Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[C:13]([OH:19])(=[O:18])[CH2:14]C(O)=O.C([O-])(=O)C.[NH4+:24]>CCO>[NH2:24][CH:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)[CH2:14][C:13]([OH:19])=[O:18]
Reactant: [NH4+]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cc(OC)cc(C(N)CC(=O)O)c1
Yield: 43.7 %

Procedure:
A mixture of 5 g of 3,5-dimethoxybenzaldehyde, 3.13 g of malonic acid and 4.64 g of ammonium acetate in 50 ml of EtOH is refluxed for 5 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water, insoluble material is filtered off, the filtrate is washed with DCM and the aqueous phase is concentrated under vacuum. The residue is taken up in water and concentrated under vacuum again. The residue is taken up in EtOH and the solvent is evaporated off under vacuum. 2.96 g of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1.CN(C)CCN(C)[CH2:19][CH2:20]N(C)C.C([Li])CCC.[Cl-].[NH4+].[CH2:33]1[CH2:37][O:36][CH2:35][CH2:34]1>CCCCCC>[F:1][C:2]1[C:7]([CH:35]([OH:36])[CH2:34][CH2:33][CH2:37][CH2:19][CH3:20])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1
Reactant: CN(C)CCN(C)CCN(C)C
Reactant: C1CCOC1
Reactant: CC1(c2ccccc2F)OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCCCC(O)c1cccc(C2(C)OCCO2)c1F
Reaction time: 1 h

Procedure:
To a THF (48 mL) solution of 2-(2-fluorophenyl)-2-methyl-1,3-dioxolane (6.0 g) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (8.0 mL) was added 1.58 M hexane solution of n-butyl lithium (25.3 mL) dropwise at −78° C. After the reaction mixture was stirred for 1 h, n-hexylaldehyde (5.88 mL) was added into the reaction mixture. After the reaction mixture was stirred for additional 1 h at −78° C., a saturated ammonium chloride aqueous solution was added into the reaction mixture. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by Colum chromatography (hexane:ethyl acetate=4:1) to obtain the compound (16) 6.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:11]
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 7-chloro-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (prepared by cyclization of N-benzyloxycarbonyl-4-chloroanthranilic acid with phosphorus tribromide) (1.0 g, 5.06 mmol) in DMF (18 ml) was added 4-dimethylaminopyridine (62 mg). After 5 mins of agitation at room temperature, 4-aminomethyl-1-diphenylmethylpiperidine (1.56 g, 5.56 mmol) was added to the solution and stirred for 5 hours. The reaction mixture was diluted with AcOEt, washed twice with H2O, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel to give 2-amino-4-chloro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 892 mg (41%): mp 161°-162° C.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:18]1(/[C:24](/[CH2:49][CH3:50])=[C:25](\[C:41]2[CH:48]=[CH:47][C:44](C=O)=[CH:43][CH:42]=2)/[C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:30]=[CH:29]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:51]1COCC1>>[CH3:51]/[C:11](=[CH:17]\[C:44]1[CH:47]=[CH:48][C:41](/[C:25](/[C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:30]=[CH:29]3)=[C:24](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:49][CH3:50])=[CH:42][CH:43]=1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(C)=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (80 mg, 2 mmol, 60% dispersion in mineral oil) in THF (10 mL) at 0° C., ethyl 2-(diethoxyphosphoryl)propanoate (0.36 g, 1.5 mmol) was added. The reaction was stirred at 0° C. for 1 h, and then a THF solution of (E)-4-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde (0.44 g, 1 mmol) was added. The resulting mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to give the crude material as pale yellow oil. LCMS: 437 [(M-THP+H)+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N(c2cccc(C#N)c2)C2CCCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Yield: 93.8 %

Procedure:
N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea (3.2 g, 7.76 mmol) was stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at ambient temperature for 1.5 h. The reaction mixture was evaporated and the residue taken up in water. The aqueous suspension was made basic (pH 11) by the dropwise addition of aqueous sodium hydroxide solution (50%). The basic aqueous suspension was extracted with ethyl acetate (2×); the ethyl acetate extracts were washed with brine, dried (Na2SO4), and evaporated to give N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.17 g, 7.28 mmol, 94%). This sample was in all respects identical to the sample of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea prepared in Example 5.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][C:24]([CH3:28])=[CH:23]2>>[CH3:28][C:24]1[N:25]=[CH:26][C:27]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:4]1[N:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:7]2[CH2:6][S:5]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Cc1cc2cccc(N)c2cn1
Agent: [I-]
Product: Cc1cc2cccc(N=C3SC[C@@H]4Cc5ccccc5CN34)c2cn1
Yield: 53.9 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (8 g) and 8-amino-3-methylisoquinoline (3.5 g) as the starting materials, (S)-3-[(3-methylisoquinol-8-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (4.1 g) is obtained in the form of pale yellow crystals, m.p.=156° C.
Reaction SMILES: Cl[C:2]1[C:3]([C@@H:13]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:3]([C@@H:13]([N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])[CH3:14])=[N:4]2
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ccccc1-c1nc2c(Cl)cccc2nc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet and a temperature probe was charged with DMF (2.16 L), (S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (273 g, 733 mmol) and 2-(methylthio)phenylboronic acid (136 g, 807 mmol). To the mixture, was added potassium carbonate (203 g, 147 mmol) and [1,1-bis(di-phenylphosphino)ferrocene]palladium(ii) chloride, complex with DCM (29.9 g, 36.7 mmol). The mixture was vacuum purged with N2 (2×), and heated to 100° C. The reaction was monitored by LC-MS, and deemed complete after 4 h. The reaction was cooled to rt (21° C.), and then divided into two batches. Each batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel. After phase separation, the organic layer was washed with brine (2×500 mL) and concentrated to afford the crude product. The combined batches of crude material were loaded on silica gel and purified by flash chromatography (ISCO/RediSep™) (hexane:EtOAc=10:0 to 6:4) to provide the product as a light brown solid 320 g with 98% LC purity and 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]([C:17](=O)[CH3:18])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[N:6]=[C:17]([CH3:18])[C:11]([CH3:10])=[C:12]2[OH:13]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1cc(Cl)ccc1N
Product: Cc1nc2c(C)cc(Cl)cc2c(O)c1C
Temperature: 170 °C

Procedure:
Prepared according to procedure R using 4-chloro-2-methylaniline (2.22 g, 15.7 mmol), ethyl 2-methyl-3-oxobutanoate (4.08 g, 31.4 mmol) in PPA (6.3 g, 62.8 mmol) and heating at 170° C. for 2 h and at rt overnight. The crude mixture was neutralized to pH 7-8 and the precipitated was filtered. The solid was then dried under high vacuum to give 6-chloro-2,3,8-trimethylquinolin-4-ol as white solid. Mass Spectrum (ESI) m/e=222 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]4[N:1]=[N:2][NH:3][N:37]=4)=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nn[nH]n2)ccc1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 37.2 %

Procedure:
Sodium azide (14 mg, 215 umol) and triethylamine hydrochloride (29 mg, 215 umol) were added to a solution of [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (20 mg, 43 umol; example 30) in DMF (0.4 ml). The solution was stirred at 120° C. for 14 h, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a solid which was crystallized from acetonitrile to obtain the title compound (8 mg, 16 umol; 37%) as off-white solid. MS: m/e=518.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1C
Yield: 98 %

Procedure:
According to J. Org. Chem. 33:494 (1968), a mixture of 4-methoxy-2-methylbenzoic acid (20 g, 120 mmol) and MeOH (97 mL) containing sulfuric acid (conc., 0.6 mL) was heated under reflux 48 h. After cooling the mixture was evaporated and the residue diluted with diethyl ether and washed with a saturated sodium hydrogen carbonate solution and brine. The organic phase was then separated and dried over sodium sulphate. After evaporation the residue was distilled through a 8 cm Vigreux column to afford the title compound (21.2 g, 98%) as a colourless liquid. Bp 60° C./1 mbar. MS: m/e=180.3 (M+).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(Cl)=[O:16].C1(C)C=CC=CC=1.[C@@:26]12([OH:35])[N:33]([CH3:34])[C@@H:30]([CH2:31][CH2:32]1)[CH2:29][CH:28]=[CH:27]2>C(=O)(O)[O-].[Na+].ClCCl.C(#N)C>[C:8]1([CH2:9][NH:10][C:15]([O:35][C@@:26]23[N:33]([CH3:34])[C@@H:30]([CH2:31][CH2:32]2)[CH2:29][CH:28]=[CH:27]3)=[O:16])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: O=C(Cl)Cl
Reactant: NCc1ccccc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)NCc1ccccc1-c1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
3.67 g (0.02 mol) of 2-phenylbenzylamine is placed in 250 mL saturated sodium bicarbonate solution and 250 mL dichloromethane. At 0° C., 52.9 mL (0.10 mol) of 20% phosgene-toluene solution are added under the surface of the dichloromethane. The mixture is vigorously stirred for 30 minutes. The two phases are separated, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 20 mL acetonitrile and 4.18 g (0.03 mol) of tropenol in 10 mL acetonitrile is added dropwise, whereupon a precipitate is formed. It is stirred for 12 hours at ambient temperature. The precipitate is suction filtered and the mother liquor evaporated to dryness. The residue is dissolved in dichloromethane and washed with water, water mixed with acetic acid (2 drops of glacial acetic acid to 100 mL of water), and 10% sodium carbonate solution. The organic phase is dried and evaporated to dryness. Yield: 2.85 g (41% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.N1C(C)=CC=CC=1C.Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[N:46]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CC(N(C)C)=O>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:34]([NH:54][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:35])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: O=C(NCCN1CCOCC1)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (example 59)(15 mg, 0.045 mmol), 2,6-lutidine (5.5 mg, 0.052 mmol), 4-nitrophenyl chloroformate (10 mg, 0.05 mmol), and DMA (0.3 mL) was stirred at 25° C. for 10 mins and then 2-morpholin-4-yl-ethylamine (12 mg, 0.092 mmol) was added and stirring continued for 30 mins. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 20-50% CH3CN in 0.1% TFA/H2O over 10 mins to give 6 mg (22%) the title cpd as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.62 (dd, 1H), 7.52 (m, 3H), 7.44 (m, 2H), 7.30 (m, 2H), 7.12 (d, 1H), 6.60 (s, 1H), 3.72 (m, 4H), 3.40 (m, 2H), 2.52 (m, 6H). Mass spectrum (ESI, m/z) calcd. for C25H24ClN5O4 493.1, found 494.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])[C:3]=1[CH3:30].O.CCO>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:30]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Temperature: 100 °C
Yield: 34.9 %

Procedure:
A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 71.4 μmol), LiOH monohydrate (15 mg, 0.357 mmol), H2O (500 μL), EtOH (absolute, 500 μL), and THF (500 μL) was placed in a sealed tube and heated to 100° C. Once the reaction was complete, it was cooled to 23° C., filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (11.5 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI− (m/z): [M—CO2—H]− calcd for C22H21BrClO: 415.2; Found: 415.0.
Reaction SMILES: B(F)(F)[F:2].CCOCC.[CH:10]1(N)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.N(OC(C)(C)C)=O>C(COC)OC>[F:2][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: NC1CCCc2ccccc21
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Solvent: CCOCC
Product: Fc1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A modified procedure of Mirsadehgi et al. was used (J. Org. Chem. 1989, 54, 3091). Boron trifluoride etherate (30.0 g, 26.8 mL, 0.21 mol) was dissolved and stirred in dimethoxyethane (50 mL) and cooled to 0° C. A solution of tetrahydro-1-naphthylamine (25 g, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise and the solution was allowed to warm slowly to room temperature over the period of 1 hour. The reaction was cooled to 0° C. and a solution of t-butyl nitrite (18.0 g, 20.7 mL, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise. The reaction was stirred for 2 hours at 0° C. upon which a large quantity of material crystallized. The solvent was removed in vacuo and chlorobenzene (200 mL) was charged to the reaction flask. The flask was stirred vigorously and heated to 135° C. (Caution: N2 evolution) for 1 hour until gas evolution ceased. The flask was cooled to room temperature and the solvent removed in vacuo. Kughelrohr distillation of the residue (1 mm Hg) afforded a yellow liquid. Wt: 14.4 g (56%). 1H NMR (300 MHz, CDCl3) δ 7.04 (dd, 1H), 6.83 (m, 2H), 2.75 (m, 4H), 1.80 (m, 4H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:46])[CH2:41][CH2:40]3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:21][C:20]=1[CH3:59])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:48]([NH:47][C:45]([N:42]1[CH2:43][CH2:44][CH:39]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]3[CH:57]=[CH:58][C:19]([OH:18])=[C:20]([CH3:59])[CH:21]=3)=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:40][CH2:41]1)=[O:46])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c(C)c3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)c(C)c3)cc2)CC1

Procedure:
4-{[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}3-methyl-phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (0.395 g, 0.520 mmol) was reacted according to Procedure H to give the title compound (eluant: 20/3(v/v) chloroform/methanol) (0.225 g, 0.373 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)O.CCN(CC)CC.O=S(Cl)Cl.[CH2:33]([Mg]Br)[CH:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)[CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(C2CC2)N1CC(F)(F)F
Reactant: CC(C)C[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CC1(C2CC2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. solution of 0.08 g (0.25 mmol) 6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 3 mL toluene was added 0.17 mL (1.25 mmol) Et3N and 0.018 mL (0.25 mmol) SOCl2. After 20 min at 0° C. 1 mL (1 mmol, 1M solution in ether) isobutyl magnesium bromide was added and the reaction mixture was stirred 30 minutes before an additional 0.5 mL (0.5 mmol) isobutyl magnesium bromide was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution and extracted with 100 mL EtOAc. The extract was washed with 75 mL brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes) followed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min) to afford afforded 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.17 (s, 1H); 7.43 (d, J=2.20 Hz, 1H); 7.15 (dd, J=2.38 and 8.61 Hz, 1H); 6.62 (d, J=8.42 Hz, 1H); 4.50 (dq, J=15.4 and 8.61 Hz, 1H); 3.96 (dq, J=15.4 and 8.60 Hz, 1H); 1.56 (m, 1H); 1.41 (dd, J=14.8 and 5.31 Hz, 1H); 1.23 (dd, J=14.8 and 5.68 Hz, 1H); 0.88 (m, 1H); 0.80 (d, J=6.59 Hz, 3H); 0.78 (m, 1H); 0.69 (m, 2H); 0.55 (d, J=6.59 Hz, 3H). High resolution mass spec (FT/ICR): calc M+H=361.1289, found 361.1283.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].[C:23]([N:26]1CC[NH:29][CH2:28][CH2:27]1)(=O)[CH3:24]>>[ClH:1].[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:26]4[CH2:23][CH2:24][CH:28]([NH2:29])[CH2:27]4)[N:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cn(-c2ccccc2)c2nc(Cl)c(F)cc2c1=O
Product: Cl
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccccc2)C1

Procedure:
In the described fashion as Example 1(f) the above ester (III) reacting with N-acetylpiperazine can give the desired 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (I) ##STR28## and its hydrochloride salt.