Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1>CO.[Ni]>[C:3]1([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][CH:6]=[C:1]([CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: N#CCc1cccc(CC#N)c1
Agent: [Ni]
Solvent: CO
Product: NCCc1cccc(CCN)c1
Reaction time: 48 h
Yield: 95.9 %

Procedure:
To a solution of 1,3-phenylenediacetonitrile (9.37 g, 60 mmol) in CH3OH (saturated with NH3, 150 mL) was added Raney-Ni (ca. 20 g, previously washed with CH3OH several times) and the mixture was hydrogenated at 45 psi on a Parr apparatus for 48 h. The reaction mixture was filtered through celite and the filtrate evaporated to give the crude product (9.45 g, 96%) as a light green oil: 1H NMR (CDCl3) δ 0.80-1.50 (br s, 4H), 2.70-2.76 (m, 4H), 2.94-2.99 (m, 4H), 7.01-7.07 (m, 3H), 7.18-7.26 (m, 1H). This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+].O>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=O)[nH]c(N)nc21

Procedure:
A solution of the compound from Step C (80 mg, 0.25 mmol) in NaOH/H2O (1.6 g/20 ml) was heated at reflux for 7 hrs., whereupon the solution was adjusted with dilute HCl to a pH of 7 and then evaporated. Chromatography of the resulting solid on silica gel with EtOAc/MeOH 8/2 afforded the product as a white solid; yield 64 mg.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[C:10]3[N:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH2:35])[CH2:28][CH2:27]1>O1CCCC1.C(Cl)(=O)OCC>[O:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH:35][C:15]([C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:18]=[C:10]3[N:11]=2)=[O:17])[CH2:30][CH2:31]1
Reactant: NCc1ccccc1N1CCOCC1
Reactant: O=C(O)c1ccn2nc(-c3ccccc3)cc2n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1N1CCOCC1)c1ccn2nc(-c3ccccc3)cc2n1
Temperature: -20 °C
Yield: 68.5 %

Procedure:
To a solution of 2-phenyl- pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (120 mg), and triethylamine (0.091 ml) in tetrahydrofuran (10 ml), ethyl chlorocarbonate (0.053 ml) was added at −40° C. It was further added with a solution of 2-morpholinobenzylamine (115 mg) in tetrahydrofuran (2 ml), and thereafter heated to −20° C. The reaction solution was distilled under a reduced pressure, and then water was added thereto, extracted with chloroform, and the organic layer was dried with magnesium sulfate. After the reduced-pressure distillation of the solvent, the residue was purified by a silica gel column chromatography, and thereafter recrystallized from acetone-diisopropyl ether to yield N-(2-morpholinophenyl)methyl 2-phenyl-pyrazolo-[1,5-a]-pyrimidine-5-amide (142 mg, 69%). mp: 190-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH2:13][N+:14]([O-])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C>O1CCCC1.[Zn]>[NH2:14][CH2:13][CH:12]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: N#Cc1cccc(C(C[N+](=O)[O-])C2(c3ccc(Cl)cc3)CCC2)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(C(CN)C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-{1-[1-(4-Chlorophenyl)cyclobutyl]-2-nitroethyl}benzonitrile (3.0 g, 8.8 mmol) was dissolved in tetrahydrofuran (37 ml) and zinc dust (8.63 g, 132 mmol) was added followed by acetic acid (7.34 ml, 8.8 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through celite and diluted with ethyl acetate. The solution was washed with aqueous sodium bicarbonate (two times), dried (magnesium sulfate) and concentrated in vacuo. Yield: 2.41 g (7.75 mmol, 88%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][C:10]=3[CH:9](OC)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(F)(F)F.CCOCC.[Br-].[CH2:34]([O:36][C:37](=[O:41])[CH2:38][CH2:39][Zn+])[CH3:35].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([CH2:17][S:18]([NH2:21])(=[O:19])=[O:20])=[CH:16][C:10]=3[CH:9]([CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:41])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC[Zn+]
Reactant: COc1cccc2c1-c1ccc(CS(N)(=O)=O)cc1C(OC)O2
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCC1Oc2cccc(OC)c2-c2ccc(CS(N)(=O)=O)cc21
Temperature: -10 °C

Procedure:
A solution of the compound of Example 46A (33 mg, 0.1 mmol) in dichloromethane (10 mL) at −15° C. was treated dropwise with boron trifluoride etherate (38 μL, 0.3 mmol) and 3-ethoxy-3-oxopropylzinc bromide (660 μL, 0.33 mmol), warmed to −10° C. for 15 minutes and treated with saturated NaHCO3 (4 mL) to provide two layers. The layers were separated, and the aqueous layer was extracted with dichloromethane. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by high throughput HPLC (0.1% TFA/MeCN gradient) to provide the desired product. MS (ESI(−)Q1MS) m/z 404 (M−H)−; 1H NMR (500 MHz, CD3OD) δ1.23 (t, 3H, J=7.2 Hz), 1.99 (m, 1H), 2.09 (m, 1H), 2.49 (m, 2H), 2.99 (s, 3H), 3.92 (s, 3H), 4.10 (q, 2H, J=7.2 Hz), 5.04 (dd, 1H, J=9.4, 4.7 Hz), 6.59 (dd, 1H, J=8.1, 1.2 Hz), 6.72 (dd, 1H, J=8.5, 1.0 Hz), 7.08 (d, 1H, J=2.5 Hz), 7.15 (t, 1H, J=8.3 Hz), 7.20 (dd, 1H, J=8.8, 2.5 Hz), 8.36 (d, 1H, J=8.8 Hz).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:36])([F:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][C:29]([F:36])([F:35])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CCC(F)(F)F
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (53 mg, 58%), MS (ISP) m/z=455.4 [(M+H)+], mp 195.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 4,4,4-trifluoro-butanoic acid.
Reaction SMILES: CO[C:3]1[C:4]([CH2:14][C:15]#[N:16])=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BrH:17].[C:18]([OH:21])(=O)C>>[BrH:17].[CH3:18][O:21][C:7]1[C:8]([O:9][CH3:10])=[CH:3][C:4]2[CH2:14][C:15]([NH2:16])=[N:13][C:12]([Br:17])=[CH:11][C:5]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CC#N)c(CC#N)c1OC
Agent: Br
Product: COc1cc2c(cc1OC)CC(N)=NC(Br)=C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 3.7 gm (0.017 mol) of 3,4-dimethoxy-o-phenylenediacetonitrile is suspended in 10 ml of glacial acetic acid and then combined at 20° C. with 12 ml of 30% hydrobromic acid in glacial acetic acid. The mixture is stirred for a further three hours at ambient temperature, and the precipitate is subjected to suction filtration, washed with glacial acetic acid and then with acetone/ether, and dried.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][N:36]([CH3:37])[C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(N(C)C)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(N(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M197) (298 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (198 mg, 83%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:19][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[CH3:20][NH2:21]>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:19][CH:6]([C:4]([NH:21][CH3:20])=[O:3])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Temperature: 100 °C
Reaction time: 96 h
Yield: 109.2 %

Procedure:
1,2,3,4-tetrahydro-7-methoxycyclopent[b]indol-2-carboxylic acid ethyl ester (10.0 g, 0.039 mole) was added to a solution of methyl amine (6.0 g, 0.19 mole) and 40 ml of ethanol in a sealed tube. The mixture was heated to 100° C. and stirred for 96 hours. The mixture was concentrated to yield a brown solid (10.4 g), which was triturated with 50% ethyl acetate in CH2Cl2 to yield a tan solid (3.3 g). A portion (1.5 g) of this material was recrystallized from acetonitrile to yield 1.1 g of the product as a tan solid, m.p. 191°-193° C.
Reaction SMILES: C(O[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:21][O:20][C:15]1[N:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CNc1cccnc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OC)nccc2c1=O
Temperature: 60 °C
Yield: 58.7 %

Procedure:
28.5 g of ethyl 2-ethoxycarbonyl-3-(2-methoxypyridin-3-yl)aminoacrylate prepared in the above (A) was dissolved in 150 ml of diphenyl ether, and the resulting solution was heated to reflux for 1.5 hours and cooled to about 60° C. Petroleum ether was added to give precipitates, which were filtered to give 14.1 g (59%) of the titled compound as brown crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([N:11](CC)CC)C.[C-]#N.[K+]>CN(C)C=O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:11])[N:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccnc(C#N)n1
Temperature: 80 °C

Procedure:
2-Chloro-4-methylpyrimidine (0.5 g, 3.89 mmol) was dissolved in N,N-dimethyl formamide (DMF) (60.8 ml) and triethylamine (0.813 ml, 5.83 mmol) and potassium cyanide (0.507 g, 7.78 mmol) were added. The solution was sonicated till most of the potassium cyanide had gone into solution then bis(triphenylphosphine) palladium(II) chloride (0.273 g, 0.389 mmol) was added. The solution was heated to 80° C. and left to stir over the weekend. LCMS showed that the product had formed. The reaction mixture was diluted in dichloromethane and washed with saturated ammonium chloride, water and brine. The organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. This afforded a crude of 1.129 g, which was purified by flash chromatography (Biotage Isolera 4, 100 g cartridge) with a gradient of dichloromethane 0-100% in iso-hexane. The solvent was removed under reduced pressure to afford the desired product in 0.199 g.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23]Cl)[CH2:17][CH2:16]2)[CH:12]=[C:11]([C:25]([F:28])([F:27])[F:26])[N:10]=1)([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O.[Cl-].[Na+].O>[N:1]([CH2:23][CH2:22][CH2:21][N:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[C:11]([C:25]([F:27])([F:28])[F:26])[N:10]=[C:9]([C:5]([CH3:6])([CH3:8])[CH3:7])[N:14]=2)[CH2:20][CH2:19]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C(F)(F)F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCN(CCCN=[N+]=[N-])CC2)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2.4 g (36.9 mmol) of sodium azide were added to 13.5 g (36.9 mmol) of 2-tert-butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-(trifluoromethyl)pyrimidine (DE 197 35 410) in 60 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, the mixture was poured into saturated brine, and the aqueous mixture was extracted with ethyl acetate. The organic phase was washed three times with an NaCl solution, dried over Na2SO4, filtered to remove the desiccant and concentrated in vacuo. Yield: 13.7 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.F[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 32.4 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.050 g, 0.134 mmol) and (4-fluorophenyl)boronic acid (0.021 g, 0.174 mmol) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.093, 0.670 mmol) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.017 g, 0.023 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.016 g (30%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]>C1COCC1>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([Br:22])=[CH:16][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1ccccc1I
Reactant: COc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(Br)cc2)n1
Yield: 44.7 %

Procedure:
2-Bromo-6-methoxypyridine (3 g, 17 mmol) is treated as described in EXAMPLE 53, Part A with n-butyl lithium (10.6 mL of a 1.6 M solution in THF, 17 mmol) and iodobromobenzene (4.8 g, 17 mmol). The crude product is purified by chromatography (5% EtOAc/hexanes) to obtain the title compound (2 g, 7.6 mmol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(Cc2cncc(-c3ccccc3)c2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccccc1N1CCN(Cc2cncc(-c3ccccc3)c2)CC1
Reaction time: 3 h

Procedure:
A mixture of 0.6 g of 1-(2-methoxyphenyl)-4-[(5-phenyl-3-pyridyl)methyl]piperazine [obtainable as described for Example 1], 1.8 g of pyridine hydrochloride and 50 ml of pyridine is boiled for 3 hours. The mixture is cooled and evaporated, and work-up is as usual, yielding 1-(2-hydroxyphenyl)-4-[(5-phenyl-3-pyridyl)methyl]piperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 86.1 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and glycine (0.097 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.28 g (86%) 140 as very pale yellow crystals: mp=195–96° C.; Rf 0.79 (A): Rf 0.75 (B): Rf 0.28 (D): IR(cm−1): 2811–3150 (OH), 3115 (C═CH), 1787 (C═O), 1730 (bs, C═O), 1622 (C═C), 1551 (N═O), 1412 (C═C), 1391 (C—O), 1351 (N═O), 1117 (C—O), 720 (C—CH); MS m/z (rel intensity) 250 (7), 249 (62), 205 (100), 122 (10).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=2)[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:32])=[N:3]1.[Cl-].O[NH3+].C([N:39](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:32])[CH:5]=4)=[O:8])[CH:31]=[CH:30][CH:29]=3)=[CH:19][N:18]2[N:39]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cc(C)nn3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)n(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (238 mg, 0.524 mmol), hydroxylammonium chloride (364 mg, 5.24 mmol), N,N-diisopropylethylamine (548 μL, 3.14 mmol), ethanol (3 mL) and methanol (3 mL) was stirred at 60° C. for 5 hr and at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate/methanol=50/50/0→40/100/0→40/90/10) and recrystallized from ethyl acetate-hexane to give the title compound (131 mg, 69%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[NH2:13][NH2:14]>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([NH:13][NH2:14])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: NN
Reactant: N#Cc1nc(F)c(F)c(N)c1Cl
Product: N#Cc1nc(NN)c(F)c(N)c1Cl

Procedure:
reacting the fluoro substituent in the 6-position of 4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) with hydrazine to produce 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (Formula D)
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C(O)C>CCOCC>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: CCOCC
Product: CN(C)C=CC(=O)C(c1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
A mixture of 21.0 g of 1,1-diphenylacetone and 40 ml of N,N-dimethylformamide dimethyl acetal in a 300 ml round bottom flask was heated in an oil bath at 120° C. for 8 hours with ethanol being distilled over. The reaction mixture was cooled and evaporated in vacuo to give an oil. The oil was boiled up in 50 ml of ether then cooled at -10° C. and gave a heavy precipitate. The precipitate was collected, washed with ether, then air dried and gave 21.5 g of crude product. A 5.0 g portion was recrystallized from 50 ml of 2-propanol, then cooled at room temperature. The material was collected and dried at 60° C. and gave 1.7 g of the desired product, mp 93°-94° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: Cl
Product: COC(=O)c1ccnc(NC(=O)C(C)C)c1
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (2.20 g, a yellow solid) from methyl 2-aminoisonicotinate hydrochloride (2.00 g, 10.6 mmol) and isobutyryl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[N:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[N:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1-c1cn(CCO)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1cn(CCO)nn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-[4-(6-chloro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl]ethanol (76 mg, 0.32 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[C:13]([CH3:15])[N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N+:11]([O-:25])[CH:12]=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 45 °C

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine at 0° C. in dioxane was added mCPBA (750 mg). The reaction mixture was heated at 45° C. for 3 h. The reaction was diluted with CH2Cl2, washed with NaHCO3 dried (MgSO4), filtered, and concentrated. It was used without purification: 1H NMR (CDCl3) δ 2.30, 2.54, 7.33, 7.42, 7.54, 8.13; 13C NMR (CDCl3) δ 14.04, 21.85, 128.10, 130.12, 131.64, 132.14, 134.07, 135.23, 136.44, 141.66, 153.87, 154.24.