Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].O.Cl>C1COCC1.CO>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.03 g (25.8 mmol) of sodium hydroxide were added to a solution of 715 mg (2.6 mmol) of (+/−)-ethyl (4-nitrophenyl)(cyclopentyl)acetate in 6 ml of THF/methanol (1:1), and the mixture was stirred at RT overnight. The reaction mixture was then poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated. The residue was taken up in 80 ml of diethyl ether, and 250 ml of petroleum ether were added. The precipitated solid was filtered off with suction and washed with petroleum ether. The product obtained in this manner was purified further by preparative HPLC. This gave 89.5 mg (14% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1.[C:20]1([C:33](Cl)=[O:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>ClCCl>[N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH:10][C:33]([C:20]3[C:32]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:34])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a suspension of 3-(pyrimidin-5-yl)aniline (0. 17g) and pyridine (0.24 ml) in dichloromethane (3 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.23 g) in dichloromethane (5 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(pyrimidin-5-yl)phenyl]fluorene-1-carboxamide (0.222 g, 61.2 %).
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([O:21]CC2C=CC=CC=2)[CH:20]=1)[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=[O:10])[CH2:3][CH3:4]>C1COCC1.C(O)C.[Pd]>[OH:21][C:19]1[CH:18]=[C:8]([CH:7]=[C:6]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])[CH:20]=1)[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=[O:10]
Reactant: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A solution of 3-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (900 mg) in THF (5 mL) and ethanol (5 mL) containing 10% palladium on carbon was stirred under an atmosphere of hydrogen overnight. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to give the required compound as a white solid (683 mg). 1H NMR δ (CDCl3): 0.95 (t, 3H), 1.27 (d, 3H), 1.54-1.80 (m, 2H), 3.79 (s, 3H), 4.31 (q, 1H), 6.57 (t, 1H), 6.81 (d, 1H), 6.96 (s, 1H), 6.98 (s, 1H), 7.30 (s, 1H), 7.57 (s, 1H), 8.84 (s, 1H); m/z 290 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5](=[O:21])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2(O)[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)=[C:9]([F:20])[CH:8]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(=O)([O-])[O-].[K+].[K+]>[CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5](=[O:21])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)=[C:9]([F:20])[CH:8]=1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)Nc1ccc(C2CCSCC2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 2-methylpropyl[3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (See Org. Proc. Res. Dev. 2001, 5, 80–83, 4.00 g, 12.2 mmol) in trifluoroacetic acid (19 mL, 244 mmol) under N2 is treated with triethylsilane (5.85 mL, 36.6 mmol) dropwise, stirred for 1 h, and then added dropwise to saturated aqueous potassium carbonate (250 mL) with vigorous stirring. The mixture is extracted with diethyl ether (200 mL), and the organic phase is washed with water (2×50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Trituration and filtration from diethyl ether/hexanes or ethyl acetate/hexanes gives the title compound, 1H NMR (CDCl3, 400 MHz) δ 7.26 (m, 1H), 7.11 (t, 1H), 6.97 (m, 1H), 6.59 (bs, 1H), 3.95 (d, 2H), 2.85 (m, 3H), 2.68 (m, 2H), 2.09 (m, 2H), 1.98 (m, 1H), 1.84 (m, 2H), 0.96 (d, 6H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+]>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure B: 1-phenylpiperazine (5{30}, 1 mL, 6.55 mmol, 1 equiv.), ethyl chloroacetate (0.77 mL, 7.20 mmol, 1.1 equiv.), NaHCO3 (0.69 g, 8.18 mmol, 1.25 equiv.), acetone (13.1 mL). Purification with flash column chromatography on silica gel (1:1 hexanes:EtOAc) afforded 6{30} (1.50 g, 93%) as a light yellow liquid. 1H-NMR (500 MHz, CDCl3): δ 7.20 (dd, 2H, J=7.0, 8.5 Hz), 6.87 (dd, 2H, J=1.0, 9.0 Hz), 6.80 (t, 1H, J=7.0 Hz), 4.15 (q, 2H, J=7.0 Hz), 3.20 (s, 2H), 3.19 (t, 4H, J=5.0 Hz), 2.68 (t, 4H, J=5.0 Hz), 1.23 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 169.6, 150.8, 128.6, 119.2, 115.6, 60.1, 58.9, 52.5, 48.5, 13.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH:6]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:7]2=[O:13])=[CH:3][C:2]=1[NH:33][CH:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1
Reactant: COc1cc2c(cc1Br)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reactant: CN1CCC(N)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1NC1CCN(C)CC1)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 110 °C

Procedure:
To a solution of 143 (75 mg, 0.174 mol) and 1-methylpiperidin-4-amine 134 (23.8 mg, 0.0208 mol) in toluene 15 mL was added cesium carbonate (113.3 mg, 0.348 mol). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (7.96 mg, 0.0087 mol) and BINAP (10.8 mg, 0.0174 mol) was added and again degassed and purged with nitrogen for another 10 min. The reaction was heated to 110° C. overnight under sealed conditions. The reaction was diluted with chloroform and filtered through celite bed. The organic layer was concentrated to get the crude compound 144 and was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 7.5% methanol in chloroform as brown coloured solid 6-methoxy-5-((1-methylpiperidin-4-yl)amino)-2-(4-((trifluoromethyl)thio)benzyl)-2, 3-dihydro-1H-inden-1-one 144. 1HNMR (400 MHz, CDCl3) δ ppm 7.55 (bs, 2H), 7.28 (bs, 2H), 7.08 (s, 1H), 6.42 (s, 1H), 4.99 (s, 1H), 3.89 (s, 3H), 3.37 (m, 4H), 2.84 (m, 6H), 2.66 (m, 3H), 2.09 (m, 4H); MS (ESI) m/z 465.0 (M+H).
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]
Reactant: OCCCCCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled round bottom blask is added 4.2 g. of 57% sodium hydride in oil, 50 ml. of hexamethylphosphoramide and 15.8 g. of 2-naphthol. After 1/2 hour the mixture is allowed to warm to room temperature and 13.6 g. of 6-chlorohexan-1-ol is added. The mixture is heated at 110° C. overnight, cooled, diluted with water and extracted with ether. The ether extract is washed with sodium hydroxide solution, then with water, dried (magnesium sulfate) and the solvent removed under vacuum. The solid is dissolved in ether and the solution washed with sodium hydroxide solution. The ether layer is dried (magnesium sulfate) and the solvent removed under vacuum to give 15.9 g. of product, as crystals, m.p. 53°-56° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:20]([OH:22])=O)=[CH:9][CH:8]=1.[C:23]([C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:20]([C@@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:13]2[C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[O:22])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)[C@@H]1CCCCCN1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.21 g, 1.38 mmol) is added drop wise at 0° C. to a solution of (S)-1-(4-chloro-phenyl)-azepane-2-carboxylic acid (0.23 g, 0.92 mmol) and 5-tert-butyl-isoxazol-3-ylamine (0.19 g, 1.38 mol) in pyridine. The reaction mixture is slowly warmed up to room temperature and stirred for three hours. The mixture is diluted with EtOAc and washed twice with saturated NH4Cl solution. The organic phase is washed with 1N HCl, and after drying over anhydrous Na2SO4 the solvent is removed under reduced pressure to afford the crude product that is purified by prep TLC to afford the title compound; m/z 376 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].Cl[CH2:20][C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:24]([N:23]([CH2:26][CH3:27])[C:21](=[O:22])[CH2:20][N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:18][CH2:17]1)[CH3:25]
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)c2occc2c1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Temperature: 225 °C
Yield: 53.8 %

Procedure:
A mixture of 1-(5-nitro-1-benzofuran-7-yl)piperazine (0.4 g, 1.6 mmol; Intermediate 21) and 2-chloro-N,N-diethylacetamide (0.48 g, 3.2 mmol) in the presence of K2CO3 (0.45 g, 3.2 mmol) in DMF was heated at 225° C. for 5 min using controlled microwave energy. The solvent was evaporated and the residue triturated with MeCN to give 0.31 g (54%) of the title compound as a yellow solid. HPLC purity 80%, RT=1.63 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.0 Hz, 3H) 1.14 (t, J=7.0 Hz, 3H) 2.58-2.77 (m, 4H) 3.14-3.50 (m, 10H) 7.14 (d, J=2.3 Hz, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.18 (dd, J=12.5, 2.3 Hz, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Boc-4-piperidinol (10 g, 50 mmol), 4-nitrophenol (7.0 g, 50 mmol) and triphenylphosphine (15.7 g, 60 mmol) were dissolved in dry tetrahydrofuran (150 mL), and cooled on the ice bath. Diisopropyl azodicarboxylate (11.8 mL, 60 mmol) was added slowly, and stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added, and the solid precipitate was filtered off. The filtrate was concentrated and the product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1). Trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. After distillation under reduced pressure, 1N sodium hydroxide aqueous solution was added, and the mixture extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the product was concentrated and dried to obtain the target substance (6.75 g, 61%).
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.N(OC(C)(C)C)=O.[Cl:17]CCl>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:17])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)ON=O
Product: Clc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (1.00 g, 3.95 mmol) in dichloromethane 6.0 ml at 0° C. was added titanium tetrachloride (1 mol/l) in dichloromethane (3.95 mL, 3.95 mmol) then tert-butyl nitrite (1.05 mL, 7.91 mmol) was added dropwise. The reaction was warmed to RT then 1 more equivalent of TiCL4 was added and stirred for 1 h. The reaction was quenched with water and extracted with DCM. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was carried to next step. MS (ESI) m/z: 272.2.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([OH:39])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)(Cl)=O.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>ClCCl>[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid dihydrochloride (19 mg, 0.033 mmol) was added to a dry flask and cooled to −78° C. Thionyl chloride (14 μL, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a stream of nitrogen then placed under high vacuum. To a solution of the crude residue in dichloromethane (600 μL) was added pyrrolidine (150 μL, 1.80 mmol). The reaction mixture was stirred at room temperature for 10 minutes then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate to 100% ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(1-pyrrolidinylcarbonyl)pyrazolo[1,5-a]pyridin-7-amine (9 mg, 49%) as a clear oil. Rf 0.13 (1:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.72 (d, 1H), 7.62 (m, 2H), 7.26 (d, 1H), 7.14(t, 2H), 6.54(d, 1H), 6.30(d, 1H), 5.11 (d, 1H), 4.31 (m, 1H), 4.19 (m, 1H), 3.66 (broad, 2H), 3.38 (broad, 2H), 2.11–1.88 (m, 8H), 1.80–1.50 (m, 12H); MS m/z 554 (M+1). To a solution of the product in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1N

Procedure:
Prepared from (3′,4′-dichloro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C7) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (485 mg).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([O-:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].[Cl-:36].[Na+].Cl.C(OC(C)C)(C)C>O.C1COCC1>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([OH:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[ClH:36]
Reactant: [Cl-]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1

Procedure:
To a suspension of crystalline Ceftiofur sodium (10 g) in water (30 ml) was added THF (87 ml) at 10-30° C. To that sodium chloride (14 g) was added. pH of the solution was adjusted to 2.5-3.5. Organic layer pH was adjusted to 0.5-1.5 using conc. HCl. Addition of diisopropyl ether followed by filtration yielded pure title compound.]
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.[OH:32][C@@H:33]([CH2:46][NH2:47])[CH2:34][O:35][C:36]1[C:44]2[NH:43][C:42](=[O:45])[NH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([NH:47][CH2:46][C@H:33]([OH:32])[CH2:34][O:35][C:36]5[C:44]6[NH:43][C:42](=[O:45])[NH:41][C:40]=6[CH:39]=[CH:38][CH:37]=5)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[S:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Nc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)cc2)S1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.50–2.70 (m, 2 H), 2.70–3.50 (m, 5 H), 3.60 (brd, J=11.6 Hz, 2 H), 4.00 (brs, 3 H), 4.60 (dd, J=9.4, 4.2 Hz, 1 H), 6.58 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.70–6.90 (m, 5 H), 7.35 (d, J=8.4 Hz, 2 H), 7.55 (d, J=8.4 Hz, 2 H), 9.70 (brs, 1 H), 10.61 (brs, 1 H), 10.72 (brs, 1 H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C31H35N6O7S2 (MH+): 677.2009. Found: 677.1999.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=O.CC(C)([O-])C.[K+].[C:26]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:27][CH2:28][C:29]([O-:31])=[O:30].Cl>C(O)(C)(C)C.O>[CH2:34]([O:33][C:26]([C:27](=[C:5]([C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:32])[CH3:35]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cccc(F)c2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Yield: 75.6 %

Procedure:
35.5 g (0.1275 mol) of 3-fluoro-4′-methanesulphonylbenzophenone, prepared in Example 10, are added in portions to a solution of 15.7 g (0.140 mol) of potassium t-butoxide in 100 ml of t-butanol. The mixture is stirred and 32 ml (0.191 mol) of ethyl succinate are added dropwise at a rapid rate. The mixture is subsequently refluxed for 30 minutes and cooled, water and 1 N hydrochloric acid are added to bring the pH to 1 and the mixture is then extracted with t-butyl methyl ether. The organic phase is treated with 2% sodium hydroxide solution and the mixture is decanted. The aqueous phase is acidified with 1 N hydrochloric acid and then extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 39.2 g of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulphonylphenyl)-3-butenoic acid in the form of a thick oil, which is used as such in the next step.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:19]1[C:23](N)=[CH:22][CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N([O-])=O.[Na+].[I-:29].[K+]>C(#N)C.O.C([O-])(O)=O.[Na+]>[CH2:12]([N:19]1[C:23]([I:29])=[CH:22][CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [I-]
Reactant: Nc1ccnn1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: Ic1ccnn1Cc1ccccc1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
p-Toluenesulfonic acid (29.82 g; 0.17 mol) was stirred in 150 ml ACN. 2-Benzyl-2H-pyrazol-3-ylamine (10.0 g; 0.06 mol) was added and cooled down to 10-15° C. Sodium nitrite (7.97 g; 0.12 mol) was dissolved in 15.0 ml water and added. The resulting mixture was stirred for 1 hour at 0° C. In 30 ml of water was dissolved potassium iodide (23.96 g; 0.14 mol) and added at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours. It was diluted with 100 ml water and neutralized with NaHCO3 solution, then extracted with DCM. The organic layers were pooled and washed with sodium thiosulfate, dried and evaporated. The crude material was purified with normal phase chromatography (2% EtOAc/Hexane).