Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([O:15][CH3:23])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol (30 g) and potassium carbonate (13.8 g) were dissolved in acetone (300 ml) and, after addition of methyl iodide (28 g), the solution was stirred for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and water was added. The mixture was then subjected to extraction with ethyl acetate and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2-propenyl)anisole (31 g) quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1.[OH-].[Na+].Cl>CO>[C:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:15])[N:5]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=3[Cl:1])[CH:6]=[N:7]2)=[CH:12][CH:11]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)cnc2c1
Yield: 78 %

Procedure:
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-4(3H)-quinazolinone (2.00 g) in a mixture of a 5% aqueous sodium hydroxide solution (20 ml) and methanol (20 ml) was heated under reflux for 1 hr. After cooling, concentrated hydrochloric acid was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (50 g) and toluene (30 ml) and dried to give the objective compound (1.50 g) as white crystals.
Reaction SMILES: F[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([O:12][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
A mixture of 5-fluoro-4-methyl-2-nitropyridine (2.75 g, 17.6 mmol), 4-hydroxy-2-chloropyridine (3.42 g, 26.4 mmol) and K2CO3 (2.44 g, 17.6 mmol) in DMF (40 mL) was heated at 80° C. for 16 h. The mixture was cooled to RT, diluted with water (400 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with water (100 mL) and 10% aq. LiCl (80 mL), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (3.0 g, 64%) as an off-white solid. MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)C>O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 70 °C
Yield: 94.5 %

Procedure:
Potassium hydroxide (3.79 g, 67.5 mmol) in water (135 mL) was added to a mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethylamino)-benzoate (5.11 g, 13.5 mmol) and ethanol. The reaction was heated to 70° C. for 14 hours. The ethanol was removed in vacuo. The resulting aqueous mixture was cooled to 5° C., acidified with satd citric acid, filtered with water wash, and vacuum dried to give the desired product as a white solid (4.65 g, 95%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:11][C:10]2[C:9]([Cl:8])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:17])[C:1]1=[O:7]
Reactant: O=C1CCCCC1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CCO
Product: O=C1C(=Cc2c(Cl)cccc2Cl)CCCC1=Cc1c(Cl)cccc1Cl
Reaction time: 4 h

Procedure:
(76) Cyclohexanone (10 mmol), 60 ml of ethanol, and 2,6-dichlorobenzaldehyde (20 mmol) were used. The reaction stirred for 4 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 3.24 g (78.6%) of bright-yellow flakes: mp 185.0-186.0° C. (lit. mp 183° C., Smith et al., supra). 1H NMR (250 MHz) δ 7.60 (s, 2 H), 7.37-7.18 (m, 6 H), 2.45 (t, 4 H), 1.73 (p, 2 H); 13C NMR (62.7 MHz) 188.2, 140.3, 134.6, 134.4, 132.4, 129.6, 128.1, 28.4, 22.1 ppm.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([I:42])[CH:37]=1>C1COCC1>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([I:42])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(I)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(I)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
Dissolved 275 mg (3.27 mmol) 2-butynoic acid in 20 ml THF under N2 and chilled to 0° C. Added 420 μl (3.23 mmol) isobutyl chloroformate and 355 μl (3.24 mmol) N-methylmorpholine and stirred for 10 minutes. Added dropwise a solution of 500 mg (1.30 mmol) 6-amino-4-[(3-iodophenyl)amino]-3-quinolinecarbonitrile and after 15 minutes, removed ice bath and stirred overnight at 25° C. Stripped solvent, washed with water and collected solids. Boiled in ethyl acetate, collected, and dried in vacuo, giving 228 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=453.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:25]\[NH:24][C:21](=[NH:22])[NH2:23])/[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19]
Reactant: N=C(N)NN
Reactant: O=C(Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: N=C(N)N/N=C(/Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a screw cap pressure vessel was added the intermediate from Step A (800 mg, 2.20 mmol), aminoguanidine hydrochloride (280 mg, 2.53 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.63 mL, 4.95 mmol). After stirring at 100° C. for 1 hour, boron trifluoride diethyl etherate (1 mL) and aminoguanidine hydrochloride (200 mg) were added and the reaction solution heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed with aqueous 1N NaOH (2×), brine and dried over anhydrous sodium sulfate. The solution was then filtered and concentrated to give the indicated product. m/z=419 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCOCC3)cc2n1
Yield: 57 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (85 mg, 0.27 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (61 mg, 57%) which was obtained as a yellow solid. MS: m/e=403.5 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.N>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Oc2ncccc2C(=O)O)ccc1Cl
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: N
Product: CC(=O)c1cc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)ccc1Cl

Procedure:
Prepared from 2-(3-Acetyl-4-chloro-phenoxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. MS (m/e): 456/458 (M++NH3, 100). NMR (CDCl3): 8.64 (dd, J=2,8 Hz, 1H), 8.18 (dd, J=2,5 Hz, 1H), 7.95 (m, 1H), 7.46 (m, 3H), 7.31 (m, 3H), 7.19 (m, 2H), 4.68 (d, J=6 Hz, 2H), 2.66 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[F:17]>CO.[Pd]>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:17]
Reactant: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)Nc1cc(N)ccc1F
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A mixture of (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (3.00 g, 10 mmol) and 10% Pd/C (300 mg) in methanol (30 ml) was hydrogenated at 23° C. The resulting mixture was stirred for 24 h. The reaction mixture was filtered through celite and concentrated to give (5-Amino-2-fluoro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.62 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 1H), 6.85 (dd, 1H, J=10.8 Hz, J=8.69 Hz), 6.73 (bs, 1H), 6.28 (m, 1H), 4.27 (t, 2H, J=8.57 Hz), 3.0-4.4 (bs, 2H), 1.06 (t, 2H, J=8.58 Hz), 0.07 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Cl)[N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)c2cccc(Cl)n2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Reactant: C1COCCN1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)n2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 110 °C

Procedure:
A mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-6-chloropyridine-2-carboxamide (0.2 g) and morpholine (3 ml) was stirred and heated to 110° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by reversed-phase column chromatography on a C18 isolute column eluting initially with water and then with a 5:1 mixture of water and methanol. There was thus obtained the title compound (0.169 g); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.19 (s, 3H), 2.25-2.39 (m, 8H), 3.52 (s, 2H), 3.57-3.6 (m, 4H), 3.71-3.75 (m, 4H), 7.05 (d, 1H), 7.22 (d, 1H), 7.4-7.49 (m, 3H), 7.64 (d, 1H), 7.76 (t, 1H), 7.82-7.88 (m, 3H), 9.92 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+ 529.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:20]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccccc3Br)C2)c1

Procedure:
The compound of Example 20 was prepared according to the general preparation protocol A from 2-bromobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:25])=[CH:4][N:3]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:25][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)N3CCCC3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N5CCCC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (0.045 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 90% ethyl acetate in dichloromethane and then 2.5% to 7% methanol in ethyl acetate. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.007 g, 12%); 1H-NMR (500 MHz, DMSO-d6) 1.78 (m, 2H) and 1.90 (m, 2H) (pyrrolidine 3-CH2 and 4-CH2), 2.65 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.18 (s, 2H, NCH2CO), 3.32 (t, J=7.29 Hz, 2H) and 3.53 (t, J=6.48 Hz, 2H) (pyrrolidine 2-CH2 and 5-CH2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.58 Hz, 2H) and 8.01 (d, J=9.58 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.14 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15]OCC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][NH:24][N:23]=1
Reactant: NN
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: Cc1n[nH]cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (1 g) in 3 mL of ethanol is stirred overnight with 0.3 g of hydrazine hydrate. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 0.3 g of 3-methyl-4-(4-(trifluoromethyl)phenylaminocarbonyl]pyrazole as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[C:11](=[CH:18][N:19]([CH3:21])[CH3:20])[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CC(=O)Nc1c(F)cccc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(2,6-difluorophenyl)-3-oxobutanamide obtained in Step A (5.00 g) and N,N-dimethylformamide (20 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (6.32 mL) over 20 min at room temperature, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.70 g).
Reaction SMILES: B.[O:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1>O1CCCC1>[O:2]1[C:10]2[C:9]([CH2:11][OH:12])=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)c1cncc2ccoc12
Agent: B
Solvent: C1CCOC1
Product: OCc1cncc2ccoc12
Reaction time: 1 h

Procedure:
Add Borane (1.0 M in tetrahydrofuran, 0.61 mL, 0.61 mmol) to a solution of furo[3,2-c]pyridine-7-carboxylic acid (0.100 g, 0.61 mmol) in tetrahydrofuran (2 mL)and stir for 1 hour. Add additional borane (0.61 mL) stir for 30 minutes, add additional borane (0.61 ml), quench with 1N HCl (10 mL)and stir for 15 minutes. Add aqueous ammonium hydroxide (28-30%, 3 mL), extract with diethyl ether, dry over magnesium sulfate, filter and concentrate to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:36]2[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]2)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)[C@H](Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a mixture of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-(4-bromo-3-methylphenyl)propanoate (1.23 g, 3.03 mmol), 1,4-dioxane (8 mL), triethylamine (1.69 mL, 12.1 mmol), palladium acetate (17 mg, 76 μmol), O-(dicyclohexylphosphino)biphenyl (106 mg, 0.303 mmol) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.57 mmol) dropwise. The greenish reaction mixture was stirred at 80° C. for 30 min. The reaction was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate twice. The organic solutions were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H), 7.3 (m, 5H), 6.9 (m, 2H), 5.22 (d, 1H), 5.10 (m, 2H), 4.64 (m, 1H), 3.70 (s, 3H), 3.06 (m, 2H), 2.48 (s, 3H), 1.33 (s, 12H); MF=C25H32BNO6; LCMS found for C25H33BNO6 (M+H)+: m/z=454.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h
Yield: 133.1 %

Procedure:
Methane sulfonyl chloride (10 mg, 0.09 mmol) was added to cold (0-5° C.) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) and Et3N (10 mg, 0.1 mmol) in DCM (1 mL); stirring was continued at 25-35° C. for 4 h. Reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford the crude compound, which was purified by preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in CHCl3 as eluent) to afford 53.63 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Reactant: C#CCO
Solvent: CCOCC
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5-fluoro-3-diazooxindole (part B) and 13.1 g. (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude product is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad; the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:16]3[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCNC(=O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c1CCN=C2c1ccc(F)cc1

Procedure:
1-(4-Fluorobenzoylamino)-2-(2-methylphenyl)-ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same way as in step (b) of Example 1 to afford 1-(4-fluorophenyl)-5-methyl-3,4-dihydroisoquinoline as colorless prisms having a melting point of 71.0 to 71.5° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(C)(=O)=O)c3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.39 g, 1.1 mmol) and commercially available (3-methylsulfonylphenyl)boronic acid (0.218 g, 1.0 mmol) according to the general procedure VI. Obtained as a white solid (0.420 g, 90%). MS (ISP) 469.1 [(M+H)+]; mp 186° C.