Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)=O.C(N(CC)CC)C.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[C:29]([C:38]1C=CC(O)=C[CH:39]=1)([C:32]1C=CC=[CH:34][CH:33]=1)(C)C>O.C(Cl)Cl>[C:19]1([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)([C:16]2[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=2)[C:21]2[C:33](=[CH:32][CH:29]=[CH:38][CH:39]=2)[CH2:34][CH2:20]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(C2(c3ccc(O)cc3)CCc3ccccc32)cc1

Procedure:
A solution of 4,4′-(2,3-dihydro-1H-indene-1,1-diyl)diphenol (“IBP”) was prepared by dissolving 8.33 g (0.0275 moles) of IBP monomer (prepared according to Example 9) in 33% aqueous caustic (15 g) and water (30 ml). To a 2 L glass reactor equipped with a pH probe, condenser, agitator, phosgene inlet, and caustic scrubber was added methylene chloride (500 ml), deionized water (140 ml), triethylamine (0.17 ml, 0.0012 moles), bisphenol-A (7.67 g, 0.0337 moles), p-cumylphenol (0.39 g, 0.0018 moles), and IBP solution. The batch was phosgenated in excess at a rate of 2 grams per min for 4 minutes, maintaining the pH between 9 and 10 with concomitant caustic addition (33% w/w). At the completion of the phosgenation, the reactor was purged with nitrogen to remove excess phosgene and the reaction mixture extracted with dilute acid (1N HCl) and deionized water. The final product IBP-BPA Copolymer (PL-11-058) was isolated as a white powder by exposing the polymer solution (in methylene chloride) to hot water, evaporating the solvent and providing a white powder. Characterization data for the IBP-BPA Copolymer (PL-11-058) is provided in Table 1, shown below.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][N:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=[N:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pt]=O.CO>[NH2:11][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:10]1
Reactant: C1=CC2=Nc3ccccc3CCN2C=C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccccc1CCN1CCCCC1
Yield: 105.7 %

Procedure:
Platinum oxide catalyst (1.0 g) is added to a solution of 11,12-dihydropyrido[2,1-b][1,3]benzodiazepine (20.0 g) in methanol (550 ml). Hydrogen gas (about 50 psig) is added and hydrogen uptake is completed in about 1 and 2 hours. The catalyst is filtered off, and the filtrate is concentrated to yield 22.0 g of material that crystallizes spontaneously, melting point 36°-38° C. Recrystallization from 150 ml of pentane yields 16.0 g of the title compound, melting point 39°-41° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1.[C-:27]#[N:28].[Na+]>>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1)#[N:28]
Reactant: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Yield: 74.4 %

Procedure:
1-(8-Bromooctyl)-4,5-diphenyltriazole (ex. example 60a) (1.8 g) was reacted with sodium cyanide in a method similar to Example 60b). Work-up and recrystallisation from dichloromethane and hexane gave 1-(8-cyanooctyl)-4,5-diphenyltriazole (1.16 g, 74.4%) as a white solid, m.p. 77-8° C. Found: C, 77.03; H, 7.25; N, 15.35%; C23H26N4 requires: C, 77.06; H, 7.31; N, 15.63%.
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:14])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])(=[O:4])[CH:2]=[CH2:3].[CH2:15](O)[CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O.[C:25](OCCCC)(=O)C>>[CH2:15]([O:14][CH:6]([NH:5][C:1](=[O:4])[C:2]([CH3:25])=[CH2:3])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCO
Reactant: CCCCOC(C)=O
Reactant: C=CC(=O)NC(O)C(=O)OCCCC
Agent: O=S(=O)(O)O
Product: C=C(C)C(=O)NC(OCCCC)C(=O)OCCCC

Procedure:
The reaction product of Example VI was employed. Butanol 130 parts, butyl acetate 130 parts, and concentrated sulfuric acid 3.0 parts were added and the water removed by azeotropic distillation under reduced pressure. An air sparge was used to help prevent premature polymerization. Butanol and butyl acetate were then distilled to yield butyl methacryl amidoglycolate butyl ether.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[C:3]=1[OH:12].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].O>N1C=CC=CC=1>[CH:15]1([C:13]2[O:12][C:3]3[C:4]([I:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH:14]=2)[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: O=[N+]([O-])c1cc(I)c(O)c(I)c1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu2O (1.9 mg, 13.2 mmol) in 100 mL of dry pyridine was refluxed for 2 h. The reaction mixture was poured into 1 L of water and stirred for 10 min. The resulting mixture was filtered. The cake was purified by column chromatography on silica gel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>S(Cl)(Cl)=O.O>[CH2:1]([O:11][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCCC/C=C/COC(=O)/C=C/CCCCCCC

Procedure:
Trans-2-decenoic acid was dissolved in thionyl chloride (10 ml) and treated in water bath for 3 hours to distill off excess thionyl chloride. Trans-2-decen-1-ol (30 ml) was added to chloride of trans-2-decenoic acid and refluxed in water bath for 2 hours. After cooling, the reaction mixture was added to 1N HCl (80 ml) to be acidic and distributed with EtOAc. The distributed liquid was purified with column chromatography (developing solvent: C6H14-EtOAc (3:1)) after concentration, and trans-2-decenoic acid-trans-2-decenyl ester shown in the following was isolated.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1)=[O:24])[CH2:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(NCC)C>CN(C)C=O>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:30][CH:29]=1)=[O:24])[CH2:17][O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C

Procedure:
93.0 g (about 102 mmol) of Fmoc-D-Trp-Ser(tBu)-Tyr(tBu)-OtBu are dissolved in 500 ml of dimethylformamide. 114.5 ml of diethylamine are added to this while stirring, reaction is allowed to take place at room temperature for 10 minutes, and the mixture is concentrated under high vacuum. The residue is triturated 3 times with petroleum ether and twice with diethyl ether. The diethyl ether is removed by distillation and then partition between ethyl acetate and water is carried out. The ethyl acetate is, after drying over Na2SO4, removed by distillation, and the residue is triturated twice with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22](COCC[Si](C)(C)C)[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(CO)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(CO)ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
194 mg of 4-{[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 25 ml of DCM. After cooling to 0° C. using an ice bath, 1.9 ml of TFA are added and the mixture is stirred at RT for 2 h 30 min. It is concentrated under RP and the solid obtained is taken up in 50 ml of water, neutralized with 2.5 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/NH4OH mixture (90/10/1 by volume). This gives 28 mg of 4-{[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide. 1H NMR: 1.60-1.73 (m, 2 H) 2.05-2.16 (m, 2 H) 2.62-2.73 (m, 2 H) 3.46 (d, J=11.2 Hz, 2 H) 3.64-3.76 (m, 1 H) 4.63 (d, J=5.4 Hz, 2 H) 5.34 (t, J=5.9 Hz, 1 H) 5.75 (s, 1 H) 5.91 (d, 1 H) 6.70 (s, 2 H) 7.32 (t, 2 H) 7.59 (s, 1 H) 7.61-7.71 (m, 1 H) 7.84 (dd, 1 H) 8.35 (d, J=8.3 Hz, 1 H) 12.66 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12].CC([O-])=O.[Na+].O>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[C:11]([NH:14][C:15](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=Cc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 20.0 g (112 mmol) 3,4-dichlorobenzaldehyde, 19.7 g (168 mmol) N-acetylglycine and 13.8 g (168 mmol) NaOAc in 80 mL acetic anhydride were heated to 120° C. (oil bath temperature) for 5 h. After the reaction had ended the reaction mixture was cooled using an ice bath and then combined slowly with 60 mL water (slightly exothermic reaction). The reaction mixture was heated to 80° C. for a further 1.5 h, cooled somewhat, then added to a mixture of 400 mL water and 200 mL toluene and stirred overnight at RT. The precipitate was suction filtered, washed with toluene and water, then combined with diethyl ether and suction filtered.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CO.CCOCC.O>[C:18]([Si:22]([CH3:25])([CH3:24])[O:10][CH:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCCc2occc21
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2occc21
Yield: 77 %

Procedure:
To a solution of 6,7-dihydro-4-(5H)-benzofuranone (5.0 g, 37 mmol) in methanol (50 ml) was added sodium borohydride (1.4 g, 37 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water (40 ml), and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethylformamide (30 ml) were added successively imidazole (4.0 g, 59 mmol) and t-butyldimethylchlorosilane (4.9 g, 32 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 3:97) as the eluent to afford the title compound (7.2 g) in a yield of 77% as a colourless oily product.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:2]([C:7]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[CH:21][NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[S:38]([OH:41])(=[O:40])=[O:39]>C(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:2]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[C:21]([S:38]([OH:41])(=[O:40])=[O:39])[NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:29][CH:30]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3c[nH]c4cccc2c34)cc1)c1ccccc1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCc3c(S(=O)(=O)O)[nH]c4cccc2c34)cc1)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 10 (0.20 g, 0.42 mmol) in CH2Cl2 (100 mL) at about 0° C. was treated with chlorosulfonic acid (0.056 g, 1.1 eq) and stirred for about 2 h. The reaction was Warmed to about rt, stirred for about 18 h and evaporated to a tan powder. The powder was purified by preparative HPLC (MeCN:water, 1:3) to give 18 (tan powder). 1H NMR (DMSO-d6) 2.1 (m, 4 H), 3.0 (m, 1 H), 3.2 (t, J=4, 1 H), 6.1 (m, 1 H), 6.7 (t, J=6, 1 H), 6.9 (d, J=5, 1 H), 7.1 (m, 4 H), 7.3-7.6 (m, 9 H), 10.3 (br. s, 2 H), 11.1 (s, 1 H). MS m/e 552.62 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.[I-].[Na+].C(#N)C.C(=O)(O)[O-].[Na+]>>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:26][C:25]4[CH:27]=[CH:28][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:23][CH:24]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 59.6 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.103 g, 0.000366 mol), 4-(trifluoromethoxy)aniline (0.0983 mL, 0.000733 mol) and sodium iodide (0.020 g, 0.00013 mol) in Acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 180° C. for 15 minutes. After cooling to room temperature, the mixture was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.092 g of an off-white solid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[CH:18]=[N:17]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:15][N:16]1[C:20]([C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:19]([CH3:30])[CH:18]=[N:17]1
Reactant: CCOC(=O)c1c(Br)cccc1OC
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: COCCOC
Product: CCOC(=O)c1c(OC)cccc1-c1c(C)cnn1C
Temperature: 100 °C
Yield: 95.2 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (402 mg, 95%). MS (ESI) mass calcd. for C15H18N2O3, 274.1; m/z found 275.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd, J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC1C=C(Br)C=C(F)C=1)C1C=CC=CC=1.[Mg]>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:4]2([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]2[O:2][CH3:1])[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC1CCCC1=O
Reactant: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Agent: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COC1CCCC1(O)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
After repetition of the above reaction, a solution of 2-methoxycyclopentanone (12.5 g) in tetrahydrofuran (10 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxy-5-fluorobromobenzene (31 g), magnesium powder (2.65 g) and tetrahydrofuran (20 ml) to 40° C. for 2 hours] and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and rarer, The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained, as a mixture of diastereoisomers, 1-(3-benzyloxy-5-fluorophenyl)-2-methoxycyclopentanol (21.7 g, 62%), as an oil.
Reaction SMILES: [NH2:1][OH:2].[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21]#[N:22])=[CH:5]/[CH3:6].CC1SC=C(C)C=1C1N(C2C=CC(O)=CC=2F)N=C(C)C=1C#N>CO>[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21](=[N:1][OH:2])[NH2:22])=[CH:5]/[CH3:6]
Reactant: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Reactant: NO
Agent: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: C/C=C(/C)c1c(C(N)=NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Yield: 47 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.5 mL, 8.11 mmol) was added to (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (22 mg, 0.08 mmol) dissolved in MeOH (1.0 mL) or Hydroxylamine (50 wt % solution in water, 0.24 mL, 3.97 mmol) was added to 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 0.04 mmol) dissolved in MeOH (0.8 mL). The reaction was heated at 150° C. in the microwave for 15 min. Purification using preparative HPLC gave 5-((Z)-but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E51) (11.44 mg, 46%), ES/MS m/z: 305.08 (M+H), 303.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.22 (m, 1H), 6.76-6.71 (m, 2II), 5.65 (m, 1H), 2.30 (s, 3H), 1.83 (s, 3H) and 1.39 (d, 3H, J=6.7 Hz) or 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E52) (4.31 mg, 30%) ES/MS m/z: 361.05 (M+H), 359.17 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.14 (t, 1H, J=8.8 Hz), 6.83 (q, 1H, J=1.0 Hz), 6.66 (m, 1H), 6.61 (dd, 1H, J=11.9, 2.7 Hz), 2.38 (s, 3H), 2.16 (s, 3H) and 1.94 (d, 3H, J=1.0 Hz).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Na+].[I-]>C1COCC1>[C:48]([O:47][C:45](=[O:46])[CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2nccc(CCN(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)CC(=O)OC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), tert-butyl bromoacetate (0.129 g, 1.5 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 67% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.C(=O)(O)[O-].[Na+].O>C(O)(=O)C.CO>[CH3:23][C:20]1[CH:19]=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH2:13][CH:14]=2)[O:22][N:21]=1
Reactant: Cc1cc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)on1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C2=CCN(CCCC(=O)c3ccc(F)cc3)CC2)on1
Reaction time: 3 h

Procedure:
A 1.65 g. portion of 3,6-dihydro-α-(p-fluorophenyl)- 4-(3-methyl-5-isoxazolyl)-1(2H)-pyridine butanol, prepared as described in Example 10, in 35 ml. of acetic acid is stirred at room temperature. A 30 ml. portion of chromic acid in acetic acid (prepared by dissolving 1.1 gm. of chromium oxide in 50 ml. of acetic acid and 10 ml. of water) is added dropwise and the mixture is stirred for 3 hours and then allowed to stand overnight. A few drops of methanol are added and sufficient solid sodium bicarbonate to neutralize the solution. Water is also added. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated yielding a pink solid which is recrystallized twice from methanol, m.p. 96°-98° C.