Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:19]=[C:18]4[C:14]([N:15]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:16](=[O:20])[NH:17]4)=[C:13](I)[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:19]=[C:18]4[C:14]([N:15]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:16](=[O:20])[NH:17]4)=[CH:13][N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c2n1CC(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)ncc2n1CC(F)(F)F
Yield: 32.3 %

Procedure:
Under an argon atmosphere, 161 mg (0.275 mmol) of the compound from example 131 were dissolved in 15 ml of dimethylformamide, admixed with 100 mg of 10% palladium on charcoal and hydrogenated under standard hydrogen pressure overnight. The reaction mixture was filtered through Celite and concentrated, and the residue was purified by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 65:30:5→0:95:5). 41 mg of the title compound were obtained (33% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:25]=[CH:24][C:15]([N:16](C(=O)C(F)(F)F)[CH3:17])=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1>[OH-].[K+].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:25]=[CH:24][C:15]([NH:16][CH3:17])=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CNc1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-]

Procedure:
7.4 g (18.8 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methyl-aniline are stirred in 200 ml of 20% potassium hydroxide solution for one hour at 30° C. Then the mixture is diluted with isopropanol, the organic phase is separated off, 10.0 g of aluminium oxide are added and the resulting mixture is evaporated to dryness. The residue is chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (4:1 and 1:1).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](#[N:12])[CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:9]#[N:12])[CH2:5][CH2:4]1
Reactant: FC1CCNCC1
Reactant: N#CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CCN1CCC(F)CC1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
4-Fluoropiperidine HCl (801 mg, 5.74 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (647 uL of a 52% aqueous solution, 6.31 mmol) at 5° C. Sodium carbonate (912 mg, 8.60 mmol) was added and the solution was stirred at 70° C. for 1.5 h. The solution was cooled, diluted with water (2 mL), washed with Et2O (3×4 ml). The organic fraction was dried and the solvent evaporated to give 2-(4-fluoropiperidin-1-yl)acetonitrile as a colourless oil. The oil was then dissolved in a 7 N solution of ammonia in MeOH (25 mL) and submitted to hydrogenation on the H-Cube using 75 bar of hydrogen pressure at 55 C with a flow rate of 0.8 mL/min and using a Raney nickel catalyst cartridge. After the reaction was complete the solvent was stripped in vacuo to give 2-(4-fluoropiperidin-1-yl)ethanamine as a translucent oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[N:5][N:4]=1)[CH3:2]>[Pt]=O.Cl>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:6]([C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(-c2ccc([N+](=O)[O-])cc2)n1-c1ccc(OC)cc1
Agent: O=[Pt]
Agent: Cl
Product: CCc1nnc(-c2ccc(N)cc2)n1-c1ccc(OC)cc1
Reaction time: 96 h
Yield: 99.9 %

Procedure:
100 g of the product of Example 1 were mixed at ambient temperature with 500 ml of 2N hydrochloric acid with stirring and a partial solution and then a crystallization were obtained. 0.5 g of 0.5% platinum oxide was then added, and stirring was continued for 4 days at 35°-38° C. under an atmosphere of hydrogen. After filtering, washing with water, the mixture was made alkaline with a pH of 11 with sodium hydroxide. The mixture was stirred for 1 hour at 20°-25° C. and filtered. The product was washed with water and dried at 60° C. to obtain 90.75 g of crude product. The latter was purified by triturating at reflux in ethyl acetate to obtain 90.7 g of 4-[5-ethyl-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-yl]-benzenamine melting at 210° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)(=[O:4])=[O:3].[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[CH3:1][S:2]([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccccc2)C(=O)O1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Yield: 53 %

Procedure:
[(5R)-3-phenyl-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (41 g, 152 mmol) was dissolved in chloroform/acetonitrile (250/250 ml). Silver trifluoroacetate (50 g, 228 mmol) was added followed by portionwise addition of iodine (58 g, 228 mmol). After stirring the reaction overnight, the silver iodide was filtered off, and the filtrate was washed with solutions of 5% sodium thiosulfate (2×500 ml), saturated sodium bicarbonate (500 ml), brine, and dried over magnesium sulfate. The dried solution was evaorated to give the desired product as a yellow solid (32 g) that was used without further purification.
Reaction SMILES: Cl.[F:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:8]([NH:15][CH2:16][C:17](O)=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(N(CC)CC)C>[F:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:17](=[O:18])[CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: F[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CC[C@H](F)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
(S)-3-Fluoropyrrolidine hydrochloride (535 mg), N-Boc glycine (746 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole (993 mg), and triethylamine (1.19 mL) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and aqueous saturated sodium bicarbonate (20 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL). The organic layer was washed sequentially with 0.1N HCl (10 mL) and saturated brine (10 mL) and dried over sodium sulfate, followed by concentration under reduced pressure, to thereby yield compound 20a (98.1 mg, yield: 9.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[C:2]1([NH:12][C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Product: O=C(O)c1ccccc1Nc1ccccc1

Procedure:
As shown in Scheme 7, coupling of 3-bromo-4-nitrotoluene with 2-amino-benzoic acid via an Ullmann reaction yields an N-phenyl-anthranilic acid. After protection of the acid with 2-amino-2-methyl-1-propanol, oxidation affords the corresponding aldehyde. Addition of vinyl magnesium bromide and deprotection provides the N-phenyl-anthranilic acid containing a latent Michael acceptor. ##STR15## Figure legends
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].O.[NH2:12][NH2:13]>C(O)CCC>[I:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:9]([NH2:10])=[N:12][NH:13][C:2]=12
Reactant: NN
Reactant: N#Cc1nccc(I)c1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2c(I)ccnc12
Temperature: 105 °C

Procedure:
3-Fluoro-4-iodopicolinonitrile (25.6 g) was dissolved in n-butan-1-ol (250 mL) then hydrazine hydrate (100%, 23.3 mL) was added. The reaction was heated at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, rinsed with water, and dried for 30 minutes under vacuum to give 7-iodo-1H-pyrazolo[4,3-b]pyridine-3-amine (25 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.35-5.55 (2H, m) 7.73-7.74 (1H, m) 7.939-7.94 (1H, m). MS [M+H] found 261.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:37]#[C:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH3:47])=[N:43][CH:44]=1>C1(C)C=CC=CC=1.C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:37]#[C:38][C:39]3[CH:44]=[N:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCCc1ccc(C#CBr)cn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc(C#Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 18.3 %

Procedure:
To a stirred solution of 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.00090 mol) and copper sulfate (0.023 g, 0.00009 mol) in toluene (15 mL) was added potassium carbonate (0.25 g, 0.0018 mol) and 1,10 phenanthroline (0.033 g, 0.000018 mol). The reaction mixture was stirred for 5 min at RT. A solution of 5-(bromoethynyl)-2-propylpyridine (0.221 g, 0.00099 mol) in toluene (5 mL) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 80° C. The reaction was monitored by TLC. After completion of reaction, water (30 mL) was added, and the mixture extracted with EtOAc (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, solvent was removed under reduced pressure, and the crude product purified by column chromatography using silica (100-200 mesh) and 3% MeOH:DCM as eluent, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.06 g, 18% yield). 8-Chloro-2-methyl-5-((6-propylpyridin-3-yl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.056 g, 0.000153 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.02 g, 0.000153 mol) in THF (2 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give the oxalate salt as an off-white solid (0.050 g, 80% yield). 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.65 (s, 1H), 7.95 (d, 1H), 7.62 (d, 1H), 7.60 (s, 1H), 7.38 (dd, 2H), 4.78 (m, 2H), 4.50 (s, 2H), 3.76 (m, 2H), 3.10 (s, 3H), 2.80 (m, 2H), 1.76 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:6]2=[CH:5][CH:4]=1.[Li]CCCC.[B:27](OC)([O:30]C)[O:28][CH3:29]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])[C:6]2=[CH:5][C:4]=1[B:27]([OH:30])[O:28][CH3:29]
Reactant: COB(OC)OC
Reactant: COc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COB(O)c1cc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)nc1OC
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a colorless solution of 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridine (5.01 g, 16.45 mmol) in THF (100 mL) was dropwise added 2nd-BuLi (21.15 mL, 29.6 mmol) at −78° C. under N2 over 5 min to give an orange solution, the mixture was stirred for 30 min, followed by dropwise addition of trimethyl borate (3.31 mL, 29.6 mmol) through a syringe over 1 min. The resulting light orange solution was stirred at −78° C. for 1 hr, quenched with sat. NH4Cl (30 mL), partitioned between H2O/Et2O (100 mL/150 mL). After seperation, the organic layer was washed with brine (50 mL), dried on MgSO4, concentrated on rotary vacuo and purified on Biotage Flash Collector eluting with 10˜50% EtOAc/Hexanes (1300 mL) to afford the expected produce methyl hydrogen 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-ylboronate (2.5 g, 42%), as a colorless thick gum. Mass spec. 363.24 (MH+) calc. for C18H31,BN2O3 Si 362.22.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12.Cl>O1CCCC1.O>[CH3:1][O:2][NH:3][C@@H:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12
Reactant: CON=C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Yield: 60.2 %

Procedure:
In tetrahydrofuran (25 ml) is dissolved 2,2,2-trichloroethyl 7-methoxyimino-3-methyl-3-cephem-4-carboxylate (5.80 g) and under ice-cooling stirring, a 1 M tetrahydrofuran solution of borane-tetrahydrofuran complex (198 ml) is added dropwise over a period of 80 minutes. The reaction mixture is diluted with water (20 ml), adjusted to pH 1 with dilute hydrochloric acid and stirred at room temperature for 1.5 hours. The organic solvent is distilled off, the residual aqueous solution is adjusted to pH 7 with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate is then distilled off, the residue is dissolved in a mixture of methanol (120 ml) and 12.5% aqueous ammonium chloride (60 ml) and the mixture is stirred at room temperature for an hour. The organic solvent is distilled off and the residual aqueous solution is extracted with ethyl acetate. The extract is washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated. The oily residue is subjected to silica gel (90 g) column chromatography and elution is carried out with ethyl acetate-methylene chloride. By the above procedure is obtained 2,2,2-trichloroethyl 7β-methoxyamino-3-methyl-3-cephem-4-carboxylate (3.51 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I>[CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN(Cc1ccccc1)C1(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 85.7 %

Procedure:
Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (6.0 mg, 0.03 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(11) (20.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound 80 mg (84%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17](=O)[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17]([Cl:48])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(=O)[nH]cnc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Cl)ncnc2c1

Procedure:
Using an analogous procedure to that described in the portion of Example 31 that is concerned with the preparation of starting materials, 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-methoxy-3,4-dihydroquinazolin-4-one (1 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazoline (0.8 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.1 (m, 4H), 3.5–3.7 (m, 4H), 3.96 (s, 3H), 4.72 (m, 2H), 6.6 (d, 1H), 6.98 (d, 1H), 8.82 (s, 1H); Mass Spectrum: M+H+ 394 and 396.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:19])[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(#N)C>[Cl:1][C:17]1[CH:18]=[C:12]([O:11][CH:10]([F:19])[F:9])[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(OC(F)F)cc1Cl
Temperature: 25 °C
Yield: 53.5 %

Procedure:
N-Chlorosuccinimide (0.84 g, 6.28 mmol) was added to a solution of 4-(difluoromethoxy)aniline (1 g, 6.28 mmol) in acetonitrile (10 ml). The reaction was refluxed for 3 hours and then cooled to room temperature. The solvent was removed in vacuum and the residue purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound as a dark pink liquid (0.65 g, 53.4%). 1H NMR (500 MHz, CDCl3): δ 4.02 (s, 2H), 6.24 (t, J=74 Hz, 1H), 6.72 (d, J=8.7, 1H), 6.89 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.11 (d, J=2.6 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:11](=[CH2:14])[C:12]#[N:13]>O>[C:12]([C:11]1[N:3]=[N:2][N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:14]=1)#[N:13]
Reactant: C=C(Cl)C#N
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-azidoacetate (1.29 g) and 2-chloroacrylonitrile (1.75 g) in water (10 ml) is stirred at about 80° C. for 16 hours. After cooling, the product is extracted with dichloromethane and the concentrated extract is purified by means of column chromatography on silica gel 60 (6 g; eluent: toluene/ethyl acetate=4:1). The purified product (yield 1.21 g; 67% of theory) of m.p. 47-48° C. (recrystallization from toluene/hexane) is obtained after concentrating the eluate and drying.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([NH:23][CH3:24])[CH:15]=3)[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:25])=[CH:15][C:16]=1[NH:23][CH3:24]
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a suspension of 4-((4-fluorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (500 mg) in AcOH (30 ml) was added zinc (885 mg), and the mixture was stirred at room temperature for 1 h. The insoluble material was removed by filtration and washed with MeOH. The filtrate was concentrated, and partitioned between EtOAc, THF and saturated NaHCO3 solution. The organic layer was then washed with brine, dried over MgSO4, and concentrated. The resulting solid was collected, and washed with IPE to give the title compound (366 mg) as a brown solid.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH2:7])=[NH:6])([CH3:4])[CH3:3].Cl.[O-]CC.[Na+].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[C:2]([C:5]1[N:7]=[C:16]([OH:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:6]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated, the residue dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried in vacuo to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+).
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2=[N:3][C:4]3[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2c(c1)N=C(Cl)c1ccccc1O2
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)N=C(N1CCN(C)CC1)c1ccccc1O2
Temperature: 110 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Compound 549 (1.06 g, 3.68 mmol) and 1-methylpiperazine (0.818 mL, 7.37 mmol) were dissolved in toluene (40 mL) and stirred at 110° C. for 16 h. The toluene was removed on the rotary evaporator. The crude product was dissolved in ethyl acetate and washed with water. The organic layer was separated and dried with Na2SO4, filtered and concentrated via rotary evaporation. The residue was purified via Isco employing a 0 to 50% methanol:ethyl acetate solvent gradient to afford compound 550 (0.86 g, 66%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13].C(O)(C)(C)C.N.[Li].[Cl-].[NH4+].Cl>O1CCCC1>[O:2]=[C:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH:4]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)CC1CC(=O)CCC1=O
Reaction time: 4 h

Procedure:
A solution of 3.6 g (20 mmol) of (2,5-dimethoxyphenyl) acetic acid, 30 g (0.4 mole) of anhydrous t-butanol, and 40 ml of anhydrous tetrahydrofuran (THF) was added to 200 ml of liquid ammonia at -78° C. via cannula. Lithium wire (1.5 g, 0.21 mol) was cut into small pieces, washed briefly with isopropylalcohol and hexane, and then added to the above mixture piece by piece. The resulting reaction mixture turned a dark blue-gray color. After 4 hours, the blue color faded to gray, some excess ammonium chloride (4 g) was added, and the ammonia was allowed to evaporate overnight under a stream of nitrogen, leaving a white solid. The residue was then treated with 80 ml of 6 N hydrochloric acid, and the resultant mixture was heated to reflux for 1.5 hours.