Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[NH2:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1ncc(Br)s1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.44 g, 5.78 mmol), HATU (2.2 g, 5.78 mmol), and DIEA (1.5 mL, 11.6 mmol)in DMF (30 mL) was stirred at room temperature for 1 h. The 2-Amino-5-bromo-thiazole hydrobromide salt (FW=259.95, 1.0 g, 3.85 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 504.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH2:13])=[S:11])=[CH:5][CH:4]=1.Cl.[C:15](=N)(N)[CH3:16].C([O-])(=O)C.[Na+].C(O)CCC>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15]([CH3:16])=[N:13][N:12]=[C:10]2[SH:11])=[CH:5][CH:4]=1
Reactant: CC(=N)N
Reactant: COc1ccc(NC(=S)NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-n2c(C)nnc2S)cc1
Yield: 83 %

Procedure:
A mixture of 13.5 parts of N-(4-methoxyphenyl)hydrazinecarbothioamide, 15 parts of ethanimidamide hydrochloride, 15 parts of sodium acetate and 120 parts of 1-butanol is stirred and refluxed for 1 hour. The reaction mixture is cooled, 100 parts of water are added, followed by the addition of 140 parts of petroleumether. The precipitated product is filtered off and dried, yielding 12.5 parts (83%) of 4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol; mp. 214.2° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CN1C(=O)N(C)CCC1>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([I:3])[CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc(I)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COCCOCOc1cccc(I)c1
Temperature: 0 °C

Procedure:
To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in THF (10 mL), cooled to 0° C., is added 3-iodophenol (8.8 g, 40 mmol) and methoxyethoxymethyl chloride (5 mL, 44 mmol) in THF (50 mL). Then DMPU (10 mL) is added, the cooling bath is removed and the reaction is stirred for an hour. The reaction is diluted with ether, washed with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:15](Br)(Br)([Br:17])[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Zn].ClCCl>[Br:16][C:15]([Br:17])=[CH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C=C(Br)Br)cc21
Reaction time: 2 h

Procedure:
5 g (24.2 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde, prepared in Example 11(a), and 50 ml of dichloromethane were introduced into a round-bottomed flask. 16.1 g (48.4 mmol) of carbon tetrabromide, 12.7 g (48.4 mmol) of triphenylphosphine and 3.16 g (48.4 mmol) of zinc powder were successively added and stirring was carried out at room temperature for two hours. The reaction mixture was evaporated and the residue obtained purified by chromatography on a silica column eluted with hexane. 7.75 g (88%) of the expected compound were recovered.
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[CH:4][C:5]([O-:7])=[O:6])#N.[K+].S(=O)(=O)(O)[OH:18].O>C(O)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:18])[O:6][C:5](=[O:7])[CH:4]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=S(=O)(O)O
Reactant: N#CC(=CC(=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)O1
Reaction time: 1 h

Procedure:
25.8 g (92 mmol) of potassium 3-cyano-3-(3,4-dichlorophenyl)acrylate were dissolved in 200 ml of 88% strength formic acid and admixed dropwise with 15 ml of concentrated sulfuric acid. The mixed was then heated under reflux for 3 h, poured at 90° C. into 2.5 l of water and stirred for 1 h, and the product was filtered off, washed with water and dried. Yield: 18.9 g, m.p. 112° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:14])[CH2:5][CH:6]([C:8]3[S:9][CH:10]=[CH:11][C:12]=3[CH3:13])[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: Cc1ccsc1C1CC(=O)C=C(N)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccsc1C1CC(=O)c2c(C)ccnc2C1
Yield: 137.2 %

Procedure:
To a solution of 1-amino-5-(3-methyl-2-thienyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 ml) were added acetylacetoaldehydedimethylacetal (4.3 g) and 85% potassium hydroxide (0.71 g), and the mixture was refluxed. With 30 minutes interval, 85% potassium hydroxide (0.15 g) was added thrice to the mixture, and the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give crystals of 4-methyl-7-(3-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]=[S:21]1(=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[O:40]=[S:21]1(=[O:20])[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (61 mg, 0.22 mmol), 5-(1,1-dioxidothiomorpholin-4-yl)-2-morpholin-4-ylpyridin-3-amine (70 mg, 0.22 mmol) and a 4.0M solution of HCl in dioxane (0.05 mL, 0.22 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(5-(1,1-dioxido-4-thiomorpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.87-7.99 (2H, m), 7.75-7.85 (2H, m), 7.61 (1H, d, J=2.7 Hz), 7.41 (1H, d, J=1.6 Hz), 7.32 (1H, s), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.94 (4H, t, J=4.7 Hz), 3.53-3.67 (4H, m), 3.25 (4H, br. s.), 2.90-3.11 (4H, m), 2.37 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH:21]=[CH2:22]>CN(C=O)C>[NH:9]([CH2:22][CH2:21][C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10]
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of glycine t-butyl ester hydrochloride (20.7 g, 123 mmol) in DMF (50 mL) was added DIEA (21.5 mL, 123 mmol) and benzyl acrylate (20 g, 123 mmol). The mixture was allowed to stir at room temperature for 4 hours. This solution was concentrated in vacuo and the residue partitioned between saturated aqueous NaHCO3 and ethyl acetate and separated. The organic layer was washed once with saturated aqueous NaHCO3 and twice with brine. The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo to give 30 g (83%) of a slightly amber oil.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[CH:11][C:10]=2[O:19]C(=O)C)=[CH:5][CH:4]=1.O.O.O.C([O-])(=[O:29])C.[Na+].CO.Cl>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:5][CH:4]=1)=[O:29]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C(Br)Br)cc2)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(-c2cc(O)ccc2O)cc1

Procedure:
A mixture of about 4.4 g. (0.01 mole) of 4'-dibromomethyl-2,5-diacetoxy-1,1'-biphenyl, prepared as described in Example 2, and about 4.4 g. (0.03 mole) of sodium acetate trihydrate in a mixture of 50 ml. of methanol and 25 ml. of water was heated at reflux under nitrogen for about 4 hours. 5 ml. of concentrated hydrochloric acid were added and refluxing continued for an additional 11/2 hours. Most of the methanol was removed by evaporation on a steam bath under nitrogen resulting in precipitation of a light cream colored solid. The mixture was diluted with 50 ml. of water, cooled in an ice bath, and the resultant solid filtered, washed with water, and dried in a vacuum oven. Yield of about 2.0 g. of 4'-formyl-2,5-dihydroxy-1,1'-biphenyl, m.p. 203°-205° C. Thin layer chromatography indicated one component. Proton nuclear magnetic resonance and infrared spectra confirmed the structure and were essentially identical to the spectra obtained from the product of Example 3. The product gave a positive test with 2,4-dinitrophenylhydrazine spray reagent.
Reaction SMILES: [C:1]1([C:7]2[C:8]([Cl:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[C:8]([Cl:14])=[N:9][C:10]([CH2:13][Br:22])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)c(Cl)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(CBr)ccc1-c1ccccc1

Procedure:
A solution of 3-Phenyl-2-chloro-6-methylpyridine (0.094 g, 0.462 mmol), NBS (0.086 g, 0.485 mmol) and AIBN (0.008 g, 0.046mmol) in CCl4 (3 mL) were heated at reflux for 2 hours. The solvent was evaporated and the residue chromatographed (Silica gel, 100% CH2Cl2 to afford the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:18])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:18])[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: CCOc1cc(N)c(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(OCC)c(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Ethyl chloroformate (2.15 g) was added dropwise to a solution of 4-bromo-5-ethoxy-2-fluoroaniline (4.21 g) and pyridine (2.84 g) in methylene chloride (36 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, this was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-5-ethoxy-2-fluorophenyl)carbamate (5.30 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[O-]CC.[Na+].Br[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CC(C)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
4-Nitro-1H-pyrrole-2-carboxylic acid ethyl ester (3.69 g, 20.04 mmol) was dissolved in 100 ml of hot anhydrous ethanol and the solution was cooled to room temperature. 30 ml of sodium ethoxide (about 1M) in ethanol was added. The reaction mixture was stirred at room temperature for 20 min and 1-bromo-3-methylbutane (8 ml) was added. The mixture was stirred at reflux for 6 h and cooled to room temperature and then poured into water. The pale yellow precipitates were collected by filtration, washed with water, and dried to give the product (1.48 g, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[Li]CCCC.[CH3:17][N:18]1[CH:22]2[CH2:23][C:24]([CH2:26][CH:19]1[CH2:20][CH2:21]2)=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][C:8]([C:24]3[CH2:23][CH:22]4[N:18]([CH3:17])[CH:19]([CH2:20][CH2:21]4)[CH:26]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc2sc(C3=CC4CCC(C3)N4C)cc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
5-Methoxy-benzo[b]thiophene (3.20 g, 19.5 mmol) was solved in diethylether (50 ml). n-BuLi (8.58 ml, 21.45 mmol) was added to the mixture at a temperature below 20° C. The cooling was removed and the mixture was allowed to stir for 30 minutes. The mixture was cooled to −70° C. Tropinone (2.71 g, 19.5 mmol) solved in diethylether (50 ml) was added during 20 minutes. The temperature was kept below −60° C. Precipitation occurred. The mixture was stirred for 2 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added. The mixture was stirred for 10 minutes. The solid intermediate product (endo/exo-3-(5-methoxy-benzo-[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol) was filtered and washed with water and diethylether. Yield 3.97 g (67%). The intermediate product was combined with acetic acid (20 ml) and hydrochloric acid (7 ml). The mixture was stirred at reflux for 1 hour. The mixture was poured out on ice. The mixture was made alkaline by adding ammonia and extracted with dichloromethane and washed with water. The crude mixture was purified by column chromatography using a mixture of dichloromethane, methanol and aqueous ammonia (6:1:1%). Yield 2.28 g, (61%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:28])[CH3:27]>C(#N)C>[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:31]1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(C)=O)C3)nc21
Yield: 88.5 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (2.7 g), triethylamine (1.01 g), 3-acetylaminopyrrolidine (2.56 g), and acetonitrile (100 ml) was heated under reflux for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was mixed with water, neutralized with acetic acid, and cooled. The precipitate was collected, washed successively with water and ethanol, and dried to give 3.2 g of 7-(3-acetylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 283°-284° C., on recrystallization from dimethylformamide-ethanol.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)[CH2:33][CH3:34]>>[CH:11]1([CH2:10][CH2:9][C:8]([N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=3[CH:29]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:43]#[C:42][C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=3)=[CH:31][CH:30]=2)=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Reactant: C#Cc1ccc(OCCC)cc1
Product: CCCOc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-(propoxy)-phenylacetylene as a beige powder (59%). M+ (ESI): 566.2. HPLC, Rt: 6.17 min (Purity: 97.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=2[C:25]([N:27]([CH3:31])[CH2:28][C:29]#[CH:30])=[O:26])[C:19]([Cl:36])=[CH:18][N:17]=1>>[Cl:36][C:19]1[C:20]([NH:22][C:23]2[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=2[C:25]([N:27]([CH3:31])[CH2:28][C:29]#[CH:30])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: C#CCN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN(C)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-N-prop-2-ynyl-benzamide was prepared from 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow thin film (19 mg, 15%). LCMS (m/e) 489 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.99 (bs, 1H), 8.35 (d, 1H, J=8.2 Hz), 8.11 (s, 1H), 7.61-7.32 (m, 4H), 7.23-7.15 (m, 1H), 7.09 (d, 1H, J=8.2 Hz), 6.97 (s, 1H), 4.51-3.99 (m, 2H), 3.35 (s, 3H), 3.18 (bs, 3H), 2.72-2.61 (m, 2H), 2.42-2.29 (m, 3H), 2.23-2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1
Product: Nc1ccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.81) (0.20 g, 0.45 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.109 g, 0.49 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 53%). MS (ISP) 460.2 [(M+H)+]; mp 166° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18]CC)=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.C[N:22](C)C=O.[NH4+].[OH-]>CO>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([NH2:22])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2ccc3cnc(N)nc3c21
Temperature: 65 °C
Yield: 50 %

Procedure:
2.5 g of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (9.16 mmol) were dissolved in 40 mL of methanol, 40 mL of dimethylformamide and 50 mL of NH4OH 30% mixture. The mixture was maintained at 65° C. under stirring for a day. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was triturated with diethyl ether and the product collected by filtration (50% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 91%). 1H NMR (200 MHz, CDCl3): δ 2.54 (s, 3H), 3.50 (s, 4H), 3.90 (s, 4H), 4.15 (s, 3H), 6.89 (d, J=8.7 Hz, 2H), 7.25-7.62 (m, 3H), 7.79 (s, 1H), 7.91 (d, J=9.0 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:9][C:8]2=[O:31])(=O)C.[BH4-].[Na+].Cl>O1CCCC1.CO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([CH:8]([OH:31])[CH2:9][C:10]([CH3:30])([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(O)c2cc(O)c(C(C)(C)C)cc2O1

Procedure:
A solution of 3.0 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 54) in 20 ml of tetrahydrofuran was dropped into a suspension containing 0.3 g of sodium borohydride in 10 ml of methanol whilst stirring over an ice bath. After the whole of the solution had been added, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then ice-cooled again, acidified weakly with 10% w/v aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give crystals. Recrystallization of these crystals from a mixture of benzene and petroleum ether gave the title compound, melting at 194°-201° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11]C)=O)[CH2:2]2.O.[NH2:14][NH2:15]>O.C(=O)([O-])[O-].[K+].[K+]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH:14][NH2:15])=[O:11])[CH2:2]2
Reactant: NN
Reactant: COC(=O)C1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NNC(=O)C1CN2CCC1CC2
Yield: 100 %

Procedure:
(±) Methyl 1-azabicyclo[2.2.2]octane-3-carboxylate* (0.36 g; 2.1 mmoles) and hydrazine hydrate (0.35 ml; 7.0 mmoles) were heated at 120° C. for 2 h. The reaction was diluted with water (10 ml), saturated with potassium carbonate and extracted into chloroform (3×15 ml). Combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as a pale oil (0.36 g; 100%) which was used in the next stage without further purification. *