Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:27])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:3].CC(C1C=CC=C(C(C)C)C=1N[C:41](=[O:54])[CH2:42]NC(C)(C)CC1C=CC=CC=1)C>>[C:41]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=1)[CH2:15][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:1])[CH3:3])=[O:27])(=[O:54])[CH3:42]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(C)(C)Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCc1ccc(N(C)C)cc1
Product: CC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(N(C)C)cc1

Procedure:
When in the procedure of Example 79 an appropriate amount of the product from Example 73 was substituted for the product of Example 5 the title compound was obtained. Total yield, 0.41 g (73%).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4(O)[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl>[CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4([F:38])[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1
Reactant: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(O)(C3)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C

Procedure:
A solution of N-[(E)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide (66 mg, 0.15 mmoles) from Example 2 in DCM (0.5 mL) was cooled to −78° C., treated with (diethylamino)sulfur trifluoride (DAST)(0.020 mL, 0.16 mmoles) and slowly warmed to room temperature over 6 hours. The mixture was quenched with aqueous saturated sodium bicarbonate (0.1 mL), filtered through a Celite cartridge and purified (silica gel, 10-15% acetone in hexane) to provide the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.63 (m, 2H), 6.68 (d, J=9.2 Hz, 1H), 4.09 (d, J=8.5 Hz, 1H), 3.69 (s, 4H), 3.09 (s, 2H), 2.69 (s, 4H), 2.27-2.22 (m, 3H), 2.06 (m, 2H), 1.94 (m, 4H), 1.58-1.54 (m, 4H); (APCI+) m/z 441 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[CH:14][CH2:15][Si](C)(C)C)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:23])[CH:14]=[CH2:15])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@H](C=CC[Si](C)(C)C)COC1(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a solution of the compound produced in Example 47 (0.196 g, 0.63 mmol) in acetonitrile (6 ml), was added Selectfluor™ (0.33 g, 1.5 eq.) and NaHCO3 (0.105 g, 2 eq.). The reaction mixture was stirred under an atmosphere of nitrogen for 20 hours before concentrating under reduced pressure. Purification by flash chromatography (diethyl ether:hexane 1:19) afforded the product (0.116 g, 72%). de=33%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])(=O)=O.[I-:15].[Na+].O>CC(C)=O>[CH3:10][C:9]([N+:11]([O-:13])=[O:12])([CH3:14])[CH2:8][CH2:7][CH2:6][I:15]
Reactant: [I-]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-Methyl-4-nitropentanol methanesulfonate (3.38 g, 15 mmol) was dissolved in acetone (50 ml) and sodium iodide (8.7 g, 58 mmol) was added. The mixture was stirred overnight. Water (20 ml) was added and acetone was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (50 ml). The extract was washed with 5% aqueous sodium thiosulfate solution (20 ml) and saturated brine (20 ml), and ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (3.84 g, yield 99.6%).
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1>C(O)C>[CH3:2][C:3]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc2ccccc2c1)C(=O)OCC
Temperature: 0 °C

Procedure:
5.15 g (224 mmol) of sodium were dissolved in 150 ml of absolute ethanol, while heating, and 37.3 ml (217 mmol) of diethyl methylmalonate were added at room temperature. A solution of 50 g (217 mmol) of 2-bromomethylnaphthalene (96% pure) in 270 ml of ethanol was slowly added dropwise at 0° C., and the mixture was heated under reflux for a further 4 to 5 hours. It was poured onto ice-water and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and evaporated. After drying under an oil pump vacuum, the oily residue was stirred with hexane at 0° C., whereupon 55 g (81%) of the compound 1 crystallized.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[C:6]([CH3:19])[C:5]=1[OH:20])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.O.[OH-].[Na+]>C(Cl)Cl>[CH3:19][C:6]1[C:5]2[O:20][CH:2]([CH2:3][OH:29])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(C)cc2c(-c3ccccc3)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(-c3ccccc3)noc2c2c1OC(CO)C2
Temperature: 0 °C
Yield: 96.4 %

Procedure:
To the ice-cooled solution of 7-allyl-6-hydroxy-5-methyl-3-phenyl-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml), 7.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the solution was subsequently refluxed for 3 hours. After cooling the solution, water and 50 ml of an aqueous solution of 2N sodium hydroxide were added, and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 4.6 g of 7,8-dihydro-5-methyl3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 130°-133° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 281.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:19])[N:17]2[C:18]3[C:9]([S:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30].Cl>CN(C=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([CH:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[S:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[N:17]([C:18]=23)[C:3]1=[O:19])=[O:30]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: O=C1Cc2cccc3c2N1c1ccccc1S3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)C1C(=O)N2c3ccccc3Sc3cccc1c32
Reaction time: 12 h
Yield: 360.3 %

Procedure:
To a suspension of sodium hydride (0.14 g) in DMF (10 ml) was added pyrrolo[3,2,-1kl]phenothiazine-1-one (0.48 g) and to the resulting solution was slowly added 2,4-difluorophenyl isocyanate (0.31 g) . The reaction mixture was stirred for 12 hours and then poured onto ice water (50 ml). The resulting mixture was acidified to pH 2.0 with 6N HCl and the precipitated solid was collected and then air dried-to yield the title compound (2.84 g). A sample recrystallized from methylene chloride had a m.p. of 208°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Into a 5000-mL 4-necked round-bottom flask, was placed aniline (93 g, 1.0 mol, 1.0 equiv.), triethylamine (202 g, 2.0 mol, 2.0 equiv.) and dichloromethane (2,000 mL). This was followed by the addition of 4-fluorobenzoyl chloride (174 g, 1.1 mol, 1.1 equiv.) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated under vacuum. The solid was filtered out. The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water. This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid. MS (ESI) m/z 216 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=O)[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][O:33][NH2:34].O.O.O.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=[N:34][O:33][CH3:32])[CH3:19])=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CON=C(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.4 %

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 460 (150 mg, 0.3 mmol) in H2O (10 mL) and dioxane (20 mL) was treated with methoxyamine hydrochloride (84 mg, 1 mmol) and sodium acetate trihydrate (138 mg, 1 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate and purified by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 20 mg, 15%). mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, 1H), 7.65 (q, J=10 Hz, 1H), 7.82 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.24 (s, 1H); MS (APCI+) m/z 464 (M+H)+; (APCI−) m/z 498 (M+Cl)−. Anal. calc. for C21H19F2N3OS: C, 54.42; H, 4.13; N, 9.06. Found: C, 54.33; H, 3.93; N, 8.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[N:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1
Reactant: O=Cc1nccc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Chloropyrimidine-2-carbaldehyde (4.53 g, 31.8 mmol) was taken up in MeOH (65 mL) and cooled to 0° C. NaBH4 (1.262 g, 33.4 mmol) was added and the mixture stirred at 0° C. for 90 minutes. Water was added and the reaction mixture was extracted with CHCl3 (3×).
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:19]([CH2:25][CH2:26][N:27]=4)[C:20]([NH2:24])=[N:21][C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:24][C:20]2[N:19]3[CH2:25][CH2:26][N:27]=[C:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][S:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:8])=[O:9])=[CH:23][C:22]=3[N:21]=2)=[O:34])=[CH:31][N:30]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Product: Nc1ccc(C(=O)NC2=Nc3cc(OCCCS(=O)(=O)N4CCOCC4)ccc3C3=NCCN23)cn1

Procedure:
The procedure used for the preparation of Example 28, Step 2 was used to prepare the title compound from 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 28, Step 1) and 6-aminonicotinic acid. Yield 50.0 mg (14%). TLC Rf=0.52 in 10% MeOH/CH2Cl2, HPLC MS RT=0.23 min, MH+=514.4; 1H NMR (MeOD) δ: 2.35 (2H, m), 3.20-3.33 (6H, m), 3.72 (4H, m), 4.26 (2H, t), 4.35 (2H, t), 4.63 (2H, t), 7.06 (1H, d), 7.19 (1H, dd), 7.36 (1H, s), 8.04 (1H, d), 8.56 (1H, dd), 8.74 (1H, s).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:14]1([CH2:13][O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
4-Trifluoromethylbenzyl bromide (0.17 mL, 1.09 mmol, 1 eq) was added dropwise to a stirred solution of 3-benzyloxy-4-hydroxybenzaldehyde (250 mg, 1.09 mmol, 1 eq) and cesium carbonate (357 mg, 1.09 mmol, 1 eq) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight, then diluted with ethyl acetate (30 mL) and washed sequentially with water (4×30 mL), 0.5M aqueous sodium hydroxide (30 mL), 10% HCl and brine. The organic solution was dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (422 mg, 99%). 1H NMR (CDCl3) δ 9.82 (s, 1H, O═C—H), 5.28 (2H, s, CH2Ar), 5.21 (s, 2H, CH2Ph).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:18][C:17](=O)[C:16]3[C:15]4[C:14]([C:20]([O:22]C)=O)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:41][N:42]=C(C=2C=34)CC1>>[CH:1]1([C:4]([N:6]2[CH2:7][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:20](=[O:22])[NH:41][N:42]=[C:17]([C:16]=3[C:15]=45)[CH2:18]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)C1CC1)C3
Agent: NN
Solvent: O
Product: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32

Procedure:
Compound 47 was prepared from methyl 2-(cyclopropanecarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.0 (s, 1H), 7.47-7.53 (m, 2H), 7.17 (dd, 1H, J=7.2, 7.8 Hz), 4.89 (s, 2H), 4.35 (s, 2H), 2.08-2.11 (m, 1H), and 0.78-0.79 (m, 4H). MS (ESI) m/e [M+1]+ 295.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:34])[C@H:7]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:6]2[C:16](=[O:33])[C@@H:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4][CH2:3]1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[Cl:1][C@@:2]1([CH3:34])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:16](=[O:33])[C@@H:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4][CH2:3]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl 3β-chloro-3α-methyl-7β-(5-methyl-3-phenylisoxazol-4-carboxamido)cepham-4α-carboxylate (210 mg), zinc metal (250 mg), and acetic acid (3 ml) is stirred at room temperature for 3 hours. The reaction mixture is filtered to remove solid, and the filtrate is evaporated to give a residue, which is dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The water layer is acidified with hydrochloric acid and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give 3β-chloro-3α-methyl-7β-(5-methyl-3-phenylisoxazol-4-carboxamido)cepham-4α-carboxylic acid (89 mg). m.p. 210°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[CH:13]([NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]([CH3:15])[CH3:16])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (24.37 g, 95.4 mmol, 1 equiv), anhydrous methylene chloride (350 mL), and H-D-Val-OtBu (20 g, 95.4 mmol, 1 equiv.). The mixture was cool to 0° C. followed by the addition of Hunig's base (38.2 mL, 219 mmol, 2.3 equiv.). The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. Starting material was consumed as determined by TLC. The reaction mixture was then diluted with methylene chloride (200 mL) and washed with H2O (500 mL), brine (250 mL). The organic layer was dried over anhydrous MgSO4, evaporated under vacuum to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester in quantitative yield (35.0 g).
Reaction SMILES: [CH3:1]I.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][CH3:25])[C:10](=[O:26])[C:9]2([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][C:29]=1[Cl:36])[CH3:27]>O1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][CH3:25])[C:10](=[O:26])[C:9]2([C:28]1[CH:33]=[C:32]([CH2:34][O:35][CH3:1])[CH:31]=[CH:30][C:29]=1[Cl:36])[CH3:27]
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(CO)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.08 ml of methyl iodide and then, at 0° C., 0.02 g of sodium hydride as a 60% suspension in oil are added to 0.2 g of the compound of Example 140 in 2 ml of tetrahydrofuran. After stirring for 16 hours at room temperature, the reaction mixture is hydrolysed with a 5% aqueous ammonium chloride solution and extraction is carried out with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The product is obtained after crystallization from n-pentane; M.p.=122° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>C(Cl)Cl>[CH:43]1([C:46]([N:23]2[CH2:22][CH2:21][CH:20]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)=[O:19])[CH2:25][CH2:24]2)=[O:47])[CH2:45][CH2:44]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone (47 mg, 0.10 mmol) and NEt3 (27 μL, 0.20 mmol) in DCM (5 mL) was added cyclopropane carbonyl chloride (10 μL, 0.12 mmol) and the resulting mixture stirred at r.t. for 3 h. The reaction mixture was quenched with H2O and extracted with DCM. The combined organic phases were dried (MgSO4) and concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 30-70%) affording 864 (13 mg, 25%). LCMS (method I): RT 4.06 min, [M+H]+ 543.3. 1H NMR (CDCl3, 400 MHz): δ 8.07-8.06 (1 H, m), 7.89-7.82 (1 H, m), 7.40-7.30 (2 H, m), 4.70-4.56 (3 H, m), 4.39-4.28 (1 H, m), 4.13 (3 H, s), 3.93-3.90 (6 H, m), 3.52-3.27 (3 H, m), 2.94-2.80 (1 H, m), 2.08-1.97 (2 H, m), 1.97-1.57 (4 H, m), 1.50 (3 H, t, J=7.40 Hz), 1.04-0.98 (2 H, m), 0.79-0.78 (2 H, m)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:11]=3)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)cc32)cc1
Product: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)cc32)cc1

Procedure:
In the described fashion as Example 1(e), the above acid (7) (R6 =C2H5, R=p-cyanophenyl), after reacting with piperazine, can give the desired 1-p-cyanophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9) ##STR30## R=p-cyanophenyl) and its hydrochloride salt.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28]
Reactant: COc1ccccc1C(=O)CN
Reactant: COC(=O)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 NHCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z 308.1 (M+H).