Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 110 °C
Yield: 86.3 %

Procedure:
Huning's base (1.18 mL, 6.77 mmol) was added to a solution of 6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (820 mg, 4.52 mmol) in POCl3 (8.42 mL, 90.0 mmol) at room temperature, and the reaction mixture was heated at 110° C. for 5 h. After cooled to room temperature, the excess POCl3 was removed by evaporation. Toluene was added to the residue, and the azeotrope was removed under reduced pressure. DCM was poured into the residue, and the suspension was treated carefully with aq. NaHCO3 at 0° C. to pH 7˜9. The insoluble solid was filtered off, and the filtrate was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM:EtOAc=10:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (780 mg, 86%) as a pale yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.86 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=8.8 Hz), 9.14 (1H, s). m/z=199.01 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:9]4[O:8][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[N:11][C:10]=34)=[O:18])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(N3CCOCC3)nc12
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(N3CCOCC3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-morpholinobenzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-morpholino-benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: CC1(C)[O:6][C@@H:5]2[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]3[CH2:25][CH:24]([CH2:26][CH2:27][C:28]4[NH:32][C:31]5[CH:33]=[CH:34][C:35]([CH:37]6[CH2:40][O:39][CH2:38]6)=[CH:36][C:30]=5[N:29]=4)[CH2:23]3)[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@H:9]1[C@H:4]([OH:3])[C@H:5]([OH:6])[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]2[CH2:25][CH:24]([CH2:26][CH2:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][C:35]([CH:37]5[CH2:38][O:39][CH2:40]5)=[CH:36][C:30]=4[N:29]=3)[CH2:23]2)[O:8]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 5.75 h
Yield: 54.8 %

Procedure:
To a cooled (ice bath) flask containing 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.28 g, 0.42 mmol) was added a precooled (ice bath) solution of trifluoroacetic acid (6.4 mL, 84 mmol) in water (0.75 mL, 42 mmol). The reaction mixture was stirred for 5.75 h at 0° C.; HPLC/LC MS indicated nearly complete consumption of starting material. At 6 h the flask was removed from the cold bath and the volatiles were removed by distillation at rt. The residue was diluted with MeOH (15 mL) and treated with potassium carbonate (0.32 g, 2.3 mmol) and water (1 mL) and the mixture was stirred for 20 min at rt; pH 2. Additional potassium carbonate (0.20 g, 1.4 mmol) was added and the mixture was stirred for 20 min; pH 8-9. The solution was filtered through a fine frit, rinsing with MeOH, and the filtrate was concentrated in vacuo to afford a tan semi-solid. Purification by column chromatography (3×8 cm silica; 10-20% 7 N methanolic NH3/CH2Cl2) afforded the title compound (123 mg, 55%) as a nearly colorless glass: MS (ESI+) for C27H34N8O4 m/z 535.3 (M+H)+; MS (ESI−) for C27H34N8O4 m/z 533.3 (M−H)−; HPLC purity >95% (ret. time 1.765 min); 1H NMR (400 MHz, d4-MeOH) mixture of cis/trans isomers δH 8.29-8.25 (m, 1H), 8.21-8.17 (m, 1H), 7.51 (s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.26 (dd, J=1.6, 8.3 Hz, 1H), 6.00-5.96 (m, 1H), 5.11 (dd, J=5.8, 8.3 Hz, 2H), 4.81-4.76 (m, 2H), 4.73-4.68 (m, 1H), 4.40-4.31 (m, 1H), 4.27-4.13 (series of m, 2H), 3.13-3.03 (m, 0.4H), 2.86-2.66 (series of m, 4.6H), 2.30-1.80 (series of m, 8.6H), 1.55-1.40 (m, 1.4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NC(=O)Cc2ncccc2Cl)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (0.192 g, 0.497 mmol) and CDI (0.322 g, 1.986 mmol) in toluene (2 mL) was heated at 110° C. After 5 h, the cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide racemic 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a bright yellow solid (0.133 g, 65% yield). Mass spectrum m/z 413 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.26 (dt, J=7.6, 0.9 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](Cl)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([C:14](=[O:15])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Reactant: [Zn+]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride, benzylzinc bromide (0.5 mol/L, tetrahydrofuran solution, 4.4 mL), dichlorobis-(triphenylphosphine)palladium(II) (153 mg) and toluene (6 mL) was stirred at room temperature under an argon atmosphere for 5 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5%-20% ethyl acetate/hexane, gradient elution) to give the title compound (307 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[C:25]([O:24][C:22]([CH2:21][O:16][CH2:15][CH:14]([NH:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[Cl:1])[CH3:17])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1ccc(NC(C)CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetate are added and the mixture is stirred for a further 16 h at ambient temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=95:5->80:20)
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.CO.[OH-].[Na+]>C1COCC1>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([C:14]([NH:13][C@@H:5]([C:4]([OH:28])=[O:3])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC[C@@H](NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid diethyl ester (250 mg, 0.65 mmol) in THF (6 mL) was added to MeOH (6 mL), followed by the addition of 1N NaOH solution (5.2 mL, 5.2 mmol, 8 eq.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. 1N HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. Product N-(1,1′-biphenyl-4-ylcarbonyl)-D-glutamic acid (189 mg) was isolated in 89% yield. MS (ESI) m/z 326.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C@H:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.[CH3:17]I>CN(C=O)C>[CH3:17][N:15]1[C@H:11]([CH2:10][O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)[CH2:12][CH2:13][C:14]1=[O:16]
Reactant: O=C1CC[C@@H](COC2CCCCO2)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@H]1COC1CCCCO1
Temperature: -40 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a mixture of NaH (0.48 g, 12 mmol, 60% mineral oil, Aldrich) in 15 mL of DMF was added a solution of (S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one (2 g, 10 mmol) in 5 mL of DMF via a syringe at −40° C. The reaction was stirred at −40° C. for 1 hr. CH3I (0.9 mL, 12 mmol, Shanghai Jingchun Reagent Ltd.) was added dropwise via a syringe. The reaction was continued to stir at −40° C. for 4 hrs, and was quenched with 10 mL of saturated NaHSO3 aqueous solution. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired product as colorless oil (1.98 g, 92%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH:13]=[C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[F:33][C:2]([F:1])([F:32])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH:13]=[C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A solution of tert-butyl 4-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)benzylidene)piperidine-1-carboxylate (50 mg, 0.107 mmol) in dichloromethane (5 mL) was cooled to 0° C. and treated with trifluoroacetic acid (123 mg, 1.07 mmol) dropwise. The reaction mixture was then allowed to warm to room temperature and stirred at that temperature overnight. The reaction was concentrated, and the residue was dissolved in water (5 mL). The aqueous layer basified up to pH ˜8 with 1M sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (3×20 mL), and organic layers were washed with water (2×10 mL), dried over sodium sulfate, and concentrated to give the crude title compound (40 mg, quant.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28][CH:29]([N-]C(C)C)C.ICC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:28][CH3:29])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (165 mg, intermediate E1) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 2.8 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodoethane (67 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h and at −20° C. for 16 hours. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (4:1) to give [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (96 mg) as a colorless foam. MS (ESI): m/z=391.3 [ M+H]+. The hydrogenation of the nitro group to give the aniline (intermediate F) was carried out as described in Scheme 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1([C:41]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([C:41](=[O:42])[C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH2:36][CH2:37]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 6,6-bis-(4-fluoro-phenyl)-hex-5-enoic acid (2.64 g, 8.75 mmol) and CDI (1.42 g, 8.75 mmol) in dry THF (30 ml) was stirred for 1 hr at room temperature under nitrogen. A solution of piperazin-1-yl-(3,4,5,-trimethoxy-phenyl)-methanone (2.45 g, 8.75 mmol) in dry THF (30 ml) was added to above solution and resulting mixture stirred at room temperature overnight. The mixture is diluted with EtOAc (30 ml) and washed with water (2×30 ml) and dried over MgSO4. Evaporation of solvent followed by column chromatography using CH2Cl2:MeOH (15:1) gave the desired product in 49% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[Si:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][C:2]=1[Cl:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)Cc1ccc(O)c(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(N)=O)cc1Cl
Yield: 77.4 %

Procedure:
A solution of 2-(3-chloro-4-hydroxy-phenyl)-acetamide (100 mg), imidazole (184 mg), and tert-butyldimethylsilyl chloride (163 mg) was stirred for 2 h in 5 mL of dimethylformamide. The solution was diluted with 50 mL of ethyl acetate and washed with 50 mL of sodium carbonate. The ethyl acetate was evaporated to afford 125 mg of 2-[4-(tert-butyldimethylsilanyloxy)-3-chlorophenyl]acetamide.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][NH:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCCOc1ccc(CNCc2ccc(C(F)(F)F)cc2)c2ccccc12
Yield: 66 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(dodecyloxy)-1-naphthaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (66%). 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.76-7.41 (m, 6H), 7.32 (d, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 4.19-4.11 (m, 4H), 3.63 (s, 2H), 1.96-1.84 (m, 2H), 1.63-1.47 (m, 2H), 1.45-1.20 (m, 16H), 0.87 (t, J=6.8 Hz, 3H). HPLC (Condition A), Rt: 5.41 min (HPLC purity: 100%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]1=[O:17])[CH:2]=[CH2:3].[C:18]([O:22][C:23](=[O:32])[NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1I)([CH3:21])([CH3:20])[CH3:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]=[CH:2][CH2:3][C:30]2[CH:29]=[N:28][CH:27]=[CH:26][C:25]=2[NH:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:32])[C:5](=[O:17])[CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccncc1CC=CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Allyl-4-(tert-butyloxycarbonyl)-piperazin-2-one (0.49 g, 2.0 mmol) is treated with (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (0.64 g, 2.0 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), P(o-tol)3 (37 mg, 0.12 mmol), and Et3N (0.56 mmol) in a seal tube. The mixture is stirred at 100° C. overnight, then diluted with CH2Cl2 and washed H2O (2×). The CH2Cl2 layer is concentrated and the residue is chromatographed (5% MeOH/CH2Cl2) to give a mixture of two isomers (0.40 g, 0.92 mmol). The mixture is separated into its constituent isomers upon further chromatography (EtOAc) to give 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.21 mmol, higher Rf value) and 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-allyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester_(0.24 g, 0.56 mmol, lower Rf value). For the former: MS m/z 433 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.38 (d, 1H), 8.28 (s, 1H), 7.93 (d, 1H), 7.48 (d, 1H), 6.67 (s, 1H), 5.10 (m, 1H), 4.15 (s, 2H), 3.70 (t, 2H), 3,46 (t, 2H), 3.39 (d, 2H), 1.48 (s, 9H), 1.45 (s, 9H). For the latter: MS m/z 433 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.39 (s, 1H), 8.37 (d, 1H), 7.98 (d, 1H), 6.77 (s, 1H), 6.52 (d, 1H), 6.07 (m, 1H), 4.23 (d, 2H), 4.12 (s, 2H), 3,69 (t, 2H), 3.40 (t, 2H), 1.52 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].Cl.Cl.Cl.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[CH:23]=[C:24]([Cl:40])[C:25]([C:38]#[N:39])=[C:26]4[C:32]=3[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]3[CH2:37][NH:36][CH2:35]3)[CH2:27]4)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:32]4[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]5[CH2:37][N:36]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:35]5)[CH2:27][C:26]=4[C:25]([C:38]#[N:39])=[C:24]([Cl:40])[CH:23]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Reactant: NC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(N)=O)C2)C3)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
2-Bromoacetamide (0.01 g, 0.09 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.18 mmol) in N,N-dimethylformamide (2 mL) and then heated to 80° C. for 2 h. The reaction was allowed to cool and was purified without work up by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compounds as two separated diastereomers: Peak #1 (Example 50): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2; Peak #2 (Example 51): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2.
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC4C=CC=CC=4)[CH:17]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.C1COCC1.[Pd]>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc(COc2cccc(-c3nc(N4CCOCC4)nc4nc[nH]c34)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3nc[nH]c23)c1
Yield: 75.4 %

Procedure:
To a solution of compound A (45 mg, 0.116 mmol) in methanol (10 mL) and THF (10 mL) was added 50 mg of 10% Pd/C. The mixture was degassed for three times with N2, and hydrogenated under H2 atmosphere over night. After removing Pd/C by filtration, the reaction was evaporated and the residue purified by prep-TLC (PE:EA=1:2) to give 1 (26 mg, 75%). 1H-NMR (300 MHz, DMSO-d6): δ=3.73-3.76 (m, 8H), 6.89-6.92 (m, 1H), 7.30-7.35 (m, 1H), 8.19 (s, 1H), 8.23 (m, 2H), 9.59 (s, 1H). LC-MS [M+H]+: 298.0.