Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:12]=3[O:11][CH2:10]2)[O:19][CH2:18][CH2:17][CH2:16]4)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[O:34]1[CH2:35][CH2:25][CH2:32][C@@H:33]1[CH2:36][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:12]=3[O:11][CH2:10]2)[O:19][CH2:18][CH2:17][CH2:16]4)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (57%) as an off-white solid: mp 151-156° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.26 (m, 1H), 7.16-7.02 (m, 3H), 6.40 (s, 1H), 6.38 (s, 1H), 4.89 (d, J=9.0 Hz, 1H), 4.644, 4.640 (d, J=9.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.11 (dd, J=5.4, 4.8 Hz, 2H), 3.99-3.69 (m, 4H), 2.63-2.52 (m, 2H), 2.10-1.85 (m, 5H), 1.79-1.67 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.3, 178.2, 160.2, 156.3, 143.0, 132.8, 132.7, 128.8, 128.7, 123.88, 123.86, 123.82, 123.76, 123.3, 121.1, 121.0, 115.24, 115.20, 109.7, 109.5, 98.9, 80.43, 80.40, 77.1, 77.0, 68.4, 68.3, 66.7, 57.8, 57.7, 44.8, 44.7, 29.4, 29.1, 25.8, 25.7, 24.8, 24.7, 22.4; MS (ES+) m/z 378.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and 1-bromo-2-phenylethane (0.44 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=80:20→70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=3.20 (t, J=7.0 Hz, 2H), 4.37 (t, J=7.0 Hz, 2H), 7.04-7.07 (m, 2H), 7.25-7.32 (m, 3H), 7.81 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:11]([O-])=O.[Na+].O.O.[Cl:17][Sn]Cl.[OH-].[Na+].CCOCC>Cl.O>[ClH:17].[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][NH2:11])[CH:8]=1
Reactant: Cc1cc(F)c(Br)cc1N
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(F)c(Br)cc1NN
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a suspension of 5-bromo-4-fluoro-2-methylaniline (11.2 g, 54.9 mmol) in concentrated HCl (35 mL) was added dropwise a solution of sodium nitrite (4.17 g, 60.4 mmol) in water (20 mL) over 30 minutes at 0° C. To the mixture was added dropwise a solution of SnCl2.2H2O (37.2 g, 165 mmol) in concentrated HCl (45 mL) over 1 hour. After stirring for 2 hours at 0° C., the reaction mixture was basified with 50% NaOH (50 mL). The mixture was further diluted with water (50 mL) and treated with another 50% NaOH (20 mL) and then crushed ice (200 g). The reaction mixture was extracted with ether (3×200 mL) and the combined organic phases were washed with brine, dried over Na2SO4, and filtered. The filtrate was acidified by adding an anhydrous solution of HCl in ether (2 N in ether, 42 mL, 82.5 mmol). The precipitate was collected and dried under reduced pressure to give 9.92 g (71%) of title compound as a pale yellow solid. 1H NMR (DMSO): 300 MHz δ 10.18 (bs, 3H), 7.98 (bs, 1H), 7.21 (m, 2H), 2.16 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[C:8](O)(=[O:10])[CH3:9]>>[CH3:9][C:8]([CH:6]1[C:1](=[O:3])[O:4][C:5]1=[O:7])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: CC(=O)C1C(=O)OC1=O
Yield: 86 %

Procedure:
To a solution of 60 ml of acetic acid and 43 ml of acetic anhydride at 0° C., was added slowly 40 g (0.27 mol) of acetone-dicarboxylic acid. The mixture was stirred and the temperature was not allowed to rise above 10° C. The acid was dissolved slowly and a pale yellow precipitate formed. After 3 h the product was filtered, washed with 30 ml of glacial acetic acid and 100 ml of benzene. The white powder obtained was dried at high vacuum to afford 30 g of acetonedicarboxylic acid anhydride (yield 86%). Mp 137-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])[CH:8]=[C:7]([CH3:26])[C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:55][O:56][C:57](=[O:69])[C@H:58]([CH2:60][NH:61][C:62]([C:64]1[S:65][CH:66]=[CH:67][CH:68]=1)=[O:63])[NH2:59].C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[CH3:55][O:56][C:57](=[O:69])[C@H:58]([CH2:60][NH:61][C:62]([C:64]1[S:65][CH:66]=[CH:67][CH:68]=1)=[O:63])[NH:59][C:4](=[O:5])[C:3]1[C:2]([CH3:1])=[CH:10][C:9]([C:11]([NH:13][C@@H:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])=[CH:8][C:7]=1[CH3:26]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Reactant: Cc1cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of 2,6-dimethyl-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid (Example 31; 100 mg, 0.29 mmol) in dichloromethane (1 mL) at 25° C. was added benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 140 mg, 0.32 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine methyl ester HCl salt (Example 301; 114 mg, 0.43 mmol), followed by diisopropylethylamine (250 μL, 1.4 mmol) slowly dropwise. After stirring for 2 h, the reaction was diluted with ethyl acetate (50 mL) and washed with 1N HCl (10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica, 50% ethyl acetate in petroleum ether) to give N-[2,6-dimethyl-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine methyl ester (88 mg, 54%) as an off-white solid.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[N:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.77 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.75 g), sodium carbonate (0.3 g) and sodium iodide (0.5 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.7 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (667 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:26][CH2:25]2.O[Li].O.O.Cl>CCO.C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([OH:34])=[O:33])[CH2:26][CH2:25]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(N5CCOCC5)cc4)oc3C)ccc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(N3CCOCC3)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Ethyl [(1S)-5-(2-{5-methyl-2-[4-(4-morpholinyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (0.058 g, 0.12 mmol) was dissolved in EtOH (1 mL), and LiOH.H2O (0.025 g, 0.6 mmol) was added. Water (1 mL) was added, followed by THF was added until the cloudy solution became clear. The resulting mixture was stirred overnight at rt. HCl (2 N) was added to adjust the pH to 2, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried, filtered and evaporated. The residue was purified by preparative HPLC to obtain [(1S)-5-(2-{5-methyl-2-[4-(4-morpholinyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1 H-inden-1-yl]acetic acid (0.038 g, 0.08 mmol) in 70% yield. 1H NMR ((CDCl3) δ 1.8 (m, 1H), 2.4 (m, 3H), 3.0 (t, 2H), 3.3 (m, 4H), 3.5 (m, 1H), 3.9 (m, 4H), 4.2 (t, 2H), 6.7 (m, 1H), 6.8 (s, 1H), 6.9 (d, 2H), 7.1 (d, 1H), 7.9 (d, 2H); MS (ES) 463 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[Br-].[C:18]([C:21]1[CH:46]=[CH:45][C:24]([CH2:25][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]>C(O)C>[C:18]([C:21]1[CH:46]=[CH:45][C:24](/[CH:25]=[CH:13]/[C:12]2[CH:15]=[CH:16][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:11]=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCO
Product: O=C(O)c1ccc(/C=C/c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
0.43 g (62 mmole) of Li was dissolved in 180 ml of ethanol under a nitrogen atmosphere. Then 6.9 g (31 mmole) of 4-(6-hydroxyhexyloxy)-benzaldehyde (15) and 14.8 g (31 mmole) of (4-carboxy-benzyl)-triphenylphosphonium bromide (14) were added. The mixture was stirred for two hours at room temperature. The precipitate was collected on a filter and washed with 50 ml of ethanol. Then the solid was mixed with 1.5 ml of concentrated hydrochloric acid and 35 ml of ethanol. It was stirred for 30 min and the product was collected on a filter. After washing with 50 ml of ethanol and drying in a dessicator 4.1 g of the product were obtained (yield 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
45.4 g (0.21 mol) of 2-chloro-3-nitrobenzoic acid methyl ester and 24.8 ml (0.21 mol) of benzyl mercaptan are dissolved in 420 ml of dimethylformamide, and then 29.2 g (0.21 mol) of potassium carbonate are added and the batch is stirred for 8 hours at 80° C. It is then poured onto ice/water and extracted twice with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.CO.COCC(O)C.Cl>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: CO
Solvent: COCC(C)O
Solvent: O
Product: C=Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
In a reaction vessel, 40.00 g of the obtained 4-acetoxystyrene polymer (with main chain terminal (M-30)), 40 ml of methanol, 100 ml of 1-methoxy-2-propanol and 1.5 ml of concentrated hydrochloric acid were added, and the mixture was stirred for 5 hours under heating at 80° C. The reaction solution was allowed to cool to room temperature and then added dropwise to 3 L of distilled water. After dissolving the solid collected by filtration in 200 ml of acetone, the solution was again added dropwise to 3 L of distilled water, and the solid was collected by filtration and then dried under reduced pressure to obtain 29.31 g of a 4-hydroxystyrene polymer (with main chain terminal (M-14)). The weight average molecular weight by GPC was 15,000, and the molecular weight dispersity (Mw/Mn) was 1.55.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]N=1.[C:8](OCCBr)(=[O:10])C.O.CN([CH:19]=[O:20])C>>[CH3:8][O:10][C:19](=[O:20])[CH2:4][C@@H:5]1[CH2:6][CH2:7][CH2:2][O:1]1
Reactant: CC(=O)OCCBr
Reactant: CN(C)C=O
Reactant: Oc1ccccn1
Solvent: O
Product: COC(=O)C[C@@H]1CCCO1
Temperature: 70 °C

Procedure:
Hydroxy-pyridine 19b (69 g, 0.32 mol) and bromoethyl acetate (64.9 g, 0.39 mol) are dissolved in DMF (500 mL) and heated at 70° C. for 18 h. The solution is cooled to RT, then water is added. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with H2O, brine, dried (Na2SO4) and concentrated. The residue is purified by chromatography (0 to 10% EtOAc in petroleum ether) to provide ester 19c.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][C:50](=[O:54])[CH2:51][CH2:52][CH3:53])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][C:50](=[O:54])[CH2:51][CH2:52][CH3:53])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)OC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)OC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 100.2 %

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-butyryloxymethyl-morpholine-4-carboxylic acid tert-butyl ester (295 mg, 0.397 mmol) in ethanol (29 mL). Add 20% palladium hydroxide on carbon (330 mg) and stir under 1 atmosphere of hydrogen gas for 48 hours. Filter through a filtering agent and wash with ethanol. Concentrate the filtrate to give the desired compound as a white foam (188 mg, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[O:29]1[CH2:32][C:31](=O)[CH2:30]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([CH:31]4[CH2:32][O:29][CH2:30]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C1COC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2COC2)C3)cc1

Procedure:
Compound fo was prepared according to the procedure described in Example 8 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with oxetan-3-one. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:26]([O:30][C:31](=[O:61])[NH:32][CH:33](C=O)[CH2:34][C:35]1[N:36]=[CH:37][N:38]([C:40]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=1)([CH3:29])([CH3:28])[CH3:27].[CH2:62]1COCC1>>[CH2:24]([O:23][C:21](=[O:22])[CH:20]=[CH:62][CH:33]([NH:32][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:61])[CH2:34][C:35]1[N:36]=[CH:37][N:38]([C:40]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=1)[CH3:25]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC(C=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCOC(=O)C=CC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Yield: 67 %

Procedure:
Ethyl (triphenylphosphoranylidene)acetate (1.52 g, 4.37 mmol) and [1-formyl-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (2.1 g, 4.38 mmol) in THF (35 mL) were stirred overnight under argon. The solvent was removed, Et2O added and the solution filtered. The filtrate was concentrated and the residue subject to column chromatography (silica gel, 25% EA/PE, Rf 0.65 50% EA/PE) to afford the title compound (1.6 g, 67%). ESMS 552 (M+H+) Mpt . 1H NMR (300 MHz, CDCl3) δ 1.28 (3H, t, J=7.5), 1.34 (9H, s), 3.01-3.05 (2H, m), 4.19 (2H, q, J=7.05), 4.47-4.57 (1H, m), 6.01 (1H, dd, J=1.5, 15.9), 6.46 (1H, d, J=9.3), 6.86 (1H, s), 6.89 (1H, dd, J=5.1, 15.9), 7.07-7.11 (5H, m), 7.21-7.3 (2H, m), 7.4-7.44 (8H, m), 8.11 (1H, s). 13C NMR (300 MHz, CDCl3) δ 166.14, 155.87, 139.86, 135.20, 132.21, 129.49, 129.70, 129.01, 128.18, 122.33, 121.19, 79.74, 78.78, 60.76, 52.09, 30.12, 28.35, 14.32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22](Br)[CH:21]=1>COCCOC>[Br:19][C:20]1[CH:21]=[C:22]([C:5]2[C:6]([C:7]#[N:8])=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Solvent: COCCOC
Product: N#Cc1cc(F)ccc1-c1cc(F)cc(Br)c1
Temperature: 65 °C
Yield: 9.4 %

Procedure:
5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.99 g, 4.0 mmol) and 1,3-dibromo-5-fluorobenzene (1.52 g, 6.0 mmol) were suspended in 1,2-dimethoxyethane (8 ml) and 2N sodium carbonate solution (4 ml) and degassed for 30 min before addition of tetrakis(triphenylphosphine)palladium(0). On complete addition the mixture was heated at 65° C. for 20 h. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml), the organic layer separated and washed with brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated onto silica. The product was purified by flash column chromatography on silica, eluting with isohexane on a gradient of diethyl ether (5-100%). Combination of the desired fractions and evaporation gave 3′-bromo-4,5′-difluorobiphenyl-2-carbonitrile (110 mg, 9%) as a white solid: δH (500 Mfz, CDCl3) 7.53-7.55 (1H, m), 7.67 (1H, s), 7.69-7.76 (3H, m), 8.03 (1H, dd, J 9 and 2).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([O:29]C)=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:35]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.N>ClCCl>[NH3:9].[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([NH2:35])=[O:29])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 139.3 %

Procedure:
A solution of methyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxylate (Preparation 72) (200 mg, 0.47 mmol) in dichloromethane (10 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol), N-methylmorpholine (77 μl, 0.70 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (134 mg, 0.70 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. Concentrated ammonia solution (0.88, 50 μl, 1.00 mmol) was then added and the mixture was stirred for 17 hours. The mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (97:3:0.3) to afford the title compound as a white solid (140 mg).
Reaction SMILES: ClC([O:4][C:5]([Cl:8])(Cl)Cl)=O.[Cl:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[CH:23][C:22]=2[CH3:32])=[N:12][CH:13]=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:11]([N:17]([C:5]([Cl:8])=[O:4])[CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[CH:23][C:22]=2[CH3:32])=[N:12][CH:13]=[N:14][C:15]=1[CH3:16]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOCCc1ccc(OCCN(C(=O)Cl)c2ncnc(C)c2Cl)c(C)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
An amount 2.0 g of trichloromethyl chloroformate (TCF) was dissolved in 30 ml of toluene and cooled to 5° C. or lower. To the solution was added dropwise a solution of 5.0 g of 5-chloro-N-{2-[4-(2-ethoxyethyl)2-methylphenoxy]ethyl}-6-methyl-4-pyrimidine amine and 1.8 g of triethylamine dissolved in 20 ml of toluene, and after the dropwise addition, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 20 ml of water was added, and the mixture was stirred at room temperature for one hour to decompose excessive TCF.