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:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.C(Cl)[Cl:39]>>[ClH:39].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Reactant: ClCCl
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1
Product: Cl
Yield: 76.1 %

Procedure:
In DCM (10 mL) was dissolved tert-butyl 4-(9-(6-methoxypyridin-3-yl)-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)piperidine-1-carboxylate (75 mg, 0.149 mmol). The solution was purged with hydrogen chloride gas for 0.5 h and a precipitate was formed. The precipitate was filtrated under reduced pressure, washed sequentially with DCM and diethyl ether and dried to give a solid (50 mg, 76.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].[H-].[Na+].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>O1CCCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:22]2[CH:23]=[C:24]3[N:31]([CH3:32])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(3,4-dichlorophenoxy)-3-fluorophenyl)methanol (0.101 g, 0.350 mmol) in tetrahydrofuran (THF) (8 mL), sodium hydride (0.021 g, 0.525 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.065 g, 0.350 mmol) in DMF (1 mL).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3C(OC)=C(C#C)C=C[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2[CH:36]=C(C3CC3)C3OC4(CC4)CC(C)(C)[C:39]=3[CH:48]=2)=[CH:29][CH:28]=1)[CH3:26].C(N(CC)CC)C.[C:60](OCC)(=[O:62])C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]2[CH:48]=[C:39]([O:62][CH3:60])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:36]=2)=[CH:31][CH:32]=1)[CH3:26]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: CCOC(C)=O
Reactant: C#Cc1ccc2c(c1OC)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.30 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.087 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.115 g, 86%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8](Br)=[CH:7][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>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>[ClH:31].[NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: N[C@H](CNc1ncc(Br)c(-c2ccncc2)n1)Cc1ccccc1
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: Cl
Product: N[C@H](CNc1ncc(-c2ccc(F)c(Cl)c2)c(-c2ccncc2)n1)Cc1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 2-((2(S)-amino-3-phenylpropyl)amino)-5-bromo-4-(4-pyridyl)-pyrimidine (204 mg, 0.53 mmol), aqueous 2M sodium carbonate (1.66 ml, 3.32 mmol) and 3-chloro-4-fluorobenzene boronic acid (103 mg, 0.637 mmol) in toluene (5 ml) was stirred for 10 min under argon. The mixture was thoroughly degassed (10 times), before the addition of tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) After heating at reflux for 16 h, the reaction mixture was diluted with toluene and washed with brine. The organic solution was dried and evaporated. Subsequent column chromatography on silica gel (dichloromethane-methanol-conc. ammonium hydroxide=95:5:04) provided the title compound which was converted into the hydrochloride by the addition of 6N hydrochloric acid (64 μl) to its methanolic solution (2 ml) followed by evaporation. MS (m/z): 434.1 (M)+; C24H21ClFN5 requir. 433.9 (free base).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: Nc1cccs1
Product: CCOC(=O)C(=CNc1cccs1)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g) and 2-aminothiophene (2.22 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-thienyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2-thienyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.05 g), as white powder (recrystallized from ethyl acetate--n-hexane), m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=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:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of Boc-L-4-bromophenylalanine (15.0 g, 43.6 mmol), 3-chlorophenylboronic acid (8.52 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.51 g, 1.31 mmol) in 1,2-dimethoxyethane (180 mL) was added 2M solution of aqueous NaCO3 (33 mL). The reaction mixture was heated to 85° C. After stirred for 2 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (13.6 g). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.08-3.17 (m, 1H), 3.21-3.31 (m, 1H), 4.65 (bs, 1H), 5.01 (bs, 1H), 7.23-7.32 (m, 3H), 7.45-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.63-7.70 (m, 2H); MS: m/z (MH+) 376.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[S:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(OCC)(=O)C>[CH2:17]([NH:21][C:7]([C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:9])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc(C(=O)O)sn1
Reactant: CCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1cc(C)ns1
Reaction time: 0.5 h

Procedure:
3-Methyl-5-isothiazolecarboxylic acid (2.3 g) was dissolved in 40 ml of ethyl acetate. After 2 g of triethylamine were added, the resultant mixture was cooled over an ice-water bath and, at 5°-10° C., 1.5 g of n-butylamine were gradually added dropwise. After completion of the dropwise addition, stirring was continued for 30 minutes. The reaction mixture was washed successively with an aqueous solution of sodium hydrogencarbonate and then with water. After dried over sodium sulfate, the solvent was distilled off so that 2.60 g of N-n-butyl-3-methyl-5-isothiazolecarboxylic acid amide were obtained as an oil.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C@@:7]1([CH3:34])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C@@H:27]([CH:30]([CH3:32])[CH3:31])[CH:28]=[O:29])[C:8]1=[O:33])[CH:5]=[CH2:6]>C1COCC1>[CH2:4]([C@@:7]1([CH3:34])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:9]([CH:27]([CH:30]([CH3:31])[CH3:32])[C@@H:28]([OH:29])[CH3:1])[C:8]1=[O:33])[CH:5]=[CH2:6]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)C(C)C)C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C(C)C)[C@H](C)O)C1=O
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (1.4 mL, 1.960 mmol, 1.4 M in 1:3 THF:toluene) was added by syringe to a solution under nitrogen of pre-dried (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutanal (Example 261, Step 1,286 mg, 0.624 mmol) in THF (6.5 mL) at 0° C. The ice bath was removed. After 2 h, the solution was recooled to 0° C. and quenched by careful addition of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0 to 40% ethyl acetate in hexanes. Fractions containing the desired product were combined and re-purified to give the title compound as a mixture of diastereomeric alcohols) as a white foam. MS (ESI) m/z=474 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[C:31]([O:32][CH3:33])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)cc1OC
Yield: 59.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-dimethoxyphenylboronic acid (27.3 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3,4-dimethoxy-phenyl)-thiazole-5-carboxylic acid (26.4 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.45 (br.s., 1 H); 8.83 (s, 1 H); 7.86 (s, 1 H); 7.66 (d, 1 H); 7.60 (dd, 1 H); 7.40 (s, 1 H); 7.08 (d, 1H); 3.87 (s, 3 H); 3.85 (s, 3 H); 3.84 (s, 3 H); 3.82 (s, 3 H). MS m/z 442 (M+1).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[NH:7][CH:6]=1)C.COS(OC)(=O)=O.C[O-].[Na+]>[N+](C(C)C)([O-])=O.CO>[N+:14]([C:13]([CH3:8])([CH3:12])[CH2:4][C:5]1[C:9]2[C:8](=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1)([O-:16])=[O:15]
Reactant: CN(C)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Agent: C[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)[N+](=O)[O-]
Solvent: CO
Product: CC(C)(Cc1c[nH]c2c([N+](=O)[O-])cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 131 %

Procedure:
The 7-nitrogramine salt (2.0 g, 5.8 mmol) is suspended in a mixture of 2-nitropropane (9.5 mL) and methanol (9.5 mL). Dimethylsulfate (1.09 mL, 11.5 mmol) is added dropwise via syringe, and the resulting yellow solution is stirred at room temperature for 5 minutes. Sodium methoxide (0.62 g, 11.5 mmol) is then added in one portion, and the mixture is stirred overnight at room temperature. The reaction is quenched by addition of saturated NH4Cl solution and ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed with brine, and dried over Na2SO4 to give 1.0 g of 3-(2-nitro-2-methylpropyl)-7-nitroindole (69%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:36])([CH3:23])[CH:33]=[C:32]2[CH3:34]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Product: COc1cc2c(Oc3ccc4c(c3)C(C)=CC(C)(C)N4)ncnc2cc1OCCCN1CCCC1
Yield: 37.9 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (90 mg, 47%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(OC(C)(C)C)C(OC)=O)C=1C.[NH2:60][C:61]1[N:66]=[CH:65][C:64](B(O)O)=[CH:63][N:62]=1>>[NH2:60][C:61]1[N:66]=[CH:65][C:64]([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:12]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])[C:21]=2[CH3:22])=[CH:63][N:62]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: Nc1ncc(B(O)O)cn1
Agent: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cnc(N)nc1

Procedure:
2-(4-(2-Aminopyrimidin-5-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (145) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-aminopyrimidine-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt form).
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[C:11](Cl)(=O)[CH2:12][CH2:13]C>ClCCl.N1C=CC=CC=1.C(O)C>[O:9]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid) are dissolved in 550 ml of dichloromethane and 188 ml of pyridine. The mixture is cooled to 0° C. with a water/ice bath and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for 3 hours at room temperature. The solution is washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated under vacuum to give an oil. This oil is dissolved in 700 ml of ethanol and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of a liquid of boiling point b.p.20 98°-100° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:28]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
To a solution of 0.520 g (1.30 mmol) of the product of Step C dissolved in 3 mL of anhydrous TEF was added 1.3 mL (1.3 mmol) of a 1N solution of tetra-n-butylammonium fluoride in THF and the mixture was stirred at room temperature 1.5 hours. The mixture was then concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 70% ethyl acetate/hexane to afford 0.230 g (62%) of the title compound.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(-c2ccccc2)cc1
Yield: 98.4 %

Procedure:
To a stirred solution of 4-biphenylcarboxaldehyde (7.289 g, 40 mmol) in MeCN (80 ml) under nitrogen at room temperature was added methyl(triphenylphosphoranylidene)acetate (16.049 g, 48 mmol). After 18 h the reaction mixture was concentrated and the residue purified by flash chromatography, eluting with 10% EtOAc/hexane. The appropriate fractions were collected, filtered, concentrated and dried to give 3-biphenyl-4-yl-acrylic acid methyl ester (9.384 g, 39.38 mmol, 98%) as a pale yellow solid, mp 144-147° C. 1H NMR (DMSO-d6) δ 3.75 (s, 3H), 6.70 (d, 1H), 7.35-7.53 (m, 3H), 7.65-7.78 (m, 5H), 7.82 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]4)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc2cc(N)ccc2n1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc2cc(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc2n1

Procedure:
The title compound was prepared from 45C by procedures analogous to those described in Experiment 2E and 2F. HPLC: 100% at 1.81 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9](OCC)=[O:10]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2cc(F)ccc2N1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
Iron powder (36.42 g) was suspended in 5% aqueous acetic acid (69 ml) and heated to 80° C. To the suspension, a solution of ethyl 5-fluoro-2-nitrophenoxyacetate (15.86 g) in acetic acid (65 ml) and ethyl acetate (65 ml) was dropwise added, and the resultant mixture was heated at 60° to 80° C. under reflux for 3 hours. After removal of residue by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 7-fluoro-2H-1,4-benzoxazin-3(4H)-one (6.82 g). m.p., 186.7° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C(O)C>[O:19]1[CH2:20][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(CNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Cc1cc([N+](=O)[O-])c(NCC2OCCO2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
N-(2,2-dimethoxyethyl)-2,6-dinitro-4-methylaniline (3.0 grams; 0.0105 mole), ethylene glycol (0.65 grams; 0.0105 mole), p-toluenesulfonic acid (200 mg) and ethanol solvent were placed in a glass reaction vessel equipped with a stirrer heating mantle and thermometer. The reaction mixture was heated to 110° C. and maintained at that temperature with stirring for one hour. Then the reaction mixture was cooled to room temperature, ethyl acetate has added and the mixture was washed with water and sodium bicarbonate solution. The solution was dried over anhydrous magnesium sulfate and evaporated to yield the desired product (2.0 grams) of a yellow oil. The product was analyzed for C11H10N3O6 :
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:18](=[O:21])(O)[O-:19].[Na+].Cl.[NH:24]1[C:32](=[O:33])[C:31]2[NH:30][CH:29]=[N:28][C:27]=2[N:26]=[CH:25]1>O.C1(C)C=CC=CC=1>[NH:24]1[C:32](=[O:33])[C:31]2[N:30]=[CH:29][N:28]([CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][O:19][C:18]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:21])[C:27]=2[N:26]=[CH:25]1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)O
Reactant: O=C([O-])O
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCCCCCn1cnc2c(=O)[nH]cnc21)C(=O)O

Procedure:
0.850 g (0.0032 mole) of leucyl-methionine and 0.824 g (0.0096 mole) of sodium bicarbonate were dissolved in 40 ml of bidistilled water, in a 150 ml flask. To the resulting aqueous solution, having pH=8, a suspension of 1.05 g (0.0032 mole) of 9-[5-chlorocarbonyloxy)pentyl]hypoxanthine hydrochloride in 40 ml of toluene was added in ice bath.