Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28]CN(CC)CC.COS(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH3:28])=[CH:15][CH:14]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CNc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 46 %

Procedure:
A solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (Example 48, 400 mg, 1 mmol), Et3N (0.16 mL, 1.1 mmol), dimethylsulfate (139 mg, 1.1 mmol) in 25 mL of toluene was stirred at rt for 18 h. The reaction was concentrated, then taken into EtOAc and washed with H2O, brine, dried over K2CO3 and concentrated to give a crude mixture of starting material and product. The material was further purified by flash chromatography (SiO2, 35% EtOAc/hexanes) to afford the title compound, 195 mg, in 46% yield. MS (ESI), (M+H)+424.1; 1H NMR (CDCl3) δ 7.65 (d, 2H, J=8.0), 7.58 (d, 2H, J=8.2), 7.47 (d, 2H, J=8.0), 7.31 (d, 2H, J=8.5), 6.24 (br s, 1H), 5.16 (br s, 1H), 4.50 (dd, 2H, J=50, 17), 4.27 (t, 1H, J=10), 2.44 (s, 3H), 1.74-1.83 (m, 1H), 1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d, 3H, J=7.0), 0.63 (d, 3H, J=7.0).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:11]([O:13]CCCC)[CH3:12])[CH3:10])[C:2]1C=CC=[CH:4][CH:3]=1>C(O)C.Cl.[C].[Pd]>[CH2:1]([O:8][C@@H:9]([CH3:10])[C@H:11]([OH:13])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@H](C)[C@@H](C)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCO[C@@H](C)[C@@H](C)O
Yield: 63.3 %

Procedure:
1.94 g of (2R,3S)-2-benzyloxy-3-butoxybutane was dissolved in a mixture of 80 ml of ethanol and 8 ml of 2 N hydrochloric acid. Thereto was added 200 mg of 5% palladium carbon. The mixture was subjected to hydrogenation at the atmospheric pressure at room temperature. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was subjected to distillation. The residue was diluted with water and extracted with dichloromethane three times. The extract was dried and concentrated. The residue was subjected to Kugel-rohr distillation (30 mmHg) to obtain 0.76 g of (2R,3S)-3-butoxy-2-butanol. The 1H-NMR and IR spectrum of this compound were completely agreed with those of (2S,3R)-3-butoxy-2-butanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C)c(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 50.6 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (114 mg, 51%). MS (ISP) 451.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH3:48])[C@H:34]([OH:47])[CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.[Cl-].[Na+].O>[OH:47][C@H:34]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:38]([CH3:40])[CH3:39])[CH:41]([CH3:42])[CH3:43])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH3:48]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(C)[Si](OC[C@@H](O)[C@@H](C)N)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Reaction time: 18 h
Yield: 91.1 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), (2S,3R)-3-amino-1-[(tripropan-2-ylsilyl)oxy]butan-2-ol (1.08 g, 4.11 mmol) synthesized in Example (89e), HOBT•H2O (0.44 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in N,N-dimethylformamide (20 mL), and WSCI•HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 18 hours under nitrogen atmosphere. To the reaction solution, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (60 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-50%) to afford the desired compound (1.69 g, 91%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]2[C:20]3[CH2:21][NH:22][CH2:23][CH2:24][C:19]=3[NH:18][C:17](=[O:25])[N:16]2[CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17](=[O:25])[N:16]3[CH:26]=[C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[F:6])[N:14]=[C:15]3[C:20]=2[CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Propionyl chloride (39 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 50 minutes, and then poured into ice water. The precipitate was collected, washed with water and 95% ethanol, and dried to yield 9-propionyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 36) as a white solid, m.p. >310° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.I[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCCc3ccccc32)cc1

Procedure:
Under the atmosphere of nitrogen, 4 parts of 1,2,3,4-tetrahydroquinoline, 20 parts of 4-iodotoluene, 20 parts of dimethylformamide (DMF), 10 parts of potassium carbonate, and 1 part of copper powder (200 mesh) were stirred at 160° C. for 10 hours. After the reaction, the resultant was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography to yield 5 parts of a precursor of the compound (303), 1,2,3,4-tetrahydro-1-p-tolylquinoline as a colorless crystal. Next, 1.7 parts of phosphorus oxychloride were dropwise added to 10 parts of chloroform and 1 part of N,N-dimethylacrolein, the temperature of which was adjusted to 5° C., while the temperature of the reaction solution was kept at 10° C. or lower. The reaction solution was then stirred at 5° C. for 1 hour. Thereafter, 2.0 parts of 1,2,3,4-tetrahydro-1-p-tolylquinoline described above were added thereto, and then the reactive components were caused to react at 25° C. for 1 hour. The reaction solution was then stirred at 70° C. for 1 hour. Thereafter, a 20% solution of sodium hydroxide in water was added to the reaction solution until the pH turned to 12. The precipitated crystal was filtrated, and the resultant crystal was washed with water. The crystal was then separated by column chromatography (hexane/ethyl acetate), and recrystallized from ethanol to yield 1.8 parts of the compound (303) as a yellow crystal.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(COc3ccccc3)CC2)cc1
Reaction time: 25 h
Yield: 41.4 %

Procedure:
0.3 g (0.00146 mol) 1-benzyl-4-hydroxymethyl-piperidine, 0.137 g (0.00146 mol) of phenol and 0.45 g (0.0017 mol) of triphenylphosphine were dissolved in 10 ml of toluene, cooled to 10° and treated slowly with 0.264 ml (0.0017 mol) of diethyl azodicarboxylate. The mixture was stirred at 90° for 25 hrs. The solvent was removed, the residue was taken up in ethyl acetate, washed three times with 40 ml of water each time and three times with 40 ml of 2N aqueous NaOH each time and the organic phase was dried over magnesium sulfate. The solvent was removed. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.17 g (41.4%) 1-benzyl-4-phenoxymethylpiperidine was obtained as white crystals; m.p. 56°-57°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1I)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I.CC([O-])=O.[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([CH:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:21])[NH:12]1)=[O:22]
Reactant: COC(=O)C(NC(=O)c1ccccc1I)c1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)C1NC(=O)c2ccccc2-c2ccccc21
Temperature: 110 °C

Procedure:
To a solution of (2-iodobenzoylamino)-(2-iodophenyl)-acetic acid methyl ester (3.4 g, 6.53 mmol) in DMF (300 mL) under argon is added PdCl2(dppf) (269 mg, 0.33 mmol) and KOAc (1.28 g, 13.06 mmol) and the mixture is heated at 110° C. for 18 h. Additional PdCl2(dppf) is added and heating is continued until all starting material is consumed. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-50% MeOH/methylene chloride as eluent to give the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[CH:40]=[C:41]([C:45]2([OH:49])[CH2:48][O:47][CH2:46]2)[CH:42]=[N:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:49][C:45]1([C:41]2[CH:40]=[C:39]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]4)[CH:44]=[N:43][CH:42]=2)[CH2:48][O:47][CH2:46]1
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Reactant: OC1(c2cncc(Br)c2)COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C4(O)COC4)c3)cnc21
Temperature: 80 °C
Yield: 6.3 %

Procedure:
A vial containing 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (350 mg, 1.4 mmol), bis(pinacolato)diboron (573 mg, 2.3 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (50 mg, 0.068 mmol) and potassium acetate (604 mg, 6.2 mmol) in 1,4-dioxane (10 mL) is flushed with Ar, sealed tightly and heated to 80° C. for 2 h. The reaction mixture is cooled to room temperature and a solution of 3-(5-bromo-pyridin-3-yl)-oxetan-3-ol (314 mg, 1.37 mmol) in 1,4-dioxane (4 mL), aqueous sodium carbonate solution (2M, 1.4 mL, 2.7 mmol) and additional 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (50 mg, 0.068 mmol) are added. The mixture is flushed with Ar, sealed tightly and heated to 100° C. for 90 min. After cooling to room temperature the mixture is partitioned between water and EtOAc. The layers are separated and the aqueous is further extracted with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. To the residue is added MeOH to form a precipitate which is collected by filtration to afford the title compound (28 mg).
Reaction SMILES: [N:1]([CH:4]1[CH:10]([F:11])[CH2:9][CH2:8][N:7]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[F:11][CH:10]1[CH2:9][CH2:8][N:7]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH:4]1[NH2:1]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)C(F)CC1
Temperature: 60 °C

Procedure:
A solution of 4-azido-5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane (1.4 g, 4.95 mmol) in THF/water (30 mL/6 mL) was treated with triphenylphosphine (1.3 g, 4.95 mmol) and the mixture was heated at 60° C. behind a blast screen for 4 hr. The mixture was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether, the resulting solid was filtered off and the filtrate concentrated under reduced pressure to give 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine contaminated with triphenylphosphine oxide as a yellow oil. To a solution of this oil (1.27 g, 4.95 mmol) in dry DCM (40 mL) at 0° C. was added slowly DIPEA (2.6 mL, 14.8 mmol) followed by trifluoroacetic anhydride (0.83 ml, 5.94 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (40 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (40% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a yellow viscous oil (1.4 g). To a solution of this oil (1.4 g, 3.97 mmol) and ammonium formate (2.5 g, 39.7 mmol) in MeOH (40 mL) under nitrogen was added 10% palladium on carbon (140 mg). The mixture was heated at 70° C. for 30 min before being cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (75 mL). The aqueous layer was extracted with DCM (2×75 mL) and the combined organic layers were separated, dried over MgSO4 and concentrated under reduced pressure to give N-((4S,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide as an orange-yellow glass (1.1 g, 69% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.12 (s, 1H), 5.02-4.85 (m, 1H), 4.69-4.55 (m, 1H), 3.66 (s, 3H), 3.42-3.20 (m, 3H), 3.11 (ddd, J=14.4, 6.7, 3.3 Hz, 1H), 2.36-2.22 (m, 1H), 2.23-1.94 (m, 2H), 1.90-1.82 (m, 1H). NH2 not observed.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.[H-].[Na+].Cl[C:12]1[C:20]2[C:19]3[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=3[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:16]=2[N:15]=[CH:14][CH:13]=1>O1CCCC1.CN(C)C=O.O.C(OCC)(=O)C>[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:16]=3[N:15]=[CH:14][CH:13]=2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O[C@@H]3CCCNC3)ccnc21
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-piperidin-3-ol hydrogen chloride (169 mg, 1.2 mmol) in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1 mL) was added sodium hydride as 60% dispersion in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.56 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes before being warmed to 40° C. for 4 hours. The cooled reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (236 mg, 100%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:22])=[C:4]2[O:9][CH2:8][C:7](=[CH2:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19]CC)=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH-].[K+]>C(O)C>[F:1][C:2]1[C:3]([F:22])=[C:4]2[O:9][CH2:8][C:7](=[CH2:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C=C1COc2c(F)c(F)cc3c(=O)c(C(=O)OCC)cn1c23
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 99 %

Procedure:
900 mg of ethyl 9,10-difluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylate was suspended in 20 ml of ethanol and 5 ml of an aqueous solution containing 500 mg of potassium hydroxide was added thereto. The resulting mixture was allowed to react for 3 hours at 50°-60° C. (bath temperature). The solvent was distilled off and 10 ml of water was added to the residue and the mixture was neutralized by addition of hydrochloric acid. The precipitate formed was collected by filtration and washed with water and then dried to give 810 mg of 9,10-difluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid as a white powder. The powder was recrystallized from ethanol to give fine needles with mp 273°-276° C. (decomposition).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][CH2:50][CH3:51])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:49]([CH2:50][CH3:51])[CH2:47][CH3:48])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCNCC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with diethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N5O3 [(M+H)+] 720.3442, observed 720.3440.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>[OH-].[Na+]>[C:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:2][CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2cc3c(c(C)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
To a solution of 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (40 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride (0.1 ml) at room temperature. After the mixture is made acidic with dilute hydrochloric acid, the resultant product is extracted with dichloromethane and the extract is dried over magnesium sulfate. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (29 mg), as white powder, m.p. 261°-263° C.
Reaction SMILES: [CH2:1]([N:7]([CH3:45])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=3)[CH:17]=2)[CH2:12][N:11]1C(OC(C)(C)C)=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(Cl)(=O)C>CO>[CH2:1]([N:7]([CH3:45])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=3)[CH:17]=2)[CH2:12][NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)Cl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1
Temperature: 40 °C

Procedure:
Compound 126 (19.92 g) was suspended in anhydrous methanol (120 mL) under argon at room temperature. Separately acetyl chloride (3 eq.) was added to anhydrous methanol (60 mL) at 10-20° C. This solution was added to the compound 126 solution at 5° C. The reaction mixture was heated at 40° C. for 3-4 hrs. After the completion of the reaction, the reaction mixture was concentrated under vacuum and then co-evaporated with 200 mL of anhydrous dichloromethane. The product was then dried in a vacuum oven at 40-45° C. Compound 127 (18.35 g) was recovered as a yellow foam in quantitative yield and 100% purity (HPLC).