Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:64][CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:71])([CH3:73])[CH3:72])=[O:74])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][CH:27]([CH3:28])[CH3:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 48) (82 mg, 0.2 mmol) and HATU (0.091 g, 0.240 mmol) was added DMF (2 mL) and the mixture treated with DIPEA (0.105 mL, 0.600 mmol) at room temperature. After 5 min, 1,1-dimethylethyl (2-aminoethyl)carbamate (0.047 mL, 0.300 mmol) was added and the mixture stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a MeOH/DCM gradient to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}carbonyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (95 mg, 0.172 mmol, 86% yield) as a pale brown foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=553.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: c1ccc2c(c1)ncn2-c1nc(NC2CCCCC2)nc2[nH]cnc12
Temperature: 110 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.42 ml of cyclohexylamine, and the mixture is then heated at 110° C. for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 84.7 mg of expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:19]([C:18]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:17]=1[O:16][CH:13]([CH3:15])[CH3:14])=[O:20])[CH2:7]2
Reactant: Clc1cc(Cl)c2c(c1)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Cl)cc(Cl)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 5,7-dichloro-1,2,3,4-tetrahydro-isoquinoline (CA [89315-56-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][N:4]=[C:3]1[O:8]CC1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH:27]([CH3:29])[CH3:28])[C:24](Cl)=[O:25])=[CH:19][CH:18]=1>C(#N)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH:27]([CH3:29])[CH3:28])[C:24]([N:4]2[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[O:5]2)=[O:25])=[CH:21][CH:22]=1
Reactant: Cn1c(OCc2ccccc2)noc1=O
Reactant: CC(C)N(C(=O)Cl)c1ccc(F)cc1
Solvent: CC#N
Product: CC(C)N(C(=O)n1oc(=O)n(C)c1=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer and a nitrogen inlet was charged with 4-methyl-3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.55 g, 2.66 mmol), (4-fluorophenyl)(1-methylethyl)carbamic chloride (0.581 g, 2.7 mmol), N,N′-dimethylaminopyridine (0.329 g, 2.7 mmol) and acetonitrile (10 mL). The reaction mixture was heated to reflux 2 h, and allowed to cool to room temperature. The entire mixture was flash chromatographed (silica gel, 9: 1, then 8:2 hexane-ethyl acetate) to provide 0.6 g (76%) of the title compound as a white solid melting at 135-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:14]([NH2:17])(=[S:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:14]1[S:16][CH:12]=[C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=2)[N:17]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Br)c1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 80 %

Procedure:
A solution of 3-bromo-(4-nitrophenyl)-ethanone (2.5 mmol) and thioacetamide (3 mmol) in N,N-dimethylformamide (20 mL) was heated at 65° C. for 8 h. Ethyl acetate (40 mL) was added and the solution was washed with water (3×20 mL). The product was purified by crystallization from ether to give the title product (80%). ESMS [M+H]+: 221.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C@@H:19]2[CH2:20][CH2:21][N:18]2[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, as prepared in step 10f below) in dimethylformamide (20 mL) was treated with ground KOH (400 mg, 7.10 mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added the 1-(t-butyloxycarbonyl)-(2S)-p-toluene-sulfonyloxymethylazetidine (1.05 g, 4.39 mmol, as prepared in Step 10b below) dissolved in dimethylformamide (5 mL) and the reaction mixture was subsequently stirred for 16 h at 80° C. The mixture was concentrated to remove the dimethylformamide and the resultant residue diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by flash chromatography (silica gel; hexane/EtOAc, 10:1) to give 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (692 mg, 56%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.05 (m, 1H), 8.20 (m, 2H); MS (CI/NH3) m/z: 283 (M+H)+. To 5-fluoro-3-(1-Boc-(2S)-azetidinylmethoxy)pyridine from above (320 mg, 1.14 nmuol) was added HCl/Et2O in methylene chloride at 0° C., and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the tide compound (250 mg): mp 165-167° C.; [α]D25 27.8 (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ 2.70 (m, 2H), 4.10 (m, 2H), 4.50 (d, J=4.5 Hz, 2H), 5.01 (m, 1H), 7.80 (tt, J=3 Hz, 1H), 8.42 (dd, J=3, 6 Hz, 2H); MS (CI/NH3) m/z 183 (M+H)+, 200 (M+NH4)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:31])[C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)O)cc1
Yield: 88.5 %

Procedure:
To 2.9 g (6.45 mmol) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid ethyl ester in 200 ml of hot methanol was added 7.1 ml (7.1 mmol) of 1.0 N NaOH. The reaction mixture was stirred at reflux for 5 minutes, 50 ml of water was added and the solvents were removed at reduced pressure. Water (300 ml) was added and the product was extracted with methylene chloride-THF (4:1). The dried extract was concentrated at reduced pressure and the residual solid was recrystallized from acetone-hexane to give 2.39 g (88% yield, mp 78°-80°) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid.
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>C1(C)C=CC=CC=1.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>[CH3:11][NH:10][C:8](=[O:9])[C:7]1[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:34])=[CH:3][C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:5][CH:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1I
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: Cc1ccccc1
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A suspension of 4.00 g (11.1 mmol) 4-iodo-N-methyl-6-(4-methyl-piperzin-1-yl)-nicotinamide and 642 mg (0.555 mmol) tetrakis(triphenylphosphine)palladium(0) in 60 ml toluene was dioxygenated with a stream of argon for 30 min. After addition of 11 ml of a 2 N aqueous solution of sodium carbonate and 1.66 g (12.2 mmol) o-tolylboronic acid, the mixture was heated at reflux overnight. Cooling to room temperature was followed by dilution with water and extraction with three 50 ml portions of ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with three 50 ml portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 2.26 g (63%) of the tide compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccccc1F
Product: CCC(NC(=O)Cc1ccccc1F)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The product from step 1 (100 mg, 0.26 mmol) was dissolved in 2 ml EtOH, and NaBH4 (7.5 mg, 0.196 mmol) in 0.5 ml H2O was added and the mixture stirred at rt for 2 h. The mixture was then quenched with 3N NaOH, and 5 ml of ether was added to extract the compound, which was dried over MgSO4 and concentrated to give yellow oil (79 mg, 90.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O>[F:23][CH:19]([F:24])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)c(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixed solution of 3-fluoro-4-hydroxybenzonitrile (3.10 g) in N,N-dimethylformamide (31 ml)/water (3.1 ml) were successively added cesium carbonate (10.3 g) and sodium chlorodifluoroacetate (7.93 g). After stirring at 110° C. for 2 hr, the reaction mixture was partitioned by adding toluene and water. The aqueous layer was extracted with toluene, and the combined organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (4.09 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][O:11][CH2:9][CH3:10])[CH:14]=[N:15][C:16]=2[N:17]([CH3:24])[C:18]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(Cc1ccccc1)c(=O)n2C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
205 g (1.2 mol) of benzyl bromide were added to a suspension of 224 g (1 mol) of 7-ethoxymethyl-3-methylxanthine and 165 g of potassium carbonate in 1000 ml of dimethylformamide and the mixture was then stirred overnight at 90° C. The reaction solution was filtered hot, the filtrate was concentrated under reduced pressure and the residue was dried to constant weight in a bulb tube at 1 mbar and 60° C.
Reaction SMILES: C1(C[O:5][C:6](=[O:34])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:14]([Cl:33])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[Cl:33][C:14]1[CH:13]=[C:12]([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:34])=[O:5])[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Yield: 86.9 %

Procedure:
2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.06 g, 0.12 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.046 g, 85%). M.p.=115-116° C. 1H NMR (300 MHz, CDCl3/TMS): δ 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H), 2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89 (m, 1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.0, 157.1, 140.3, 138.8, 133.8, 130.8, 129.3 (q), 128.2, 124.6, 124.3 (q, 1JCF=271.0 Hz), 121.6, 111.2, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[C:25]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:17][CH:16]=1)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Yield: 99.5 %

Procedure:
Sodium hydroxide (10 g, 0.25 m) is dissolved in water (300 ml). To this solution 4-nitrophenylalanine (50.3 g, 0.22 m) is added and stirred until complete dissolution. To the resulting solution the sodium carbonate (28.8 g, 0.26 m) is added and stirred suspension is cooled in an ice bath to +8° C. Benzyl chloroformate (44.7 g, 0.26 m) is added dropwise with vigorous stirring, maintaining internal temperature in +6° to +9° C. range. The mixture is stirred at +6° C. for additional 1 hr, transferred to the separatory funnel and washed with ether (2×150 ml). Aqueous phase is placed in a large Erlenmeyer flask (2L) and is cautiously acidified with dil. aq. HCl to pH=2 and extracted with ethyl acetate (4×500 ml). The combined extracts are washed with water and dried with MgSO4. The solution is filtered and filtrate evaporated, residue is dissolved in ethyl acetate (150 ml) and diluted with hexane (500 ml). Crystalline material is filtered off and rinsed with cold solvent, air dried to give Cbz-4-nitrophenylalanine, 75 g (99.5% yield). 1H-NMR, DMSO-d6, (δ): 12.85 (bs, 1H), 8.12 (d, 2H, J=9 Hz), 7.52 (d, 2H, J=9 Hz), 7.30 (m, 5H), 4.95 (s, 2H), 4.28 (m, 1H), 3.32 (bs, 1H), 3.10 (m, 2H).13C-NMR (δ): 173.1, 156.3, 146.6, 137.3, 130.8, 128.5, 128.0, 127.8, 123.5, 65.6, 55.1, 36.6. MS (m/z): 367.1 [M+23].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-:14].[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([F:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
3-Nitrobenzenesulphonyl chloride (10 g) was dissolved in 1,4-dioxane (30 ml) and stirred at room temperature. To this solution was added a solution of potassium fluoride (3.9 g) in water (5 ml) and the stirring continued at room temperature for 5 hours. The reaction mixture was allowed to stand at room temperature overnight and was poured into ice/water. The product was extracted into dichloromethane, the solvent was dried (MgSO4) and evaporated under reduced pressure to give the title compound (8 g). This material was sufficiently pure for the next stage of the synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].C(OC(C1C(=O)C2C(=CC=CN=2)N(CC2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]([CH2:9][C:38]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Product: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2cccnc2c1=O
Yield: 49.46 %

Procedure:
4-Oxo-1-(1-phenyl-cyclopentylmethyl)-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (9) (140 mg, 49.46%) was synthesized as a sticky liquid from 200 mg of 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6).
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20](Cl)[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20]([C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2
Reactant: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)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: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
The mixture of N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 0.254 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.073 g, 0.28 mmol), Pd (PPh3)4 (0.015 g, 0.013 mmol) and Na2CO3 (0.081 g, 0.762 mmol) in dioxane (20 mL) and H2O (5 mL) was heated to 100° C. for 16 h under N2 atmosphere. Then it was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:2) to afford methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 78%) as a yellow solid. LC-MS: 474 [M+H]+, tR=1.84 min.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1C(C)=[N+:17]([O-])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:14][C:15]1[C:7]([CH2:6][OH:11])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Br)ccc[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCc1ncccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Trifluoroacetic anhydride (0.52 mL, 3.6 mmol) was added to a solution of 3-bromo-2-methylpyridine 1-oxide (140 mg, 0.72 mmol) in methylene chloride (2 mL) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as a yellow oil (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=4.7 Hz, 1H), 8.10 (dd, J=8.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 4.64 (s, 2H); OH peak not observed.