Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][C:11]1[N:15]=[C:14]([CH2:16][C:17](O)=[O:18])[O:13][N:12]=1>O>[CH3:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]([O:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:18])[O:13][N:12]=1
Reactant: CCCCCCCO
Reactant: Cc1noc(CC(=O)O)n1
Agent: Cl
Solvent: O
Product: CCCCCCCOC(=O)Cc1nc(C)no1

Procedure:
Under anhydrous conditions, a stream of gaseous hydrochloric acid was passed through 25 ml of n-heptanol and as soon as a saturated solution was reached at room temperature, 5.7 g (0.04 mol) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid were introduced. Introduction of a slow stream of hydrochloric acid was continued for two hours and the reaction mixture was then stirred for 60 hours at room temperature whereby conversion of the carboxylic acid was virtually completed. The reaction mixture was thoroughly mixed with 75 ml of cold water and the layers were separated. The organic layer was washed three times with 10 ml volumes of a saturated solution of sodium bicarbonate in water, and two times with 10 ml of cold water. All water-layers were combined and extracted twice with 20 ml volumes of ethyl acetate. The combined ethyl acetate extracts were once washed with 10 ml of iced water and the water-layers were discarded. The two organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was distilled and fractionated at reduced pressure to obtain 6.8 g of n-heptyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate of about 95% molar purity (impurity mainly a small amount of n-heptanol with a b.p. of 108° C. at 0.25 mm Hg and a refractive index nD20 =1.450.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12])=[CH:6][CH:5]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:12][CH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:13]([F:14])([F:15])[F:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: OCC(c1ccc(Cl)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 135 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 0.30 g or 2-(4-chlorophenyl)3,3,3-trifluoropropanol and 0.34 g of 3-phenoxybenzyl bromide in 20 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/toluene (2:1) mixture] to obtain 250 mg of the desired compound.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]([F:37])([F:36])[C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:9][NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2>CCOCC>[F:37][C:5]([F:4])([F:36])[C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:9][N:10]([C:2]#[N:1])[CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2
Reactant: N#CBr
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Solvent: CCOCC
Product: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
Add a solution of cyanogen bromide (68 mg, 0.63 mmol) in ether (2.6 mL) to a solution of isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (512 mg, 1.0 mmol) in ether (2.6 mL). Stir the mixture overnight at room temperature. Filter off the resulting solid and wash with ether. Wash the filtrate with water, dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (204 mg, 38%): MS (ES+): 534 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)#[N:28]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[C:27]#[N:28])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3C#N)C2=O)CC1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-cyanobenzyl bromide, to give the desired product as a light yellow solid (81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:23]=[N:22][C:21]([O:24][CH3:25])=[N:20][CH:19]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Reactant: OB(O)c1cccnc1F
Product: COc1ncc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)cn1
Yield: 34 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 34% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.47 (s, 2 H), 8.19-8.13 (m, 1 H), 8.01-7.91 (m, 1 H), 7.88-7.81 (m, 1 H), 7.77 (d, J=5.56 Hz, 1 H), 7.52-7.48 (m, 1 H), 7.46-7.32 (m, 6 H), 6.88 (br s, 2 H), 3.80 (s, 3 H); MS (ESI) m/z 412 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[O:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([OH:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1nccc(Oc2ccc(F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)c1nccc(Oc2ccc(F)cc2)n1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (0.150 g 0.646 mmol) was taken up in 2.5 mL 4:1 MeOH:DCM, and cooled to 0° C. NaBH4 (49 mg 1.30 mmol) was added. Fizzing was observed. After 10 min, cold bath was removed, and the reaction was stirred 1 h. Solvent was removed in vacuo. White residue was taken up in 10 mL water, and extracted with (2×10 mL) EtOAc. Washed organics with 10 mL brine. Dried over Na2SO4. Filtered and concentrated to give 143 mg (95%) 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol as a colorless oil. Anal. RP-HPLC tR=1.38 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 235.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[N:10]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc(Br)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 1b (1.32 g, 5.26 mmol), imidazole (0.75 g, 11.00 mmol), K2CO3 (1.13 g, 8.16 mmol) and 18-crown-6 according to Method B. Yellow solid. Yield: 0.75 g, 60%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.12 (s, 2H), 6.88 (t, J=1.2 Hz, 1H), 7.13 (s, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 8.28 (d, J=2.5 Hz, 1H); MS (ESI): m/z=239.08 [M+H]+.
Reaction SMILES: BrC1C=[C:4]([C:10]2[O:14]C(=O)NN=2)C=NC=1CC.[Br:16][C:17]1[C:18]([CH2:27][CH3:28])=[N:19][CH:20]=[C:21]([CH:26]=1)[C:22](NN)=[O:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:16][C:17]1[C:18]([CH2:27][CH3:28])=[N:19][CH:20]=[C:21]([CH:26]=1)[C:22]([O:14][CH2:10][CH3:4])=[O:23]
Reactant: CCc1ncc(C(=O)NN)cc1Br
Reactant: CCc1ncc(-c2n[nH]c(=O)o2)cc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Reaction time: 1 h
Yield: 58 %

Procedure:
Step-3: 5-(5-Bromo-6-ethylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one: To a stirred and cooled (0° C.) solution of 5-bromo-6-ethylnicotinohydrazide (2.50 g, 10.24 mmol, 1.0 eq) and diisopropylethylamine (3.58 mL, 20.48 mmol, 2.0 eq) in DCM (20 mL) was added a solution of triphosgene (1.21 g, 4.10 mmol, 0.4 eq) in DCM (10 mL) over a period of 10 min. The resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was then diluted with DCM (50 mL) and washed with water (50 mL), aqueous sodium bicarbonate (10%, 50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 1.60 g (58%) of the desired product as a white solid. 1HNMR (400 MHz, DMSO) δ 8.83 (d, J=1.5 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 2.92 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 270, 272 [(MH)+ Br79, 81].
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].Cl>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=[S:29])[CH2:2]1
Reactant: O=C1COc2ccc(Nc3nc(Nc4cccc(O)c4)ncc3F)cc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=S)CO4)n2)c1

Procedure:
N4-[2H-1,4-Benzoxazin-3(4H)-one-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (800 mg, 2.18 mmol) and phosphorus pentasulfide (800 mg, 1.80 mmol) were stirred in pyridine (5 mL) at 70° C. for 2 h. The reaction solution was treated with 1N HCl solution to pH 5. The precipitation was collected with filtration, washed with water, dried to give N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Cl)cc(Cl)c3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Cl)cc(Cl)c2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5,7-dichlorobenzoxazole (250 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1/[C:11](/[N:14]([CH2:17][CH3:18])[N:15]=[CH2:16])=[CH:12]/C.[Cl:19]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:12]=1[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=NN(CC)/C(=C\C)c1cc(C(=O)OC)sc1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)sc1Cl
Yield: 95.9 %

Procedure:
Methyl 5-chloro-4-[(1Z)-1-(1-ethyl-2-methylidenehydrazino)-1-propen-1-yl]-2-thiophenecarboxylate (260 mg, 0.96 mmol) and 1-chloro-2,5-pyrrolidinedione (154 mg, 1.15 mmol) in THF (4 mL) were heated at 70° C. under N2 for 2 h, concentrated and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.281 g, 83%) as a syrup: LC-MS (ES) m/z=305 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19](=[O:27])[N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:23]([N:20]1[C:21]2[N:22]=[C:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=3)[NH:15][C:16]=2[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cn1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)nc3)nc21

Procedure:
This compound was prepared by the method similar to that described in example 11 (method 1) except that the hydrochloride salt of (6-acetylamino-pyridin-3-yl)-acetic acid was used in place of N-acetyl-4-aminophenylacetic acid and the coupling to 5,6-diamino-1-butyl-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione was performed with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and diisopropylethyl amine in N,N-dimethylformamide. MS, m/z(M+)=464.1971.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnn(CCCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnn(CCCc2ccccc2)c1

Procedure:
The ester was then dissolved in methanol (30 ml), and potassium hydroxide (1.5 g) added. The mixture was refluxed for 5 hours under nitrogen, then the solvent removed under reduced pressure. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and acidified to pH 1-2 with 6N hydrochloric acid, then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and the solvent removed under reduced pressure, to give 1-(3-phenylpropyl)pyrazole-4-carboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([Cl:34])[CH:27]=2)=O)=[O:21])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[Cl:34][C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][O:22][C:20](=[O:21])[C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(C(=O)COC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
To a 0° C. solution of 2-(3-chloro-4-methoxyphenyl)-2-oxo-ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 1.58 mmol) in DMF (10 mL) was added NaH (190 mg, 3.95 mmol). The reaction mixture was then stirred at RT for 1 h, quenched with ice and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (40 mg, 6%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H). MS: M+H: m/z=458.1. HPLC: 93%, (Condition-H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: C1CNCCOC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCOCC1
Yield: 52 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-oxazepane gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepane as a yellow oil (72 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.94 (t, J=5.6 Hz, 2H), 3.88-3.84 (m, 2H), 3.80 (s, 3H), 3.40-3.35 (m, 4H), 2.07-1.99 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH3:16]>>[Cl:1][C:2]1[N:11]=[C:10]([NH2:16])[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1Cl
Reactant: N
Product: COc1cc2nc(Cl)nc(N)c2cc1Cl
Yield: 58 %

Procedure:
Reaction of 2,4,6-trichloro-7-methoxyquinazoline with ammonia as described above afforded 2,6-dichloro-4-amino-7-methoxyquinazoline as a white solid, M.P., 300° C. in 58% yield.
Reaction SMILES: BrC1C=CC([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=CC=1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:11]2[N:12]=[C:13]([CH2:24][CH3:25])[N:14]=[C:9]([NH2:8])[N:10]=2)[CH:21]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2cc(Cl)ccc2C)n1
Yield: 36.1 %

Procedure:
The reaction of the title compound of Example 20 (200 mg, 0.49 mmol) with ethyl magnesium bromide (1 M in diethyl ether, 7.5 ml, 7.5 mmol) in tetrahydrofuran (2 ml) using the method described in Example 22 provided the title compound (44 mg, 22% yield). 1H NMR (CDCl3) 7.80 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.09-7.12 (m, 2H), 2.79 (q, J=7.4 Hz, 4H), 1.13 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[CH2:14][CH2:15][NH2:16].C(=O)(O)[O-].[Na+].O>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:12]=2[Cl:11])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine (0.7 g), 2,4-dichlorophenethylamine (0.82 g) and sodium bicarbonate (0.88 g) in ethanol (25 mL) is heated at 80° C. for three hours and poured into water (400 mL). The resulting solid is filtered and air dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[O:19][CH:20]=1.[I-].[Na+]>CN(C)C=O.O>[F:27][C:25]1[CH:24]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=[C:21]([C:18]2[O:19][CH:20]=[C:16]([CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[N:17]=2)[CH:26]=1
Reactant: Fc1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1coc(-c2cc(F)cc(C(F)(F)F)c2)n1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottomed flask was placed diethyl malonate (3.72 g, 23.25 mmol, 5 equiv.) and N,N-dimethylformamide (10 mL). To the solution was added sodium hydride (60% suspension in mineral oil, 744.0 mg, 18.6 mmol, 4.0 equiv.) at room temperature portionwise over 10 minutes. After stirring for 30 minutes a solution of 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole (1.30 g, 4.65 mmol) in N,N-dimethylformamide (10 mL) was added at 0° C. over 15 minutes, and the reaction mixture allowed to warm up to ambient temperature. To the mixture was added sodium iodide (697.0 mg, 4.65 mmol, 1 equiv) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water was then added to the reaction mixture (30 mL) and the whole was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine (30 mL) and dried with sodium sulfate. After removal of the solvent under reduced pressure the crude mixture was purified by a silica-gel column chromatography (SiO2=80 g, hexane:EtOAc=7:1) repeatedly. The desired product, diethyl 2-({2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl)propane-1,3-dioate, was obtained as colorless powder (1.75 g).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22](=O)[CH2:23][C:24](=O)[CH3:25])[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:60][NH2:61]>CCO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[CH:23]=[C:24]([CH3:25])[NH:61][N:60]=2)[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:2])[CH3:3]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CC(C)=O)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: NN
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C)[nH]n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 0 °C
Yield: 37.8 %

Procedure:
Add slowly cold (ice bath) absolute EtOH (1.7 mL) to a cooled 0° C. stirred mixture of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (221 mg, 0.34 mmol) and phosphorus pentoxide (880 mg, 6.2 mmol). Add hydrazine hydrate (0.105 mL, 3.4 mmol) while keeping the mixture cooled at 0° C. Seal the tube and heat the reaction mixture at 100° C. overnight. Cool down the mixture and remove the solvents under reduced pressure. Partition the residue between water and dichloromethane. Separate the layers and dry the organic phase, filter, and concentrate in vacuo. Purify the residue by silica gel flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (82 mg, 38%). MS (ES+): 638 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O.Cl>>[OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)CCC(=O)O)c(O)c1
Agent: Cl
Product: COC(=O)CCC(=O)c1ccc(C)cc1O

Procedure:
3-(2-Hydroxy-4-methylbenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1 (i), to give methyl 3-(2-hydroxy-4-methylbenzoyl)propionate, m.p. 61°-63°.