Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:45][C:46]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:47])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH2:41][CH2:42][OH:43])[C:33]=2[F:44])[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:76](O)(=[O:78])[CH3:77]>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[C:76]([O:43][CH2:42][CH2:41][O:40][C:34]1[C:33]([F:44])=[C:32]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:45][C:46]([O:48][CH2:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:47])=[CH:8][CH:7]=2)[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)(=[O:78])[CH3:77]
Reactant: CC(=O)O
Reactant: CCC(CC)C(=O)OCOc1nc([C@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)OCOc1nc([C@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-ethylbutanoic acid 5-{(R)-(4-{amino[2,2-dimethylpropoxycarbonylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester (37 mg), DMAP (0.6 mg), and triethylamine (0.056 mL) were dissolved in DMF (2.5 mL) and dichloromethane (2.5 mL). To the solution, a mixture of TFFH (26.5 mg), acetic acid (0.00576 mL), and dichloromethane (3 mL) was slowly added, and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, ice, THF, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous ammonium chloride solution were added to the residue obtained, and the resulting mixture was extracted with the mixture of THF and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:32])[F:31])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C(F)(F)F)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (1.97 g, 7.35 mmol) and 4-(trifluoromethyl)benzohydrazide (1.50 g, 7.35 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (1.13 g, 7.35 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (2.82 g, 14.7 mmol) at −45° C. followed by triethylamine (2.0 mL, 14.7 mmol). The reaction mixture warmed to room temperature and stirred for 23 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a off white solid (3.09 g, 92%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 10.71 (s, 1H), 10.31 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.67 (d, J=7.6 Hz, 1H), 5.31 (d, J=5.7 Hz, 1H), 4.14 (sextet, J=6.1 Hz, 1H), 3.94 (dd, J=5.7, 7.2 Hz, 1H), 2.30 (s, 3H), 1.28 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][C:38]([F:41])([F:40])[F:39])[CH:36]=1)[C:32]#[N:33]>CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[C:35]([O:37][C:38]([F:39])([F:41])[F:40])[CH:34]=1)[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2)#[N:33]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CCl)cc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 83.4 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (75 mg, 0.274 mmol) and cesium carbonate (134 mg, 0.412 mmol) in DMF (2 mL) was added 3-(chloromethyl)-5-(trifluoromethoxy)benzonitrile (78 mg, 0.329 mmol). The reaction was heated at 75° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (108 mg). LCMS m/z=473.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.51-1.62 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.5 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.93 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.14 (s, 2H), 6.18 (s, 1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 7.71 (s, 1H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([OH:24])(=[O:23])[CH3:22].[CH:1]1([CH:7]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C(=C(c1ccccc1)c1ccccc1)c1ccccn1
Solvent: CC(=O)O
Product: C1CCC(C(CC2CCCCN2)C2CCCCC2)CC1
Temperature: 115 °C

Procedure:
To a nitrogen-purged ten gallon autoclave is added a slurry of 400 g. of a 5 percent rhodium-on-carbon catalyst (Engelhard Industries) followed by a warm (50° C.) solution of glacial acetic acid and 4.0 kg (15.5 moles) of 2-(2,2-diphenylethenyl)pyridine. The charging system is rinsed using an additional 3.5 liters of glacial acetic acid. The system is purged with nitrogen and then hydrogen gas is introduced to a pressure of 40 atmospheres. The reaction mixture is stirred and heated to a temperature of about 115° C. Hydrogenation is continued at this temperature until no further hydrogen is taken up by the reaction mixture, usually a period of three to four hours. The reaction mixture is cooled to 30°-40° C. and the catalyst removed by filtration. The autoclave is rinsed several times with acetic acid which is then used to wash the catalyst. The combined filtrates are concentrated in vacuo to obtain an oily residue of 2-(2,2-dicyclohexylethyl)piperidine acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]3[NH:25][N:24]=[N:23][N:21]=3)[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(Oc2c(C)nn(CC#N)c2C)c2c1CCC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2c(C)nn(Cc3nnn[nH]3)c2C)c2c1CCC2
Temperature: 95 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a stirred solution of [4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (3.0 gm, 0.0101 mole) in Dimethylformamide (30 ml), Sodium azide (1.2 gm, 0.0185 mole) and Triethylamine hydrochloride (4.0 gm, 0.0303 mole) were added at room temperature (27-30° C.). The reaction mixture was stirred at 90-100° C. for 4 hours. The reaction mixture was cooled and poured into dilute Hydrochloric acid (100 ml) and stirred for 30 minutes. The separated solid was filtered and dissolved in Ethyl acetate (100 ml). The Ethyl acetate layer was dried over Sodium sulphate and distilled under vacuum to get a 1.5 gm of desired product as a solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:17]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccc2c(c1)OCCO2
Product: O=C(CCCCCl)c1ccc2c(c1)OCCO2

Procedure:
Using 2,3-dihydro-1,4-benzodioxine (10.0 g) and 5-chlorovaleryl chloride (10.4 ml) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (15.1 g) having a melting point of 52 to 53° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.OO.[C:14](=O)([O-])[O-:15].[Na+].[Na+].Cl.C(=O)C.[Cl-].[Na+]>O>[CH3:14][O:15][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: O=C([O-])[O-]
Agent: CC=O
Agent: Cl
Agent: OO
Solvent: O
Product: CON1C(C)(C)CC(=O)CC1(C)C
Reaction time: 2 h
Yield: 62 %

Procedure:
The intermediate, 1-oxy-2,2,6,6-tetramethyl-piperidin-4-one, can be produced by reacting 2,2,6,6-tetramethyl-piperidin-4-one with 3 equivalents of hydrogen peroxide in excess water, with 10% sodium carbonate added, for 5 h at 50°. When the reaction is complete, the solution is slightly acidified with 2 N hydrochloric acid to pH 5, then 3 equivalents of acetaldehyde and one equivalent of sodium chloride are added, and two equivalents of 30% hydrogen peroxide are added slowly at 50°. The mixture is stirred at 90° for 2 h, and then cooled. The work-up, as above in example E, gives 62% of liquid product, crystallizes slowly.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:3]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccc(F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 90.6 %

Procedure:
Methyl 2-[2-(4-{2-[ethyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]-benzoate (0.223 g, 0.479 mmol) was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), lithium hydroxide (0.229 g, 0.958 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.196 g of 2-[2-(4-{2-[ethyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid (yield 90.6%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[NH:11][C:10](=[O:12])[C:9]=3[C:8]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Solvent: c1ccccc1
Product: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Yield: 79.6 %

Procedure:
To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (4.00 g, 17.9 mmol) in benzene (2000 ml) under nitrogen was added N-bromosuccinimide (4.00 g, 22.5 mmol). The reaction mixture was stirred just below reflux for 30 minutes, then at a gentle reflux for 30 minutes. The resulting suspension was allowed to cool for 2 hours, the solid filtered and dried at 70° C. under reduced pressure to give 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g, 83% purity by NMR). 1H NMR (DMSO-d6, 300 MHz) δ: 2.45 (s, 3H, CH3, 4.96 (s, 2H, CH2), 7.65 (d, J=9 Hz, 1H, Ar), 7.70 (dd, J=8,2 Hz, 1H, Ar), 8.05 (d, J=8 Hz, 1H, Ar), 8.16 (d, J=9 Hz, 1H, Ar), 9.89 (s, 1H, Ar), 12.7 (br s, 1H, NH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[N:17]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.O>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH2:22])=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[N:17]=2)[CH2:2]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Yield: 66.7 %

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (416 mg, 2.079 mmol), 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (500 mg, 1.386 mmol), and N,N-diisopropylethylamine (0.484 mL, 2.77 mmol) in N-methyl-2-pyrrolidinone (3 mL) was heated to 120° C. overnight. The reaction mixture was diluted with water. The grey precipitate was filtered and the solid was purified by chromatography (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g+12 g stack silica gel columns) to give 485 mg of (R)-tert-butyl-1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 g (25 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman (Ex. 1 e) were introduced in portions at 10° C. into a suspension of 1.2 g (30 mmol) of sodium hydride (60 percent dispersion) in 75 ml of DMA. After stirring at RT for 2 h, 1.9 ml (30 mmol) of methyl iodide were added dropwise, the temperature rising to 50° C. The mixture was then heated to 50° C. for 2 h, concentrated in vac., the residue was treated with water, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using n-heptane/EA (2:1). 7.4 g of product were crystallized from appropriate fractions using petroleum ethendusopropyl ether (1:1), m.p. 114-116° C.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:25]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(N(C)S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(4-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in an analogous manner to Step 2d and was isolated as a tan solid (0.038 g, 33%). MP=202-204° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.9 Hz, 1H), 8.06 (d, J=7.4 Hz, 2H), 7.58 (d, J=7.1 Hz, 1H), 7.52 (d, J=7.4 Hz, 2H), 7.36 (s, 1H), 7.25-7.19 (m, 1H), 7.00-6.95 (m, 2H), 6.83 (s, 1H), 6.59 (d, J=8.4 Hz, 1H), 3.39 (s, 3H), 3.30-3.25 (m, 4H), 2.90 (s, 3H), 2.63-2.58 (m, 4H), 2.37 (s, 3H). MS=492 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C:12]([B-](F)(F)F)([CH3:14])=[CH2:13].[K+].C(Cl)Cl.C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1)([CH3:14])=[CH2:13]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(C(F)(F)F)nc1
Yield: 58.5 %

Procedure:
A mixture of 5-bromo-2-(trifluoromethyl)pyridine (452 mg, 2.0 mmol), potassium isopropenyltrifluoroborate (355 mg, 2.4 mmol), PdCl2(dppf).CH2Cl2 (82 mg, 0.1 mmol) and triethylamine (0.28 ml, 2.0 mmol) in n-propanol (20 ml) was treated in the same procedure as described in Example 10B. The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and EtOAc (20/1) to afford 219 mg (59% yield) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.27 g), piperidine (0.3 ml), N,N-diisopropylethylamine (0.53 ml) and KI (0.25 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (5.75 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-(2-piperidin-1-ylethoxy)quinazolin-3(4H)-yl]benzoic acid (0.14 g); NMR Spectrum: (DMSOd6) 1.42 (m, 6H), 2.13 (s, 3H), 2.48 (m, 4H), 2.72 (m, 2H), 4.20 (m, 2H), 7.49 (m, 2H), 7.56 (m, 1H), 7.69 (d, 1H), 7.88 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 408.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(C)s1
Yield: 99.8 %

Procedure:
5-Methyl-4-nitro-thiophene-2-carboxylic acid methyl ester [15.09 g., 75.0 mM, Intermediate (23)] is dissolved in ethyl acetate (200 mL) to which 10% palladium on charcoal (1.03 g) is added and the mixture is shaken under 50 psi of hydrogen. The catalyst is removed by filtration and the solvent is removed leaving 4-amino-5-methyl-thiophene-2-carboxylic acid methyl ester [12.82 g., 99.8%, Intermediate (24)] as a yellow solid; MS 171.9 (100%, M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1N
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To solution of (4-cyano-2-nitrophenyl)-carbamic acid tert-butyl ester (3.6 g, 13.8 mmol) in methanol (18 mL), ethyl acetate (28 mL) and triethylamine (1.9 mL, 13.6 mmol) was added 10% Pd on carbon (0.73 g, 0.69 mmol). The reaction mixture was hydrogenated under 1 atm H2 for 24 hours, filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 20% ethyl acetate in n-heptane as eluent to afford (2-amino-4-cyanophenyl)-carbamic acid tert-butyl ester (2.6 g, 82%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[NH:11][N:12]=[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([B:32]4[O:33][C:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[O:36]4)=[CH:30][CH:31]=3)[C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (12.0 mg, 0.0383 mmol), 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0383 mmol) and potassium carbonate (5.3 mg, 0.0383 mmol) in acetone (2.5 mL) is stirred at room temperature overnight. The solvent is evaporated under reduced pressure. The residue is directly purified by chromatography to give 7.0 mg product as white solids (Yield: 38.0%). MS (ESI) m/z 530.3 [M+H]+.