtain the isolated MMBC product. The 1H NMR spectrum of the product was collected in CDCl3, and the peak positions and integrated areas matched that of the reported 1H NMR spectrum for this molecule.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[O:23])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:41]>CO>[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:29]2[CH:30]=[C:31]([C:35]([NH2:41])=[NH:36])[CH:32]=[CH:33][CH:34]=2)=[O:23])=[CH:19][CH:20]=1)(=[O:8])(=[O:7])[NH2:5]
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2=C(c3cccc(C#N)c3)CCC2)cc1
Agent: CC(=O)[O-]
Solvent: CO
Product: N=C(N)c1cccc(C2=C(C(=O)Nc3ccc(-c4ccccc4S(N)(=O)=O)cc3)CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3-cyanophenyl)cyclopent-1-enyl]carboxamide (70 mg, 0.137 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-(2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}cyclopent-1-enyl)benzenecarboxamidine (40 mg, 63%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 461.15
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 80.7 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (573 mg) described in Reference Example 6, 555 mg of the title compound was afforded (yield 80.1%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[N:24]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
36 mg (0.90 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 173 mg (0.75 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 214 mg (0.75 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to yield 227 mg (63%) of the title compound as white crystals.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ncc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ncc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methanol (389 mg, 1.93 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.35 mL, 2.50 mmol) followed by DMAP (24 mg, 0.19 mmol) and Ms-Cl (0.19 mL, 2.40 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC (1:1->1:2 hept-EA+1% Et3N) gave pure (2-(2-methyl-[1,3]dioxolan-2-yl)thiazol-5-yl)methyl methanesulfonate as a pale yellow oil. Part of this material (140 mg, 0.50 mmol) was dissolved in dry DMF (1 mL) and treated with NaN3 (35 mg, 0.53 mmol) at 80° C. for 1 h30. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)thiazole as a brown oil. LC-MS-conditions 01: tR=0.80 min; [M+H]+=226.96.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=2)[CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (210 mg, 0.77 mmol) [prepared according to the procedure of Example 188], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (294 mg, 0.764 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (442 mg, 0.94 mmol) in chloroform (7.6 mL). DIEA (670 μL, 3.84 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])OC)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(F)(F)F.[CH3:29]COCC.C[Zn]C.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])[CH3:29])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOCC
Reactant: CCOc1ccc(F)c(Cl)c1C(OC)c1c[nH]c2ncc(Br)cc12
Agent: C[Zn]C
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 5-Bromo-3-[(2-chloro-6-ethoxy-3-fluorophenyl)-methoxymethyl]-1H-pyrrolo[2,3-b]pyridine (3.0 g, 7.2 mmol) in THF (30 mL) was added BF3.OEt2 (7.1 mL, 56.3 mmol). The reaction mixture was stirred for 1 h, and 2M solution of dimethylzinc in toluene (28 mL, 56 mmol) was added dropwise. The reaction mixture was stirred for 12 h at 50° C. and was quenched with saturate aq. ammonium chloride. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to give a yellowish residue. The residue was adsorbed on silica and purified (100% DCM→5% methanol/DCM) by small pad of silica. The resulting solid was recrystallized with diisopropyl ether to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7.0 Hz), 1.79 (d, 3H, J=7.0 Hz), 3.74 (bs, 1H), 3.96 (q, 1H, J=7.0 Hz), 5.05 (q, 1H, J=7.0 Hz), 6.66-6.69 (m, 1H), 6.97 (t, 1H, J=9.0 Hz), 7.69 (s, 1H), 8.25 (s, 1H), 9.24 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([OH:16])=[O:15])([CH3:10])([CH3:9])[CH3:8].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>C(N(CC)CC)C>[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([O:16][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])=[O:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCN(O)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)OC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 43.2 %

Procedure:
Following the procedure of Example II, the compound is prepared from 3.17 g of oxalyl chloride, 6.25 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 2.53 g of N,N-diethylhydroxylamine, and 2.53 g of triethylamine. The residue is recrystallized from petroleum ether to give 3.47 g of a white solid: mp 129°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18]CC4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][Cl:28])[C:9]2=[O:29])=[CH:4][CH:3]=1.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][Cl:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: O=C1C(CCCl)C(c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CO
Product: O=C1C(CCCl)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A stirring mixture of 1-(4-fluorophenyl)-3-(2-chloroethyl)-4-[4-(benzyloxy)phenyl]azetidin-2-one (prepared according to Bioorg. Med. Chem. Lett. 1996, 6, 1271-1274; 2.00 g, 4.88 mmol), Pd(OH)2/C (0.500 g, 20%) and cyclohexene (6 ml) in MeOH (60 ml) was heated to 70° C. After 2 hours, the reaction mixture was cooled to room temperature and was filtered through diatomaceous earth. The solvent was removed under reduced pressure to give the title compound (1.57 g; -quantitative yield). No further purification was necessary. NMR (CD3OD, 400 MHz) 2.20-2.40 (m, 2H), 3.20-3.40 (m, 1H), 3.70 (t, 2H), 4.85 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.00 (m, 2H), 7.15-7.30 (m, 4H); m/z: 320.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)([CH3:44])[CH3:43]>>[CH:42]([C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]2[C:16]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=2)=[CH:47][CH:46]=1)([CH3:44])[CH3:43]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccc(N)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccc(C(C)C)cc1

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy )-2-morpholino-4-pyrimidinyloxy]propionic acid and 4-isopropylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C[O-].[Na+].[Cl-:12].[NH4+:13]>CO>[ClH:12].[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:13])=[NH:8])=[CH:3][CH:2]=1
Reactant: N#Cc1ccncc1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1ccncc1
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A solution of 4-pyridinecarbonitrile (370 g, 3.55 mol) and sodium methoxide (20.0 g, 0.37 mol) in methanol (1.7 l) was stirred at room temperature for 1.5 hours, then ammonium chloride (200 g, 3.7 mol) was added. The reaction mixture was stirred for 24 hours, the resulting solid was collected by filtration and the filtrate was evaporated to dryness. The two crops were combined and recrystallized from water to afford 394 g (70%) of 4-pyridinecarboxamidine hydrochloride, m.p. 250°-252° C. (dec.).
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.FC(F)(F)S(O[C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([CH3:55])[CH:49]=1)(=O)=O>>[ClH:27].[ClH:27].[CH3:55][C:50]1[CH:49]=[C:48]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH:53]=[C:52]([CH3:54])[N:51]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)n1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (12) (25 mg, 42 μmol) and 2,6-dimethylpyridin-4-yl trifluoromethanesulphonate (91) (8.8 mg, 40 μmol) in accordance with Method L2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12]C2CCCCO2)=[CH:10][CH:9]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)Cl>[C:8]1([CH:20]=[CH:19][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:7].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1=COCCC1
Reactant: c1cc(OC2CCCCO2)ccc1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1ccc(O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C1CCOCC1
Reaction time: 12 h

Procedure:
Another functionalization substance may be 2-[2-(undec-10-enyl)-4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]tetrahydro-H-pyran. This molecule, whose structure is shown in FIG. 13, may be synthesized from 2-[4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]tetrahydro-2H-pyran using any prior art process. The intermediate may be synthesized by first adding dihydropyran (0.83 mL, 9.1 mmol) and pyridinium p-toluenesulfonate (0.11 g, 0.45 mmol) to a solution of hydroquinone (0.25 g, 2.3 mmol) in CH2Cl2 (3 mL). This reaction mixture is then stirred for about 12 hours and diluted with 10 mL of CH2Cl2. The mixture is subsequently washed by 3×5 mL of NaHCO3 and 1×5 mL brine, dried over MgSO4, and concentrated to a white solid. Silica gel chromatography (4:1 hexane/ethyl acetate) provides the di-tetrahydropyran hydroquinone as a white solid (0.48 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([O:23][C:21]([CH:20]([O:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[CH:3]=1)[CH3:26])=[O:22])[CH3:25]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Temperature: 80 °C
Yield: 181.3 %

Procedure:
A mixture of 40 g of 7-hydroxy-3-phenyl-4H-1-benzopyran-4-one, 46 g of ethyl 2-bromopropionate, 250 ml of dimethylformamide and 46.5 g of potassium carbonate was stirred well with heating at 80° C. for 2 hours and poured into 270 ml of ice water. The resulting crystalline precipitate was collected by filtration and recrystallized from ethyl acetate-ethanol to give 103 g of 7-(1-ethoxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one as white crystals. m.p. 165°-166° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.Br[CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O.C1COCC1>[Br:1][C:2]1[C:3]([O:18][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2
Reactant: O=C(O)CCBr
Reactant: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CCOc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 0 °C
Reaction time: 15 h
Yield: 141.3 %

Procedure:
THF (100 mL) was added to a mixture of 7-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (4.54 g, 14.8 mmol) (97, R1=4-Fluorophenyl) and 3-bromopropionic acid (34.0 g, 222 mmol). The mixture was cooled to about 0° C. NaOH (2 M aqueous solution, 150 mL, 300 mmol) was added over about 15 min. The ice bath was removed. After about 15 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. 3-Bromopropanoic acid (6.00 g, 39.2 mmol) was added in portions over about 5 min. After about 6 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 14 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 2 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 15 h, the solution was cooled to about 0° C. 2 M aq. HCl (250 mL) and EtOAc (400 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were washed with water (400 mL) and sat. aq. NaCl (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (220 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford a light tan solid. DCM (50 mL) was added. The solid was collected by filtration rinsing with 2×10 mL DCM (2×10 mL) then dried under reduced pressure to afford 3-((7-bromo-1-(4 fluorophenyl)-1H-indazol-6-yl)oxy)propanoic acid (98, R1=4-Fluorophenyl) (7.93 g, 30% yield) as an ivory solid. LC/MS, method 3, Rt=1.97 min, MS m/z 379 and 381 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.56-7.46 (m, 2H), 7.39-7.30 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 4.34 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:34]([C:31]3([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:32][CH2:33]3)=[O:35])[C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 46 %

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7B with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light yellow viscous oil (46%). MS ISP (m/e): 505.2/507.2 [(M+H)]+.