Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][N:4]=1.[N:21]1([CH2:30][C:31](O)=[O:32])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=[CH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][N:21]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[CH:7][N:8]=1
Reactant: COc1ncc(-c2ccccc2N2CCNCC2)cn1
Reactant: O=C(O)Cn1ccc2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2ccccc2N2CCN(C(=O)Cn3ccc4cccnc43)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To 2-methoxy-5-(2-piperazin-1-yl-phenyl)-pyrimidine (7.4 g, 27.37 mmol) dissolved in dichloromethane (100 mL) is added pyrrolo[2,3-b]pyridin-1-yl-acetic acid (4.82 g, 27.37 mmol), TBTU (8.79 g, 27.37 mmol), and DIPEA (14.66 mL, 82.12 mmol). The reaction is stirred for 16 h at ambient temperature. The product is purified on a 100 g Biotage SNAP column with 40% EtOAc in hexanes to provide the title compound (8.3 g, 19.37 mmol, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[O:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][N:25](CC)[CH2:26][C:27]1C=CC=CC=1)([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: [H][H]
Reactant: CCN(Cc1ccccc1)CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Yield: 98.9 %

Procedure:
A solution of 5-amino-N-(2-{[ethyl(phenylmethyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.39 g, 0.813 mmol) in ethanol (35 ml) was stirred under an atmosphere of hydrogen over Pearlman's catalyst (45 mg) for 7 hours (32 ml of hydrogen taken up). The catalyst was filtered off and the filtrate was evaporated to give the title compound (0.313 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl)C1CC1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (250 mg, 0.62 mmol) according to the general procedure M. Obtained as a yellow solid (215 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]I>O1CCCC1.CCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: CI
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccncc1NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-tert-butoxycarbonylaminopyridine (13.5 g, 69.5 mmol) in tetrahydrofuran (300 ml) was cooled to -70° C. and treated with tert-butyllithinum (102.2 ml, 1.7M in pentane, 173.7 mmol) at such a rate as to maintain the temperature at below -60° C. The mixture was aged at -60° C. to -70° C. for 3.5 hours and then treated with a solution of methyl iodide (11.2 g, 79.1 mmol) in tetrahydrofuran (50 ml) while keeping the temperature below -60° C. The mixture was stirred at -50° C. to -60° C. for 30 minutes, warmed to -30° C. and quenched with water (300 ml). The mixture was extracted with ethyl acetate (2×300 ml) and the combined organic fractions were washed with saturated brine (200 ml), dried (Na2CO3), filtered and concentrated in vacuo to residue. The crude product was purified by chromatography on silica gel (50% ethyl acetate/50% hexane) and swished in hot hexane to afford the title compound as a pale beige crystalline solid; yield: 7.34 g (51%); mp. 91°-93° C.; Analysis Found: C, 63.44; H, 7.72; N, 13.38. C11H16N2 O2 requires C, 63.44; H, 7.74; N, 13.45%. 1H NMR (CD2 Cl2 /TMS) δ1.50 (9H, s), 2.26 (3H, s), 7.12 (2H, d+br.s, J=5.0 Hz), 8.22 (1H, d, J=5.0 Hz), 8.80 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14].CC(C)=O.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(N)ccc1Oc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Zinc dust (3.86 g, 59.1 mmol) was added to a stirred solution of 4-(2,6-dimethyl-phenoxy)-3-methyl-nitrobenzene (1.5 g, 5.9 mmol), acetone (20 mL) and saturated aqueous ammonium chloride (20 mL) at 0° C. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with 200 mL EtOAc and filtered through diatomaceous earth. The organic layer was washed with brine, dried with sodium sulfate and concentrated to provide the crude titled compound (0.79 g, 59%). This material was used without purification: MS (ESI): mass calcd. for C15H17NO, 227.3; m/z found, 227.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.07 (d, J=7.2 Hz, 2H), 7.01 (dd, J=8.3, 6.5 Hz, 1H), 6.60 (t, J=3.4 Hz, 1H), 6.31 (dd, J=8.5, 2.9 Hz, 1H), 6.06 (d, J=8.5 Hz, 1H), 3.36 (s, 2H), 2.34 (s, 3H), 2.11 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cccc(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(3-fluorophenoxyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:20])[C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:23]1[C:27]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=C[NH:25][N:24]=1>C(O)(=O)C>[C:28]([C:27]1[CH:23]=[N:24][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH3:20])[C:14]([CH:16]4[CH2:17][CH2:18][CH2:19]4)=[O:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:21]=12)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CCC2)c1
Solvent: CC(=O)O
Product: CN(C(=O)C1CCC1)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1

Procedure:
A reaction mixture comprising 2.86 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylcyclobutanecarboxamide, 1.88 g of 3-amino-4-benzoylpyrazole and 100 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected, giving 3.05 g, mp 168°-170° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[C:21](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (600 mg) is dissolved in methanol, and potassium carbonate (839 mg) and dimethyl 1-diazo-2-oxopropylphosphonate (786 mg) are added. The mixture is stirred at room temperature for 3 hours. After aqueous work-up, the mixture is extracted with ethyl acetate and the extracts are dried with sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (493 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[N+:32](=[CH2:34])=[N-:33]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:21](=[O:23])[CH:34]=[N+:32]=[N-:33])=[CH:19][CH:18]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(NC(Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Product: [N-]=[N+]=CC(=O)C(Cc1ccc(F)cc1)NC(=O)OCc1ccccc1

Procedure:
In a manner analogous to that described in Example 19(i), 7.70 g of N-(benzyloxycarbonyl)-3-(4-fluorophenyl)-DL-alanine were treated with isobutyl chloroformate followed by reaction with diazomethane to give 7.15 g of benzyl [2-(4-fluorophenyl)-1(RS)-(2-diazoacetyl)ethyl]carbamate as a yellow solid of melting point 97° C.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].CN(C=O)C.OC1O[C@H](C)[C@H](O)[C@H](O)[C@H]1O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O

Procedure:
For example, L-fucopyranose was transformed into a 4'-acetyl-2',3'-O-benzyl-L-fucopyranose following a method described in Dale, J. K. et al., J. Chem. Soc. 52:2534 (1930); and Hockett, R. C. et al., J. Am. Chem. Soc. 61:1658 (1939). See Scheme I in FIG. 12 (DMF=dimethylformamide; DMAP=4-(dimethylamino)pyridine; Bn=benzyl; and pyr=pyridine.). Similarly, D-fucopyranose can be converted to 4'-acetyl-2,3-O-benzyl D-fucopyranose.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NCCC(OCC)=O.[CH3:43][NH:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([N:44]([CH3:43])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methyl)amino]benzoic acid (92 mg), ethyl β-alaninate hydrochloride (37 mg), ethyl 3-(methylamino)propanoate (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg), hydroxybenzotriazole monohydrate (37 mg) and triethylamine (33 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 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 (81 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C([O-])(=O)C.[K+]>CCO.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.200 g, 12.66 mmol), 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 14.86 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (514.9 mg, 0.7272 mmol), and potassium acetate (4.180 g, 42.59 mmol) were suspended in EtOH (50 mL) and water (10 mL) and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (80° C.), and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, poured into water (125 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel, 40:1 DCM/2 N ammonia in MeOH). The fractions with product were collected, concentrated, and washed repeatedly with hexanes and dried to give 6-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g), which was used for the next step. MS (ESI pos. ion) m/z 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][NH:30][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=1)[CH3:36]
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and ethyl glycinate were reacted by the procedure of Example 60 to afford the title compound [4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid ethyl ester. 1H-NMR (CDCl3) δ 1.21 (m, 3H), 3.59 (m, 2H), 4.12 (m, 2H), 5.91 (br s, 1H), 6.41 (m, 2H), 7.25-7.62 (m, 9H). LC MS (m/e)=469 (MH+). Rt=2.12 min.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:9](O)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC(=O)O
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-hexenoic acid (15.2 mL, 0.131 mol) in DCM (375 mL), cooled to 0° C., tert-butanol (176 mL, 1.84 mol) and then 4-dimethylaminopyridine (3.21 g, 26.3 mmol) were added. The mixture was stirred at room temperature for 22 hrs, filtered and concentrated. The residue was redissolved in DCM/n-hexane and concentrated under reduced pressure. The crude oil was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 5 to 10%), affording the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cc(Br)c(OCc3ccccc3)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2cc(Br)c(OCc3ccccc3)cc2n1
Yield: 62.9 %

Procedure:
A mixture of 7-benzyloxy-6-bromo-4-chloro-2-methyl-quinoline (10.0 g, 27.6 mmol) and pyrrolidine (47 mL, 0.562 mol) was refluxed during 3h. The mixture was cooled down and the pyrrolidine was evaporated under high vacuum. The residue was taken up in dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 6.9 g of the title compound were obtained. Brown solid, ISP-MS: m/e=399.2 ([M+H]+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH:11]([C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]2)[C:14]=1[Cl:30])[CH3:12])(=O)C.O>O1CCCC1>[C:26]([C@@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[C:14]([Cl:30])=[C:13]([CH:11]([OH:10])[CH3:12])[N:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(=O)OC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Reaction time: 8 h

Procedure:
1.5 g (40 mmol) of lithium aluminum hydride were placed in 100 ml of dry tetrahydrofuran, and a solution of 14 g (40 mmol) of 6-(1-acetoxyethyl)-4-(cis-4-tert-butylcyclohexylamino)-5-chloropyrimidine (Example 30) in 50 ml of dry tetrahydrofuran was added dropwise at a temperature of 20° to 30° C. The mixture was then heated at reflux for 2 hours. After cooling, 5 ml of water were added carefully dropwise and, after standing overnight, the mixture was filtered with suction to remove the inorganic material. The filtrate was concentrated and the residue was chromatographed on silica gel (ethyl acetate/methanol 9:1) to give 6.0 g (48.1% of theory) of a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1.CCCCCC>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][Si:20]([CH3:22])([CH3:21])[CH3:19])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCC#C[Si](C)(C)C
Yield: 91 %

Procedure:
To a solution of 135 g (682 mmol, 1.0 equiv.) of 1-t-butyldimethylsilyloxy-4-pentyne in 700 mL of THF at -78° C. was added 311 mL (716 mmol, 1.05 equiv.) of a 2.3M solution of n-butyllithium in hexane. The -78° C. bath was removed and the reaction temperature was monitored as it rose to 0° C. The reaction was recooled to -78° C. and 90.8 mL (716 mmol, 1.05 equiv.) of trimethylsilyl chloride was added dropwise. The reaction was then allowed to warm slowly in the cold bath for 16 hours. The reaction was diluted with 2000 mL of hexane, washed with 500 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting liquid was distilled at 71°-74° C. at 0.05 mm Hg to yield 168 g (91%) of 1-t-butyldimethylsilyloxy-5-trimethylsilyl-4-pentyne.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=2[N:15]=1>O>[N+:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:12][C:13]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2o1
Solvent: O
Product: O=C(Nc1nc2ccc([N+](=O)[O-])cc2o1)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
Benzoyl chloride (1.17 mL, 10.0 mmol) was added to a suspension of 2-amino-6-nitrobenzoxazole (1.50 g, 8.37 mmol) in pyrdine (10 mL). After stirring for 24 h at 80° C., the solution was poured into water (250 mL). The mixture was stirred overnight at r.t. and the resulting precipitate was separated by filtration. N-(6-Nitrobenzoxazol-2-yl)benzamide (2.08 g, 7.32 mmol, 88%) was thus obtained as a yellow solid. LC/ESI-MS: /z =284 [M+H]+; m/z=282 [M−H]−; Rt=3.13 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+]>CCO.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Nc1c(F)cccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyloxy-3-fluoro-2-nitrobenzene (10.0 g, 40.5 mmol) in 100 mL of EtOH and 50 mL of 1N HCl is added SnCl2 (38.3 g, 202.5 mmol) and the solution is refluxed for 2 h. After cooling the mixture to RT, it is adjusted to PH>7 with solid K2CO3 and extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the product as a yellow liquid.