Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12]>CC(OC(C)=O)=O>[CH3:5][C:6]1[NH:7][C:8]([N+:1]([O-:4])=[O:2])=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1c(C)c[nH]c1C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HNO3 (0.28 mL of a 69% w/v aq solution, 4.37 mmol) was added dropwise to Ac2O (5 mL) at room temperature, keeping the internal temperature ≦25° C. The nitrating mixture was stirred at room temperature for 15 min before cooling to −40° C. 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (500 mg, 3.64 mmol) was dissolved in Ac2O (6 mL) and added dropwise, keeping the internal temperature ≦−30° C. The mixture was stirred at −40° C. for 30 min then at −10° C. for a further 30 min. The mixture was poured into ice-water (50 mL) and was extracted with Et2O (3×60 mL). The combined organic eztracts were washed (brine), dried (Na2SO4), filtered, and evaporated in vacuo to give a dark brown solid. This was recrystallised from MeOH to afford 1-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-ethanone (158 mg). An aliquot (150 mg, 0.82 mmol) was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (0.42 mL, 2.02 mmol) in a N2-flushed flask and was heated at 70° C. for 18 h. The mixture was triturated in EtOAc to afford the title compound (119 mg) as a brown solid. 1H-NMR (DMSO-d6) δ: 2.30 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.80 (br. s, 3H, CH3), 3.07 (br. s, 3H, CH3), 5.19 (d, 1H, J=12.7 Hz, CH), 7.45 (d, 1H, J=12.4 Hz, CH), 12.76 (br, 1H, NH).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]1=[O:23].[OH:24][C:25]1[C:26]([C:33](O)=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:24][C:25]1[C:26]([C:33]([NH:1][C@H:2]2[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH2:13][CH3:14])([CH3:15])[CH3:16])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]2=[O:23])=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: CCC(C)(C)O[C@H]1COC[C@H](N)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)(C)O[C@H]1COC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7-(1,1-dimethylpropoxy)-8-isobutoxy-9-methyl-1,5-dioxonan-2-one and 3-hydroxy-4-methoxypicolinic acid (79.0 mg, 0.466 mmol) in DCM (2.0 mL) were added 4-methylmorpholine (0.205 mL, 1.86 mmol) followed by HATU (189 mg, 0.497 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a white solid (50.0 mg, 42%): mp 138-140° C.; IR (neat) 3370, 2926, 1750, 1650, 1529, 1243, 1085 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.08 (dq, J=9.1, 6.3 Hz, 1H), 5.00 (ddd, J=8.1, 6.1, 3.8 Hz, 1H), 4.00 (dd, J=12.1, 6.1 Hz, 1H), 3.94 (s, 3H), 3.95-3.89 (m, 2H), 3.79 (dd, J=8.6, 5.6 Hz, 1H), 3.56-3.45 (m, 2H), 3.07 (dt, J=12.6, 8.4 Hz, 2H), 1.90-1.78 (m, 1H), 1.56-1.43 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.15 (s, 3H), 1.14 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.91-0.85 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 170.17, 169.09, 155.47, 148.89, 140.79, 130.47, 109.68, 85.26, 81.29, 81.18, 77.82, 75.32, 75.19, 73.37, 56.23, 53.07, 35.01, 29.10, 25.16, 25.08, 19.95, 19.60, 18.97, 9.06; HRMS-ESI (m/z) [M]+ calcd for C24H38N2O8, 482.2628; found, 482.2631.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17]I.[C-:19]#[N:20].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][C:19]#[N:20]
Reactant: [C-]#N
Reactant: COc1cc(CCCI)c(OC)c2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CCCC#N)c(OC)c2ccccc12
Yield: 92.3 %

Procedure:
A solution of 5.08 g of 3-(1,4-dimethoxy-2-naphthyl)propyl iodide (prepared as described in Preparation 30), and 0.70 g of sodium cyanide in 60 ml of dry dimethyl sulfoxide was stirred at 60° C. (external temperature) for 80 minutes. At the end of this time, the reaction mixture was cooled and poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.36 g of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][NH:6][CH2:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([CH3:39])[CH:26]=3)([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=2)[CH:11]=1)=[O:9])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:37][C:34]([CH3:35])([CH3:36])[C:33](=[O:38])[CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:8]([CH2:7][NH:6][CH2:5][C:4]([OH:40])=[O:3])=[O:9])[CH:19]=[CH:18]3)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:26][C:27]=1[CH3:39]
Reactant: CCOC(=O)CNCC(=O)c1ccc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)CNCC(=O)O)ccc2c1
Temperature: 50 °C
Yield: 84.5 %

Procedure:
Treat a solution of [(6-{1-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl)methylamino]acetic acid ethyl ester (0.090 g, 0.16 mmol) in THF (1.25 mL) and EtOH (2.5 mL) with 2N NaOH (0.80 mL, 1.6 mmol). Heat the mixture to 50° C. for 16 h. Acidify the reaction mixture to pH 1 using 1N HCl. Concentrate the resulting mixture. Dilute the residue with EtOAc and water (25 mL each). Separate and discard the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrated the filtrate to give the title compound as a white solid (0.070 g, 85%). MS (ES) m/e 518 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O-:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[NH2+]1CCCCC1.Cl>O.CO>[OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)Nc2ccccc2C(=O)[O-])ccc1O
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 98.5 %

Procedure:
A 10 g quantity of piperidinium N-(4-hydroxy-3-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 60 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (98.5% yield), m.p. 230°-233° C. The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][CH:9]([CH2:11][CH3:12])[CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][CH:9]([CH2:11][CH3:12])[CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCNC(=S)N1CC(CC)C=N1
Solvent: CO
Product: CCN=C(SC)N1CC(CC)C=N1
Temperature: 50 °C
Yield: 0.8 %

Procedure:
1.80 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 36 mL methanol; 6.1 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 4 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to yield 1.68 g (87%) 4,N-diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.5 Hz, 3H), 1.16 (t, J=7.3 Hz, 3H), 1.45-1.70 (m, 2H), 2.45 (s, 3H), 2.97-3.07 (m, 1H), 3.44 (dd, J=11.0, 8.3 Hz, 1H), 3.51-3.58 (m, 2H), 3.83 (t, J=11.0 Hz, 1H), 6.81 (s, 1H).
Reaction SMILES: [OH-:1].[Na+].O.[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:26]3[C:21]([CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25]3)=[CH:20][CH:19]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:26]3[C:21]([CH:22]=[N:23][C:24]([OH:1])=[N:25]3)=[CH:20][CH:19]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
10 M sodium hydroxide in water (2.74 mL, 52.4 mmol) was heated at 100° C. N-tert-butyl-3-(2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (780 mg, 1.91 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes and then cooled to room temperature. Glacial acetic acid was added to adjust the pH to 4 and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and washed sequentially with water (75 mL) and Et2O (50 mL) to obtain N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a red-orange solid (460 mg, 70%). LCMS (m/e) 347 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.00 (s, 1H), 8.68 (s, 1H), 8.47 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.7 Hz), 7.71-7.64 (m, 1H), 7.59 (s, 1H), 7.30 (d, 1H, J=4.8 Hz), 7.01 (d, 1H, J=4.8 Hz), 1.91 (s, 1H), 1.13 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([C:10]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]2[S:13][CH2:14][CH2:15][C:8]=2[C:7]2[C:2]([OH:1])=[CH:3][C:4]([CH3:16])=[CH:5][C:6]=2[O:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCCCCC[Mg]Br
Product: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno [2,3-c] [1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]O)[CH:5]=[CH:6][C:7]=1[F:8].[BrH:12]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:12][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: Br
Reactant: OCCc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Fc1ccc(CCBr)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
A mixture of 2-(3,4-difluoro-phenyl)-ethanol (5 g, 0.032 mol, from step (iii) above), 51.84 ml (49%, 0.64 mol) of HBr in acetic acid and 5 ml of sulfuric acid was stirred at 100° C. for 4 h. The reaction mixture was poured into ice and extracted with diethylether. Organic layer was washed with NaHCO3, water and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification (three times) over silica gel using petroleum ether as eluent afforded (1.8 g) of the title compound as a liquid.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH:1]([NH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)=[O:2]
Reactant: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1N
Reactant: O=CO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1NC=O
Temperature: 50 °C

Procedure:
1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroquinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(3-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative), Separately. 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state), The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 130 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]2[NH:25][CH:24]([C:26](O)=[O:27])[CH2:23][S:22]2)[CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:26]([CH:24]2[CH2:23][S:22][CH:21]([C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[NH:25]2)=[O:27])=[CH:12][CH:13]=1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: CC(C)CCOc1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCOc1ccc(CNC(=O)C2CSC(c3cccnc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of 1.13 g of p-(3 methylbutoxy)benzylamine, 1.29 g of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 1.25 g of dicyclohexylcarbodiimide and 0.82 g of 1-hydroxybenzotriazole in 20 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure Purification of the thus-obtained residue by silica gel column chromatography (eluent: ethyl acetate) gave 2.20 g of N-[p-(3-methylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide. To a solution of this compound in 60 ml of ethyl acetate was added 4 ml of 4N hydrogen chloride solution in dioxane. The precipitate solid was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 2.30 g of N-[p-(3-methylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 120°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:23]5[CH2:22][CH:21]([CH3:20])[NH:26][CH:25]([CH3:27])[CH2:24]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93.1 mg (73%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.75 (br s, 1H, NH), 9.23 (br s, 1H), 8.32 (s, 1H), 7.73 (dd, J=2.6 & 6.7 Hz, 1H), 7.41 (m, 1H), 7.33-7.38 (m, 2H), 6.57 (d, J=2 Hz, 1H), 4.22 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.52 (m, 2H, 2×CH), 2.22 (s, 3H, CH3), 0.99 (d, J=6 Hz, 6H, 2×CH3), 0.98 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17](O)=[O:18])[CH:12]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:29]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17]([NH2:29])=[O:18])[CH:12]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)O)c(Br)o2)c(C)cn1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(N)=O)c(Br)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoic acid (10.0 g, 29.6 mmol) in THF (950 mL) at −20° C. was added TEA (4.55 mL, 32.5 mmol) over 20 min. The reaction mixture was allowed to stir for 10 min after addition was complete and then isobutyl carbonochloridate (10.7 g, 88.8 mmol) was added over 10 min. The reaction mixture was allowed to stir for 20 min at −20° C. and was then allowed to warm to rt. A solution of NH3 in THF was added and the reaction mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was diluted with water and filtered to give 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furamide (8.5 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][C:5]2=[CH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O.[NH2:20][NH2:21].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:21][N:20]=[C:5]2[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN
Reactant: O=C1OC(=Cc2cccnc2)c2cc(Cl)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12

Procedure:
5-Chloro-3-(pyrid-3-yl)methylenephthalide (2.68 g) was dissolved in 100 ml of ethanol, followed by the addition of 2.0 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 4 hours, followed by the addition of 200 ml of water. The resulting mixture was neutralized with dilute hydrochloric acid to precipitate crystals, which were recovered by filtration to give 1.87 g of the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[O:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:24][CH:25]=[C:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:2]3[CH:7]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([O:16][CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[C:12]([CH:15]=4)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=3)=[N:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccc(C2=CCOCC2)cn1
Reactant: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OC1CCOCC1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(C4=CCOCC4)cn3)c2)ccc1OC1CCOCC1
Yield: 23 %

Procedure:
With 5-(2-chloropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile and the 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-ylamine prepared, 5-{2-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-ylamino]pyridin-4-yl}-2-(tetrahydropyran-4-yloxy)benzonitrile is obtained in 23% yield under the Buchwald-Hartwig conditions indicated; HPLC-MS Rt. [min] 1.717; HPLC-MS [M+H] 455;
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[CH:34]([O:33][CH2:32][CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([CH3:36])[CH3:35]
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (2.76 g, 8.72 mmol), and sodium hydride (0.38 g, 9.5 mmol) in dimethylformamide (30 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2.5 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give (1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine: Rf=0.73 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide, 90/10/0.1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1)[CH:6]=[CH:5]2
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(-c2ccc3cc(O)ccc3c2)nc1
Temperature: 120 °C

Procedure:
Followed procedure described in Step 1 of Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and 2-chloropyrimidine-5-carboxylic acid with modifications: the solvent was dioxane/water (6/1), and the reaction was heated to 120° C. by microwave for 0.5 h. Purified by prep-HPLC. 1H-NMR (DMSO-d6 500 MHz): 13.70 (brs, 1H), 10.12 (s, 1H), 9.29 (s, 2H), 8.97 (s, 1H), 8.42-8.44 (d, J=9.0 Hz, 1H), 8.00-8.01 (d, J=8.5 Hz, 1H), 7.82-7.84 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.15-7.18 (dd, J=2.0, 9.0 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.