Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C=O)C>[CH2:29]([O:28][CH2:27][CH2:26][NH:25][C:23]([C:6]1[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[O:44][CH3:45])[C:13]2[C:8]([C:7]=1[OH:22])=[N:9][CH:10]=[C:11]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH:12]=2)=[O:24])[CH3:30]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)OC)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.02 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0036 mL, 0.047 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue treated with 1 N NaHSO4, filtered, then washed with 1 N NaHSO4 and Et2O before drying in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.0 Hz, 3 H), 3.3 (m, 2 H), 3.4 (s, 3 H), 3.5 (m, 7 H), 4.1 (s, 2 H), 4.3 (t, J=6.0 Hz, 2 H), 7.1 (t, J=8.8 Hz, 2 H), 7.3 (m, 1 H), 7.4 (m, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 17.1 (s, 1 H); ES+ MS: 487 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[CH:23][N:22]=[C:21]([NH2:27])[C:20]=2[N:19]=[C:18]1[CH2:28][O:29][CH2:30][CH3:31]>>[NH2:27][C:21]1[C:20]2[N:19]=[C:18]([CH2:28][O:29][CH2:30][CH3:31])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:25]=2[C:24]([CH3:26])=[CH:23][N:22]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N(C)c1ccccc1

Procedure:
Using the method of Examples 147-164, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 411.2532.
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: CC(=O)C(C)NC(C)(C)c1cc(F)cc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(F)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 3.0 g of (2-fluorophenyl)acetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by evaporation, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was condensed by an evaporator, and then subjected to silica gel chromatography to obtain 2.2 g of 1-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][O:20][CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([O:20][CH3:21])[C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)Nc1ccccc1
Temperature: -10 °C

Procedure:
The preparation of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl O-methylhydroxylamine is described in Parts A-H of Example 1. Triethylamine (0.23 mL, 1.64 mmol) was added to a solution of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl O-methylhydroxylamine (0.45 g, 1.37 mmol) in dichloromethane (10 mL) cooled to −10° C. Phenyl isocyanate (0.15 mL, 1.37 mmol) was added to the reaction mixture and it was allowed to warm to 0° C. over 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and saturated sodium bicarbonate (40 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (30 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow material. The material was purified by HPFC (0-25% CMA in chloroform) and recrystallized from acetonitrile to afford an off-white solid. The solid was dried at 100° C. under high vacuum to afford 0.388 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxy-N′-phenylurea as an off-white powder, mp 155-156° C. Anal. calcd for C24H29N7O2: C, 64.41; H, 6.53; N, 21.91. Found: C, 64.20; H, 6.64; N, 21.93.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Brc1cnc2nccnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nccnn23)ccc1F
Temperature: 80 °C
Yield: 21.2 %

Procedure:
A stirred mixture of 7-bromoimidazo[1,2-b][1,2,4]triazine (0.22 g, 1.105 mmol), dried potassium phosphate (0.425 g, 2.002 mmol) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (0.649 g, 2.008 mmol) in anhydrous N,N-dimethylacetamide (4 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol) was added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. for 4.5 h. The mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered. The filtrate was washed with brine (200 ml), and the aqueous portion extracted with more ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, EtOAc) then recrystallisation (EtOAc) to give 74 mg (24%) of the title compound: mp 211-215° C.; 1H NMR (360 MHz, CDCl3) δ 7.36-7.41 (1H, t, J 7.2 Hz), 7.53-7.61 (2H, m), 7.70-7.74 (1H, m), 7.83 (1H, d, J 7.7 Hz), 8.12-8.16 (2H, m), 8.35 (1H, s), 8.50 (1H, dd, J 2.1, 11.6 Hz); MS (ES+) m/z 316 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]#[N:22])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH2:23].[OH-].[Li+]>CO.O1CCCC1.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:21]([NH2:22])=[O:23])[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1cc(C#N)cc(C(F)(F)F)c1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cc(-n2nnnc2CO)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of {1-[3-cyano-5-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 30, 3.33 g) in methanol (10.0 mL), tetrahydrofuran (20 mL) and water (10.0 mL) was cooled in an ice-water bath before the addition of lithium hydroxide monohydrate (0.449 g, 10.7 mmol). The reaction was stirred at 0-5° C. for 2 hours. The reaction was diluted with water (30 mL) and the organic solvent removed under vacuum. The suspension was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried and the solvent removed to yield a white solid. The solid was triturated with diethyl ether (2×25 mL), the solvent decanted and the residue dried under vacuum to yield the intermediate 3-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide as a white solid (1.37 g).
Reaction SMILES: C([O:7][C:8]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[N:10]2[CH:19]([CH2:32][CH2:33][OH:34])[CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22](=[O:23])[C:9]=12)(=O)C(C)(C)C.C[O-].[Na+]>CO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:21]2[CH2:20][CH:19]([CH2:32][CH2:33][OH:34])[N:10]3[C:11](=[O:18])[N:12]([CH:15]([CH3:17])[CH3:16])[C:13](=[O:14])[C:8]([OH:7])=[C:9]3[C:22]2=[O:23])=[CH:30][CH:29]=1
Reactant: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCO)CN(Cc1ccc(F)cc1)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCO)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-(4-fluorobenzyl)-4-(2-hydroxyethyl)-7-isopropyl-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-yl pivalate (Example 74, Step 2, 40 mg, 0.08 mmol) in methanol (0.5 mL) was added sodium methoxide (25 wt. % solution in methanol, 1.6 mL) and the mixture stirred at room temperature for 20 min. The reaction was quenched by dropwise addition of 1 N hydrochloric acid and the solvent was removed in vacuo. The resulting residue was taken up in methylene chloride, filtered, and the filtrate concentrated. The residue was purified by reverse phase preparative HPLC (95:5 to 5:95 A:B where A=0.1% TFA-H2O and B=0.1% TFA-MeCN over 30 min) to afford the title compound. 1H NMR (CD3OD, 400 MHz): δ 7.44-7.40 (m, 2 H), 7.13-7.08 (m, 2 H), 5.19-5.15 (m, 1 H), 4.92-4.75 (m, 2 H), 4.51 (d, J=14.4 MHz, 1 H), 3.75 (dd, J=3.8 MHz, 13.4 MHz, 1 H), 3.51 (dd, J=1.6 MHz, 13.6 MHz, 1 H), 3.42-3.30 (m, 2 H), 1.76-1.71 (m, 1 H), 1.62-1.57 (m, 1 H), 1.45 (d, J=7.2 MHz, 6 H). HRMS (FT/ICR) M+H: calcd for (C19H23FN3O5)+ 392.1616. found 392.1625.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11]2.[BrH:20]>OS(O)(=O)=O.C(O)(=O)C.O>[Br:20][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11]2
Reactant: Br
Reactant: COC(=O)c1ccc2cccc(N)c2c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2cccc(Br)c2c1
Temperature: 10 °C
Yield: 83 %

Procedure:
To a cooled (10° C.) stirred solution of NaNO2 (2.18 g, 31.5 mmol) in concentrated H2SO4 (28.3 mL) and glacial acetic acid (26.1 mL) (prepared by adding NaNO2 to cooled [10° C.] H2SO4, heating to dissolve, re-cooling and adding HOAc) was added a solution of 8-amino-2-naphthoic, methyl ester (VII) (5.72 g, 26.36 mmoles) in glacial acetic acid (88.7 mL) over 10 minutes. The resulting solution was then added slowly (over 10 minutes) to a heated (60° C.), stirred solution of CuBr (16.59 g, 43.31 mmoles) in concentrated HBr (160 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with H2O (350 mL), and filtered to give 5.8 g (yield: 83%) of 8-bromo-2-naphthoic acid, methyl ester; 1H-NMR: δ9.00 (s, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.85 (d, J=6.5 Hz, 2H), 7.40 (dd, J=8.2, 7.5 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C.CCOC(C)=O.[Pd]>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 7-2 (3.6 g, 16 mmol) in DMF (50 mL) was added Cs2CO3 (7.8 g, 238 mmol). After 15 min., tert-butyl bromoacetate (3.2 mL, 35 mmol) was added and the reaction mixture stirred for 20 hrs at ambient temperature. The reaction mixture was diluted with EtOAc and then washed with H2O, and brine, dried (MgSO4), and concentrated to give a yellow oil. The crude yellow oil (5.4 g, 15.8 mmol), 10% Pd/C (500 mg), and EtOAc (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hr. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give 7-3 as a white solid.
Reaction SMILES: ClC1C=CC=C([C:8]([O:10]O)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](C=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl>[CH:8]([O:10][C:20]1[C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:26])[CH3:27])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1C=O
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
3-Chloroperbenzoic acid (4.73 g) was added to a solution of 4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-carboxaldehyde (3.55 g) in dichloromethane (100 mL) and the reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and the filtrate was washed in turn with water, saturated sodium bisulfite solution, sodium bicarbonate solution and brine. After the dried (MgSO4) organic layer was evaporated, the crude product was purified by HPLC (ethyl acetate-hexane; 1:49) to afford 2.5 g of 4'-fluoro-3-(1-methylethyl)[1,1'biphenyl]-2-ol formate as a oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1>CO.Cl.O1CCOCC1>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a mixture of 120 mg (0.32 mmol) of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine from Example 10 in 3 ml of methanol, 12 ml of 4N HCl in dioxane was added. The mixture was stirred for 8 hours and concentrated in vacuum. The residue was triturated with ethyl ether. The solid material was filtered out, washed with ethyl ether and dried. The above solid was dispersed in 30 ml of saturated aqueous sodium bicarbonate and the suspension was stirred for 1 hour. The solid base was collected, washed with water and dried in high vacuum for 24 hours to yield 95 mg of 131 (90%). ESI MS m/z 292.1 (M+1). 1H NMR (400 MHz, DMSO): 9.32-9.21 (m, 1H), 8.81 (s, 1H), 8.61 (dd, J=4.7, 1.4 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.21-8.06 (m, 1H), 7.55 (dd, J=7.9, 4.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.53 (s, 1H), 6.28 (s, 1H)
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]2[C:16]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[C:17]3[C:21](=[C:22]([CH3:26])[C:23]=2[O:24][CH3:25])[CH2:20][O:19][C:18]3=[O:27])(=[O:10])[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:41][CH2:42][CH3:43])(=[O:40])[C@H:37]([CH3:39])O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH2:42]([O:41][C:36](=[O:40])[CH:37]([O:10][P:8]([CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]1[C:16]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])([O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:9])[CH3:39])[CH3:43]
Reactant: CCOC(=O)[C@H](C)O
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(O)Oc1ccccc1)C(=O)OC2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34 mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol). The solution was stirred at room temperature for 16 hours and concentrated. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg (83%) of the desired product. MS (m/z) 641 [M+Na]+.
Reaction SMILES: C(OC(C1C=NC2C(C=1[Cl:16])=NC(F)=CC=2)=O)C.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1O)=[CH:30][N:29]=[C:28]([Cl:34])[CH:27]=2)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[Cl:16])=[CH:30][N:29]=[C:28]([Cl:34])[CH:27]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Reactant: CCOC(=O)c1cnc2cc(Cl)ncc2c1O
Product: CCOC(=O)c1cnc2cc(Cl)ncc2c1Cl

Procedure:
The title compound was prepared following the procedure described for 4a using 7-chloro-4-hydroxy-[1,6]naphthyridine-3-carboxylic acid ethyl ester (11). 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 8.02 (1H, s), 9.37 (1H, s), 9.62 (1H, s). m/z 272.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=S)[CH:9]2C)=[O:5])[CH3:2].C([OH:20])C>[Ni]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=[O:20])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1cc(C)c2c(c1)C(C)C(=S)N2
Agent: [Ni]
Product: CCOC(=O)c1cc(C)c2c(c1)CC(=O)N2
Yield: 67 %

Procedure:
An 0.80 g (3.01 mmol) portion of the 5-ethoxycarbonyl-7-methyl-3-methylthio-2-oxindole in 130 ml of absolute ethanol was treated with Raney Nickel by the above described procedure to give 0.44 g (2.01 mmol, 67% yield) of 5-ethoxycarbonyl-7-methyl-2-oxindole, m.p. 238°241°;
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH:10]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=2[N:14]=1)=[CH:11][CH3:12]>>[O:19]=[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=1[NH:14][C:13](=[O:18])[CH:10]=[CH:11][CH3:12])[CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:3]
Reactant: CC=Cc1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Product: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 70.6 %

Procedure:
Using the procedure of Step A of Example 1, 19.44 g of 2-acetylamino thiazole and 17.3g of 2-(1-propenyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one [prepared by Step A of Example 12 of European patent No. 40,573 from crotonyl chloride and 2-amino-trifluoromethyl benzoic acid] were reacted to obtain 19.03g of β-oxo-2-[(1-oxo-2-butenyl)-amino]-N-(2-thiazolyl)-3-trifluoromethyl-benzene-proponamide melting at 206°-208° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Yield: 95.9 %

Procedure:
A mixture of Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (2.0 g) and 10% palladium on carbon (50% wet, 0.2 g) in tetrahydrofuran (20 ml) was stirred for 8 hours under atmospheric pressure of hydrogen at ambient temperature. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give Methyl 3-[4-(4-pentylphenyl)phenyl]propionate (1.93 g).
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][C:47]4[S:48][CH:49]=[CH:50][CH:51]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[S:48]1[CH:49]=[CH:50][CH:51]=[C:47]1[CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCCCc4cccs4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCCc1cccs1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 41.3 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[3-(2-thienyl)propyl]-1-piperidinecarboxamide (0.182 g, 0.230 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.095 mmol)
Reaction SMILES: [C:1]([N:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CS([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)=O>CN(C)C=O>[C:1]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13](=[O:15])[CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2ccccc2)CC(=O)N1
Reactant: CS(=O)(=O)CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CC(=O)N(CCc2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
12 g (0.055 mol) of 4-benzoyl-2,6-dioxopiperazine are dissolved in 200 ml of dimethylformamide. 3.5 g (0.065 mol) of sodium methylate are added and the reaction medium is left for 1 hour at ambient temperature. To the reaction medium is added, dropwise and in an inert atmosphere, a solution of 16 g (0.080 mol) of (2-methane-sulphonyl ethyl)-benzene in 50 ml of dimethylformamide and is brought to 70° C. for 5 hours. Evaporation to dryness is carried out under vacuum and the residue is taken up in a mixture of water and dichloromethane. The decanted organic phase is dried over dry sodium sulphate. The evaporation of the solvent leaves an oily residue which is purified by silica column chromatography (elutrient: toluene/ethyl acetate 7/3). In this way, there is obtained the 4-benzoyl-2,6dioxo-1-phenethyl piperazine which, after recrystallisation from a cyclohexane/ethyl acetate mixture, melts at 102° C.