Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([C:25]2[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1.C(=O)([O-])O.[Na+].O>COCCOC.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>[CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[C:25]2[N:30]=[CH:29][C:28]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[CH:27][N:26]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-3-{(5-bromo-pyrimidin-2-yl)-[3-chloro-5-(trifluoromethyl)benzyl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (0.19 mmol, 100 mg), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.23 mmol, 48 mg), tetrakis(triphenylphosphine)palladium(0) (0.02 mmol, 22 mg) and 2M aqueous sodium hydrogen carbonate (0.19 mL) in 1,2-dimethoxy-ethane (0.6 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: CH2Cl2/EtOAc). To the obtained mixture in CH2Cl2 (1 mL) is added saturated aqueous sodium carbonate (0.04 mL) and NaIO4 (82 mg). The mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (67 mg, 67%); ESI-MS m/z: 523 [M+1]+, Retention time 2.16 min (condition A).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:41]([O:42][CH3:43])=[CH:40][C:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:41]([O:42][CH3:43])=[CH:40][C:25]3[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])[CH2:29][CH2:30][C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 71 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product isolated as a pale yellow foam (78 mg, 71%). MS (ESI+): 622.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.95 (s, 1H), 7.34 (s, 1H), 6.65 (s, 1H), 5.41 (d, J=7 Hz, 2H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 3H), 3.74 (t, J=5 Hz, 4H), 3.09 (s, 1H), 2.89 (br s, 5H), 2.71 (br s, 6H), 2.57-2.52 (m, 7H), 2.27 (d, J=9 Hz, 1H).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH2:30])[CH:29]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:29]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1ccc(F)cc1N
Product: Cc1ccc(F)cc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (5-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.11 (s, 3H), 2.17 (s, 3H), 4.39 (d, J=1.6 Hz, 2H), 7.77-7.88 (m, 2H), 7.09-7.20 (m, 3H), 7.34 (d, J=9.8 Hz, 1H), 7.45 (s, 1H), 7.64 (t, J=7.5 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9](C)(C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2].C[O-].[Na+].CO>Cl>[CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:12]=1[C:11]([O:10][CH3:9])=[O:13])=[CH2:2]
Reactant: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1cccc(O)c1C(=O)OC
Yield: 57.3 %

Procedure:
To 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.01 g, 19.6 mmol) was added 0.5 M sodium methoxide in methanol (85 mL, 42.5 mmol) at rt. Aqueous 1 N HCl (100 mL) was added to the solution after 15 min. The cloudy solution was extracted with ether (2×100 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford 2-ethenyl-6-hydroxybenzoic acid, methyl ester (2.0 g, 57%) as a yellow oil. This material was used without further purification in the next step: 1H NMR (CDCl3) δ 3.96 (s, 3H), 5.26 (dd, J=10.8, 1.5 Hz, 1H), 5.49 (dd, J=17.3, 1.5 Hz, 1H), 6.95 (m, 2H), 7.23–7.39 (m, 2H), 11.12 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 66.7 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (139 mg, 0.30 mmol), 2-(methyloxy)-4-[4-(4-morpholinyl)-1-piperidinyl]aniline (79 mg, 0.27 mmol) and p-toluenesulfonic acid (137 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 129 mg (60%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.38 (br s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.46-7.35 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 6.96 (t, J=6.8 Hz, 1H), 6.65 (m, 1H), 6.48-6.43 (m, 2H), 3.77 (s, 3H), 3.71 (d, J=12.4 Hz, 2H), 3.56-3.54 (M, 4H), 2.67-2.62 (m, 2H), 2.49-2.46 (m under DMSO peak, 4H), 2.27-2.22 (m, 1H), 1.86-1.83 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=717 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH:23]([F:25])[F:24])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH:23]([F:24])[F:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C

Procedure:
A solution of 18.0 g of isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate in 60 ml of methylene chloride is stirred intensively for 5 minutes with 100 ml of concentrated sulphuric acid and subsequently poured onto 1 kg of ice. The resulting crystals are filtered off under suction, washed twice with 50 ml of water each time and dissolved in 300 ml of methanol. The mother liquor is extracted twice with 100 ml of methylene chloride each time and the organic phase is washed to neutrality with water and combined with the methanolic solution. This solution is dried over anhydrous sodium sulphate and evaporated to dryness. The crystalline residue is suspended with 100 ml of ethyl acetate at 70° C. and cooled to room temperature, and the crystals are filtered off under suction and washed with diethyl ether. There is obtained 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, m.p. 247°-248° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>ClCCl>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, dichlormethane) (89%, oil). HPLC-MS m/z=389.1 (M+1), Rt: 5.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:12]=[CH:11][C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[N:8][N:7]([C:9]3[C:10]([OH:23])=[C:11]([CH2:10][C:11]4[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([N:7]5[N:6]=[C:5]6[CH:24]=[CH:25][CH:2]=[CH:3][C:4]6=[N:8]5)[C:26]=4[OH:27])[CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=3)[N:6]=2)[CH:5]=[CH:24][CH:25]=1
Reactant: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C=C(C)C(=O)OCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3cccc(Cl)c3n2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3′-N,N-diethylaminomethyl-2′-hydroxy-5′-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 11.1 g (31.0 mmols) of 5-chloro-2-(2′-hydroxy-5′-methacryloyloxyethylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate•methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this stage were separated through filtration, and recrystallized from chloroform to obtain 13.1 g of 6-(4-chloro-2H-benzotriazol-2-yl)-4-methacryloyloxyethyl-2-[3′-(2H-benzotriazol-2-yl)-2′-hydroxy-5′-methylphenyl]methylphenol (hereinafter abbreviated as “RUVA-2” as white crystals (yield 70.3%, purity 98.8%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH3:23])[CH:16]=[CH:15]2.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH:23]=[CH:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[CH:1]=[O:10])[CH:16]=[CH:15]2
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2cc(F)c(F)cc2n1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Yield: 59429.1 %

Procedure:
A solution of isophthalaldehyde (312.4 g, 2.33 mmol), 6,7-difluoro-2-methylquinoline (278.4 g, 1.55 mmol) and acetic anhydride (416 mL) in 2 L of xylene was heated to reflux overnight. The solvent was evaporated and the product was swished in 2.5 L of EtOAc to yield the title compound (272 g, 56%). 1H NMR (CD3COCD3): δ 10.12 (1H, s), 8.4 (1H, d), 8.29 (1H, s), 8.1-7.85 (6H, m), 7.7-7.55 (2H, m).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][NH:12][C:13](=[O:39])[CH2:14][C@@H:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:19]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:18]=2[N:17]2[C:35]([CH3:38])=[N:36][N:37]=[C:16]12)C(=O)[O-])(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[C:19]3[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:18]=3[N:17]3[C:35]([CH3:38])=[N:36][N:37]=[C:16]3[C@H:15]([CH2:14][C:13]([NH:12][CH2:11][CH2:10][NH:6][CH3:5])=[O:39])[N:21]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCN(CC(C)(C)C)C(=O)[O-])c1nnc(C)n1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Intermediate 16 (189 mg, 0.342 mmol) and trifluoroacetic acid (0.022 mL, 0.285 mmol) were dissolved in DCM (3 mL) and stirred at 25° C. under N2 for 2 h. The solvent was evaporated under vacuum and the residue obtained dissolved in DCM and re-evaporated under vacuum to give a yellow oil which was dried under high vacuum to afford the title compound as a yellow solid (153 mg, 0.270 mmol, 95% yield). LC/MS (M(35Cl)+H)+ 453, (M(37Cl)+H)+ 455; RT 0.74 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:10])[F:9])[CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:41][O:42][C@H:43]1[C:48](=O)[CH2:47][CH2:46][O:45][CH2:44]1.[OH-].[Na+]>ClCCl.O>[C:23]([O:22][C:20]([N:16]1[CH2:15][C@@H:14]2[CH2:19][C@H:17]1[CH2:18][N:13]2[C:11]([C@@:4]1([CH2:7][CH:8]([F:9])[F:10])[CH2:5][CH2:6][C@@H:2]([NH:1][C@@H:48]2[C@H:43]([O:42][CH3:41])[CH2:44][O:45][CH2:46][CH2:47]2)[CH2:3]1)=[O:12])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)CC[C@@H](N)C1
Reactant: CO[C@@H]1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A 0° C. solution of tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.45 g, 9.2 mmol) in dichloromethane (50 ml) was treated with sodium triacetoxyborohydride (5.34 g, 25.2 mmol) and (3R)-3-methoxytetrahydro-4H-pyran-4-one (2.31 g, 17.8 mmol). The reaction was stirred under nitrogen at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 47 hours. The reaction was treated with 2.5N NaOH (35 mL) and stirred for 10 minutes. The reaction was diluted with water and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13 g, 47%) which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1onc(-c2ccncn2)c1CO
Reactant: COC(=O)c1ccc(O)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of (5-methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol (313 mg, 1.63 mmol) in THF (20 mL) was added methyl 6-hydroxynicotinate (276 mg, 1.8 mmol) and triphenylphosphine (644 mg, 2.5 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (95 mg, 18%) as a white solid. MS: m/e=327.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[CH:9]([O:8][C:4]1[N:3]=[C:2]([CH:20]=[O:21])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C=O)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
6-isopropoxypyridine-2-carbaldehyde was prepared in a manner similar to that described in D. L. Comins, M. O. Killpack, J. Org. Chem. 1990 55 69-73 for the methoxy analog. 2-bromo-6-isopropoxypyridine (1 g, 4.6 mmole) was dissolved in 10 ml dry THF under argon, cooled to −78° C. and treated with added 2.5 M n-Butyl lithium (1.9 mL, 4.8 mmole) keeping the temperature of the reaction below −65° C. After the reaction had stirred 45 min DMF (0.717 mL, 9.25 mmole) was added, again keeping temp below −60° C., the reaction was stirred for 15 min, then quenched with saturated bicarbonate solution. The layers were separated, the aqueous extracted with CHCl3, the organic layers dried over Na2SO4, filtered and evap carefully, and the residue chromatographed in 0-50% Ether/hexanes to give the product as an oil. LCMS (m+1)=165.2
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])[C:6]([CH2:12]Cl)=[N:7]2.[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:24])([F:23])[F:22])[C:4](=[O:25])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:28]=[C:27]([I:26])[C:35]=12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1C(F)(F)F
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1C(F)(F)F

Procedure:
To a solution of the quinazolinone, obtained as described above, (100 g, 90% pure, 210 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.4 g, 193 mmol) in DMF (600 mL) at RT was added potassium carbonate (80.0 g, 580 mmol) and after 18 hr the reaction mixture was poured into water (1.2 L). The resulting precipitate was collected by filtration, and was washed sequentially with water (500 mL), with EtOAc (600 mL) and finally with Et2O (400 mL). The resulting cake was dried in vacuo to afford the title compound, Intermediate A, as an off white solid (115 g, 89%); Rt 2.28 min, m/z 656/658 (M+H)+ (ES+).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(OCC)C.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25]>CCCCC>[OH:1][CH:2]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC=O
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC(O)C(C)(C)C

Procedure:
1.94 g. of 6-[(6-oxo-3-methyl-2-hexenyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 80 ml. of absolute diethyl ether and treated dropwise at 0° C. under nitrogen over a period of 20 minutes with 5 ml. of a 2-M solution of tertbutyl lithium in pentane. The mixture is then poured into ice-cold saturated aqueous ammonium chloride solution and extracted twice with diethyl ether. The extracts are dried over sodium sulfate and evaporated. There is obtained crude 6-[(6-hydroxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran which is used in the process without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9]([Cl:19])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH2:34][CH3:35])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CC(CC)=O>[CH2:34]([N:33]([CH:30]1[CH2:29][CH2:28][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:32][CH2:31]1)[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([Cl:19])[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:35]
Reactant: COc1cc(NC(=O)C(F)(F)F)c(Cl)cc1C(=O)Cl
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCN(C(=O)c1cc(Cl)c(NC(=O)C(F)(F)F)cc1OC)C1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
A solution of 2-methoxy-4-trifluoroacetylamino-5-chlorobenzoyl chloride (17.4 g; 0.055 moles) dissolved in anhydrous ethyl methyl ketone (75 ml) was added little by little to another solution of 1-benzyl-4-ethylamino-piperidine (10.9 g; 0.05 moles) and triethylamine (7.0 ml; 0.05 moles) in anhydrous ethyl methyl ketone (75 ml) at room temperature. On completion of the addition, the mixture was left at room temperature and stirred for 48 hours, and then the mixture was concentrated at reduced pressure, poured into water, and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo. The residue was recrystallized from a mixture of methanol and diethyl ether to give N-ethyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-trifluoroacetylamino-5-chlorobenzamide (17 g), m.p. 198°-200° C.