Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH:8]([CH3:9])[CH2:7][CH:6]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:5]1)=C=O.[Li+].[OH-]>C1COCC1>[NH2:1][CH:4]1[CH:8]([CH3:9])[CH2:7][CH:6]([NH:10][S:11]([CH:14]2[CH2:15][CH2:16]2)(=[O:13])=[O:12])[CH2:5]1
Reactant: CC1CC(NS(=O)(=O)C2CC2)CC1N=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CC(NS(=O)(=O)C2CC2)CC1N
Temperature: 50 °C
Yield: 73.9 %

Procedure:
To a mixture of N-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide (1.00 g, 4.09 mmol, Preparation #NNN.1) in THF (2.0 mL) was added aqueous LiOH (4 N, 20.5 mL, 82 mmol). The reaction was heated to about 50° C. for about 16 h, cooled to ambient temperature and partitioned between water (5 mL) and EtOAc (10 mL). The organic portion was separated and the aqueous portion was extracted with DCM (3×20 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give crude N-(3-amino-4-methylcyclopentyl)cyclopropanesulfonamide (0.66 g, 74%) as a white solid: LC/MS (Table 1, Method n) Rt=0.020 min; MS m/z: 219 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:28].[OH-].[Na+].Cl>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc(O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzaldehyde (0.18 g, 0.60 mmol, Example 28, step a) in dichloromethane (6.0 mL) at 0° C. was added m-chloroperoxybenzoic acid (0.22 g, 0.905 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (2×10 mL) and water. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the solution was added 1 N NaOH (1.81 mL, 1.81 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, acidified with 2 N HCl and washed with brine. The solvent was evaporated and the residue was purified by preparatory TLC eluting with acetone-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenol as an oil (0.08 g, 47%): 1H NMR (200 MHz, DMSO-d6): δ 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (m, 1 H), 6.51 (s, 2 H), 6.32 (m, 1 H), 3.71 (s, 3 H), 3.18 (m, 1 H), 1.95 (s, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (4:1); Rf=0.44.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25][O:10][C:3]2[C:2]([I:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=2[I:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cc(I)c(OCCC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2,4,6-triiodophenol (0.78 g, 1.65 mmol) and potassium carbonate (0.25 g, 1.82 mmol, 1.1 eq) in 5 ml of dimethylformamide was heated at 60° C. for 1 hr, cooled and then 3,3-diphenylpropyl bromide (0.5 g, 1.82 mmol) was added. After stirring for 30 minutes at room temperature the mixture was heated at 60° C. for 24 hrs. The mixture was then cooled, poured into water and the crude product was isolated by ethyl acetate extraction. The product was purified by silica gel chromatography (2.5% ethyl acetate-hexanes) followed by recrystallization from hexanes to give 0.53 g (48%) of a solid. Mp: 120°-121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[N:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2ccc(F)cc2)n1
Yield: 48.1 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 12-(d) except for using tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (7.00 g, 20.7 mmol) obtained in Reference Example 12-(c), and using 4-fluorobenzenesulfonyl chloride (4.00 g, 20.6 mmol) in place of 3-pyridylsulfonyl chloride to afford the title compound (4.91 g) as a white solid. (Yield: 48%)
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH2:22][CH2:23][CH3:24])(C(OCC)=O)[C:12]([O:14]CC)=[O:13])C(=O)C2=CC=CC=C12.[ClH:31]>>[ClH:31].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:22][CH2:23][CH3:24])[C:12]([OH:14])=[O:13]
Reactant: CCCC(CCCCCN1C(=O)c2ccccc2C1=O)(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCCC(CCCCCN)C(=O)O
Temperature: 190 °C

Procedure:
A mixture of diethyl 2-(5-phthalimidopentyl)-2-propylmalonate (6 g) and 26% hydrochloric acid (36 ml) was heated in a sealed tube at 190° C. for 4 hours. After cooling, insoluble substance was remeved by filtration. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed on silica gel column. A fraction eluted with the upper phase of a mixture of butanol:acetic acid:water (4:1:5 volume by volume) was concentrated by dryness to give colorless sticky oil of the desired compound (yield 1.3 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43].CS(C)(=O)=O>O1CCOCC1>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1
Reactant: CN(C)CCN
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)CCNc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, N*1*,N*1*-dimethyl-ethane-1,2-diamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*2*-(2-dimethylamino-ethyl)-N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 460.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4F)nc23)CC1
Yield: 73.6 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.053 mMol) 2,4-difluorobenzoyl chloride, 0.012 gm (77%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C@:11]1([CH3:26])[C@@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([N:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[N:20][C:19]2=[O:25])[O:12]1)(=[O:8])[O:5]CC)C.N1C(C)=CC=CC=1C.C[Si](I)(C)C>C(#N)C>[NH2:24][C:21]1[CH:22]=[CH:23][N:18]([C@@H:13]2[O:12][C@:11]([CH3:26])([O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[C@@H:15]([OH:16])[C@H:14]2[OH:17])[C:19](=[O:25])[N:20]=1
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: C[C@]1(OCP(=O)(O)O)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of compound 30.5 (112 mg, 0.29 mmol) in acetonitrile (10 mL) was added 2,6-lutidine (0.20 mL, 1.7 mmol) and then trimethylsilyl iodide (0.41 mL, 2.8 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was done, 0.30 mL of 2,6-lutidine was added to the mixture and the mixture was concentrated under reduced pressure. The residue was then put into solution with water (3 mL) and treated with sodium hydroxide 1N to pH=10. The solution was then acidify to pH=3 using acetic acid and subjected to a reverse phase (YMC-Pack ODS-A) to give compound 30.6 (69 mg, 72% yield). 1H NMR (300 MHz, D2O): δ 1.39 (s, 3H), 3.54 (m, 2H), 3.99 (d, 1H, J=4.6), 4.63 (m, 1H), 6.09 (d, 1H, J=7.0), 6.14 (d, 1H, J=7.0), 8.0 (d, 1H, J=7.6). LRMS (ESI) MH+ C10H16N3O8P requires 338.2. Found 337.8.
Reaction SMILES: CS(C)=O.Br[C:6]1[C:11]([Br:12])=[C:10]([O:13][CH3:14])[C:9]([Br:15])=[CH:8][C:7]=1[NH:16][C:17]([NH:19]C(=O)OCC)=[S:18].C(=O)([O-])[O-].[K+].[K+]>O>[Br:15][C:9]1[C:10]([O:13][CH3:14])=[C:11]([Br:12])[C:6]2[S:18][C:17]([NH2:19])=[N:16][C:7]=2[CH:8]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Br)c(OC)c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(Br)cc2nc(N)sc2c1Br
Temperature: 90 °C

Procedure:
Anhydrous DMSO (2 mL) was added to a mixture of ethyl N-[(2,3,5-tribromo-4-methoxy-phenyl)carbamothioyl]carbamate (426 mg, 1.02 mmol), CuO (8 mg, 0.10 mmol) and potassium carbonate (211 mg, 1.53 mmol). The mixture was sonicated then heated to 90° C. in a pre-heated heating block under air. The mixture was cooled to rt after 55 minutes and diluted with water. The mixture was extracted into EtOAc (3×50 mL) and the combined organic layers were washed with water then brine. The organic layer was dried over Na2SO4 and the mixture filtered through a PTFE filter to remove copper salts, then the filtrate was concentrated to dryness under reduced pressure. The desired compound was obtained as an off-white solid, 208 mg (60% over 2 steps). m/z: 337.01/339.01/340.97 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[NH2:16])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:15]([NH:16][S:18]([CH3:17])(=[O:20])=[O:19])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)c(OCC2CC2)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3-(cyclopropylmethoxy)-4-aminobenzoate (8.86 g) was dissolved in pyridine (80 mL) at room temperature under N2 atmosphere. Methanesulfonyl chloride (4.04 mL) was added and the mixture was stirred at r.t. for 18 hours. The reaction mixture was evaporated to dryness, the crude was treated with 1N HCl (500 mL) and extracted with CH2Cl2 (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated off to yield 11.7 g of the desired intermediate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:30][CH3:31].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH2:30]([O:28][C:25]1[N:26]=[CH:27][C:22]([C:20]2[CH:19]=[CH:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)=[CH:23][CH:24]=1)[CH3:31]
Reactant: O=c1ccc(-c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(-c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)cn1
Temperature: 60 °C

Procedure:
5-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-1H-pyridin-2-one (Ex. 1.37) (1 eq, 0.096 mmol, 35 mg), iodoethane (1.5 eq, 0.144 mmol, 22.5 mg), sodium iodide (1.5 eq, 0.155 mmol, 21.5 mg) and cesium carbonate (2.99 eq, 0.287 mmol, 93.6 mg) are dissolved in DMF (2 ml) and heated at 60° C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with Na2CO3. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 8/2 to yield 7-(6-ethoxy-pyridin-3-yl)-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=393 and 1-ethyl-5-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-1H-pyridin-2-one as a yellow solid; [M+H]+=393
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23]Br)=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCn2cnc(-c3cc(C(=O)O)ccn3)c2)cc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 4-methoxyphenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.02 (2H, t, J=7.2 Hz), 3.71 (3H, s), 4.24 (2H, t, J=7.2 Hz), 6.83 (2H, t, J=8.6 Hz), 7.12 (2H, t, J=8.6 Hz), 7.58 (1H, d, J=3.7 Hz), 7.62 (1H, s), 7.82 (1H, s), 8.26 (1H, s), 8.63 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H17N3O3, 324. Found, 324.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][NH2:11].[C:12](N)(=[O:15])[CH:13]=[CH2:14].[Na]>C(O)C.C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[N:10]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: C=CC(N)=O
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2cc(Cl)ccc2Cl)N1

Procedure:
2,5-Dichlorophenylhydrazine hydrochloride (240 g, 1.1 mol) and acrylamide (100 g, 1.4 mol) is refluxed in a solution of sodium (56 g, 2.4 mol) in ethanol (1000 ml) and toluene (1000 ml) for 3 hours. Evaporation of the solvents, acidification with acetic acid dilution with water, filtration and drying (high vacuum, +100° C.) gives the 1-(2,5-dichlorophenyl)-3-pyrazolidone.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][CH:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[N+:11]([C:4]1[CH:3]=[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH:15]2[CH3:14])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-Fluoro-1,2-dinitrobenzene (0.93 g, 5.0 mmol, commercially available from Oakwood Products) and tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol) were dissolved in 3 mL of DMA, and 3 mL of diisopropylethylamine was added. The mixture was stirred at 50° C. overnight, and then cooled to room temperature, separated between ethyl acetate and water. The combined organic were washed with water, brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column (20% to 40% ethyl acetate in hexanes) to give 1.0 g of tert-butyl 4-(3,4-dinitrophenyl)-3-methylpiperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3): δ 8.05 (d, 2H), 6.84 (m, 2H), 3.90-4.10 (m, 3H), 3.05-3.60 (m, 4H), 1.50 (s, 9H), 1.10 (s, 3H). MS (EI): 367 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.FC(F)(F)S(OC1C=CC(F)=CC=1[N+]([O-])=O)(=O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35]2.C(O)CCO.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:37]2[CH2:36][CH2:35][C:34]3[C:39](=[CH:40][CH:41]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:38]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: OCCCO
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(c1ccc(F)cc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Synthesized from 4-fluoro-2-nitrophenol (3.0 g) according to an analogous synthetic method to Preparation Example 80 described below, 4-fluoro-2-nitrophenyl trifluoromethanesulfonate (5.5 g) was obtained. To a suspension of (6-methoxynaphthalen-2-yl)boronic acid (2.5 g) in diethyl ether (60 ml) was added 1,3-propanediol (0.9 ml), and the solution was stirred for 2 hours at room temperature. Tetrahydrofuran and anhydrous magnesium sulfate were sequentially added thereto, the solution was stirred, then filtered, and the filtrate was concentrated in vacuo. To a solution of the resulting 2-(6-methoxynaphthalen-2-yl)-[1,3,2]dioxaborinane (3.1 g) and 4-fluoro-2-nitrophenyl trifluoromethanesulfonate (2.8 g) in N,N-dimethylformamide (50 ml) were added tetrakis(triphenylphosphine)palladium(0) (350 mg) and cesium carbonate (6.0 g), and the solution was stirred for 2 hours at 100° C. under a nitrogen atmosphere. Ethyl acetate and tetrahydrofuran were sequentially added thereto, the solution was stirred, then insoluble material was removed by filtration, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide 2-(4-fluoro-2-nitrophenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene (2.4 g). The total amount of this compound was used according to an analogous synthetic method to Example 22 to provide the title compound (1.6 g).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=O.N1C=CC=CC=1.N1CCCCC1>O>[OH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][C:26]([F:27])([F:28])[F:29])=[C:17]([Cl:16])[CH:18]=1
Reactant: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 0.60 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone, 1.99 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 10 ml of pyridine and 88 μl of piperidine was heated under refluxing overnight. After cooling to room temperature, 50 ml of water was added to the reaction mixture, and precipitated crystals were filtered, and washed with 40 ml of tetrahydrofuran, and 60 ml of hexane to obtain 0.92 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (3c-32)] as a yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CCC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)O)CC1

Procedure:
The title compound was prepared analogously to step 5 of example B(29)where 4-(4-ethoxycarbonyl-butyl)-piperidine-1-carboxylic acid tert-butyl ester from step 3 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-propionic acid ethyl ester in that example. 1H NMR (400 MHz, CDCl3): δ 1.07-1.39 (m, 7H), 1.45 (s, 9H), 1.59-1.70 (m, 4H), 2.33-2.38 (m, 2H), 2.64-2.68 (m, 2H), 4.09-4.12 (m, 2H). ESIMS (MH−): 284.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)=[C:7]([C:9]2[CH:18]=[CH:17][C:12]3=[N:13][N:14]([CH3:16])[N:15]=[C:11]3[CH:10]=2)[N:8]=1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][N:14]1[N:13]=[C:12]2[CH:17]=[CH:18][C:9]([C:7]3[N:8]=[C:4]([CH:3]=[O:2])[NH:5][C:6]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[CH:10][C:11]2=[N:15]1
Reactant: COC(OC)c1nc(-c2ccc3nn(C)nc3c2)c(-c2cccc(C)n2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole (700 mg, 1.92 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran. 6M hydrochloric acid solution in water (3.2 ml, 19.2 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added until approximately pH 8. The organic solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted three times with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde (600 mg, 98% yield) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:32][O:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1N(C)C(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)cc1N(C)C(C)=O
Yield: 92.3 %

Procedure:
A mixture of 0.070 g (0.36 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-methoxy-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 135 mg of N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 92%).