Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:31])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=3)[O:8][C:7](=[O:29])[C:6]=2[CH:30]=1.[CH3:32][NH2:33].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:30]=[C:6]([C:7]([NH:33][CH3:32])=[O:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.8 %

Procedure:
To a suspension of the 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) in tetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 45 minutes. Thin layer chromatography then showed the reaction to be complete. Ethyl ether (100 mL) was added, and the reaction mixture was stirred for 2 hours while a precipitate formed. The precipitate was collected by filtration and then recrystallized from acetonitrile to yield a white solid (0.82 g). A second crop of white solid (0.35 g) precipitated from the acetonitrile mother liquor and was collected by filtration. The initial ether/tetrahydrofuran mother liquor was concentrated to dryness, and the residual solid was recrystallized from acetonitrile to yield a third crop of white solid (0.95 g). The three crops were combined, totaling 2.12 g (after drying) of the title compound, isolated as a white solid, melting at 207-208° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=1>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][N:17]([C:25]3[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=3)[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: CC(=O)NCc1ccc(Br)cc1C
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Sodium tert-butoxide (0.3 g), Tris(dibenzylidene acetone)dipalladium(0) (chloroform adduct) (0.04 g) and xantphos (0.07 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.59 g) and N-(4-bromo-2-methylbenzyl)acetamide (0.5 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 5 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylbenzyl}acetamide (0.6 g). 1H-NMR (CDCl3) δ: 2.13-2.18 (6H, m), 2.51-2.53 (1H, m), 2.81-2.83 (1H, m), 3.45-3.56 (2H, m), 3.75-3.78 (1H, m), 4.01-4.04 (1H, m), 4.25 (1H, s), 4.57 (1H, s), 6.40-6.44 (2H, m), 6.93-6.96 (1H, m), 7.30-7.38 (3H, m)
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11](S(O)(=O)=O)=[CH:12][CH:13]=1.O.[O:19]1C=CC=[N:20]1.[F-].[K+]>O>[O:19]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[N:20]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1cnoc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2oncc2c1
Temperature: 40 °C

Procedure:
To a 100 L cylindrical vessel with heating coils were charged EtOAc (20 L) and TsOH/H2O (2.304 kg, 12.11 mol), and the mixture was heated to 35-45° C. to dissolve. The acid solution was fed into the isoxazole batch with further distilling, maintaining a constant volume of 25 L. An additional 20 L of EtOAc was distilled to azeotropically dry the mixture. A slurry began to form, and it continued to thicken on addition and concentration. The final KF was 400 ppm water. The batch was heated to 60° C. and allowed to slowly cool to ambient temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]N)=[O:10])[CH:6]=[CH:5][N:4]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(C(=O)NN)ccn1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyridine-4-carbohydrazide 8 (167 mg, 1.0 mmol) in 10 mL of THF was added maleic anhydride (110 mg, 1.1 mmol). The mixture was stirred at ambient temperature for 2 h. After removal of the solvent, the residue was diluted with 10 mL of dichloromethane. The solid was collected by filtration to give (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 as a solid. Yield: 190 mg, 71%.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21][N:20]=1>Br.O>[CH3:25][C:23]1[N:22]=[CH:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[CH:24]=1
Reactant: Cc1cc(N)ncn1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (3.43 ml, 22.1 mmol) in concentrated hydrobromic acid (1.1 ml) and water (1.1 ml) was heated at reflux under nitrogen for 2 h, then poured into ethanol (57 ml). The solution was neutralised to pH 7 with solid sodium hydrogen carbonate, then filtered. To the filtrate was added 4-amino-6-methylpyrimidine (1.0063 g, 9.22 mmol) and the mixture was stirred at room temperature for 30 min then at 60° C. for 19 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2CO2) to give 0.5071 g (41%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 2.54 (3H, s), 7.33 (1H, s), 7.59 (1H, s), 7.62 (1H, d, J 1.2 Hz), 8.96 (1H, s); MS (ES+) m/z 134 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(S(N)(=O)=O)c3)cc21

Procedure:
Prepared according to procedure B from 3-bromobenzenesulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 242-244° C. (dec) 1H-NMR (DMSO-d6) δ 10.28 (s, broad 1H), 8.07(s, 1H), 7.9(d, 1H, J=7.80 Hz), 7.78 (d, 1H, J=7.86 Hz), 7.64 (t, 1H, J=7.79 Hz), 7,59 (m, 2H), 7.42(s, broad 2H), 7.02(d, 1H, J=8.86 Hz), 1.68 (s, 6H); MS m/z 331 (M+H). Anal. Calc. for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43. Found: C, 57.49; H, 5.08; N, 8.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][C:30]12[CH2:37][CH:34]([NH:35][CH2:36]1)[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:35]3[CH2:36][C:30]4([CH3:29])[CH2:37][CH:34]3[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]4)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.132 g). 1H NMR (400 MHz, CHCl3-d; 80° C.); □ 7.6 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.0 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 3.0 (m, 1H), 2.9 (m, 1.9 (m, 2H), 1.7 (m, 1H), 1.6-0.9 (m, 26H).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:30])[C:24](=[CH:28][CH:29]=1)[C:25](O)=[O:26].C1N=CN(C(N2C=NC=C2)=O)C=1.O>C1COCC1>[CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=3)[NH:30][C:18]2=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cc1cccc(S(=O)(=O)N=C=O)c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)Cc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Following the Synthesis Method (A), 3.27 g (11.6 mmol) of 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100 ml of anhydrous THF, then 1.98 g (11.5 mmol) of 4-chloroanthranilic acid was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol) of CDI was added and the resultant mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the mixture was extracted with ethyl acetate. The organic layer was washed, dried, and concentrated to obtain a crude product. This was crystallized with a small amount of ethyl acetate to obtain 2.0 g (yield 40%) of 3-(3-allyloxycarbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. The allyl product thus obtained was dissolved in 100 ml of a formic acid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. The reactor was shaded from light and under nitrogen atmosphere, then 700 mg of tetrakis(triphenylphosphine)palladium (0) was added and the resultant mixture was stirred while shaded at room temperature overnight. The reaction solution was concentrated in vacuo and the solid obtained was washed with methylene chloride to obtain 1.47 g (yield 81%) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.76 (2H, s), 7.13 (1H, s), 7.24 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H, d), 8.05 (2H, s), 12.50 (1H, br).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:25][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(c2ccccc2)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolved in N,N-dimethylformamide (30 mL), and then K2CO3 (4.2 g) was added and the reaction stirred at room temperature for 60 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with 2.11 aqueous Na2CO3 and brine, then dried over Na2SO4. After filtration and concentration, the crude material was purified by column chromatography using 1.5-2.0% ethyl acetate in hexanes.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH:45]([CH3:47])[CH3:46])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:39]=[CH:40][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:42][CH:43]=2)[CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)N(C(=O)CN1CCCCC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C(=O)CN2CCCCC2)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H36N4O4
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1.[C-]#N.[Na+]>O.CO>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCO3)CC1

Procedure:
Using general procedure A with 3,4-(methylenedioxy)aniline (250 mg, 1.8 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (329 mg, 2.0 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amine as a white solid (281 mg, 68% over 2 steps) after work-up and purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC[C@@H](n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)C1
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
To a mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol) in anhydrous DCM (3 mL) was added acetone (90 μL, 1.24 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (132 mg, 0.621 mmol) was added and stirring was continued for 22 h. The mixture was then treated with NaOH (1N, 2 mL) and then vigorously stirred for 10 min. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) affording 132 (58 mg, 35%). LCMS: RT 1.91 min [M+H]+ 405.1. 1H NMR (DMSO, 400 MHz): δ 12.97 (1H, s), 8.33-8.06 (2H, m), 7.96 (1H, br), 7.72 (1H, d, J=7.33 Hz), 7.62 (1H, d, J=7.14 Hz), 7.24-7.07 (2H, m), 5.93 (1H, s), 4.66-4.52 (1H, m), 3.00-2.83 (2H, m), 2.81-2.65 (2H, m), 2.23 (1H, t, J=11.59 Hz), 2.15-2.01 (1H, m), 1.84-1.57 (5H, m), 1.26-1.07 (1H, m), 0.96 (6H, d, J=6.51 Hz)
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[C:5]=1[O:22][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(N)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 16.3 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (94 mg, 0.375 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)[CH:7]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12]([NH:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:13]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(N)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate. LC-MS m/z 463 (M+H)+, 1.73 min (ret time).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:3]1.[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[CH2:16]([O:18][C:8]([C:7]1[CH2:2][NH:3][C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:6]=1)=[NH:9])[CH3:17]
Reactant: CC(C)(C)Cc1ccc(C#N)c(=O)[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1=CC=C(CC(C)(C)C)NC1
Reaction time: 2 h

Procedure:
A solution of 1,2-dihydro-2-oxo-6-neopentyl-3-cyanopyridine (8.8 g) and 400 ml of absolute ethanol is cooled in an ice bath and a slow stream of anhydrous hydrogen chloride is passed therethrough for 2 hr. The resulting solution is allowed to stand at ambient temperature for 3 days. Thereafter the solvent is evaporated under reduced pressure at ambient temperature, and the resulting material dissolved in warm trichloromethane. Acetone is added and following cooling the material is recovered by filtration and washed with acetone, yielding ethyl-1,2-dihydro-6-neopentyl-3-pyridine-carboximidate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C>[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=1[C:19]([NH:21][C:22]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[N:7]=1)=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)n1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(-c2ccc(Cl)cc2)c(Cl)n1

Procedure:
6-Chloro-5-(4-chlorophenyl)-2-pyridylamine (0.3 gram) was dissolved in 25 ml acetonitrile and treated with 2,6-difluorobenzoyl isocyanate (0.5 gram) under nitrogen at room temperature. A precipitate formed almost immediately and after about three hours stirring, the solid was collected and washed with acetonitrile, yield 0.36 gram, m.p. 237°-241° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O)[CH3:2].C1(C)C=CC=CC=1.[CH3:29][NH:30][NH2:31]>O>[CH3:29][N:30]1[N:31]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([CH2:20][CH3:21])=[CH:19][C:3]=2[CH2:1][CH3:2])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CNN
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)c(CC)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2nn(C)c(=O)c3ccccc23)c(CC)c1
Yield: 55.9 %

Procedure:
A mixture of 2-(2,4-diethylbenzoyl)benzoic acid (40 g, 0.14 mol), toluene (120 mL) and methyl hydrazine (7.5 mL) were refluxed for 3 hours with removal of water via a Dean Stark trap. Additional toluene (100 mL) and methyl hydrazine (4.0 mL) were added and the mixture was refluxed until 2.8 mL of water was collected. The mixture was cooled, extracted with CH2Cl2 /2N NaOH, then 1N HCl and the organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from ethanol/water and recrystallized from ethanol/water to afford 22.86 g (55.9%) of 2-methyl-4-(2,4-diethylphenyl)-1-(2H)-phthalazinone, m.p. 94.5°-96.5° C.