Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CI
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(OC)CC1
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (1 g, 5.81 mmol) in tetrahydrofuran (20 mL). Sodium hydride (349 mg, 8.72 mmol, 60%) was added to the reaction at 0° C. in portions, then stirred for 20 min. This was followed by the addition of CH3I (865 μL, 11.6 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature, quenched with 6 mL of brine and extracted with 3×40 mL of ether. The combined organic layers were washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 800 mg (74%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl[C:13]1[C:18]2=[CH:19][N:20]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[N:20]1[CH:19]=[C:18]2[C:13]([NH:3][C:4]3[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][N:9]=3)=[N:14][CH:15]=[CH:16][C:17]2=[N:21]1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: N#Cc1ccc(N)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc1
Yield: 51.5 %

Procedure:
Sodium hydride (12 mg, 0.30 mmol) was added to a solution of 6-amino-3-pyridinecarbonitrile (36 mg, 0.30 mmol) in DMF (2 mL) and the resultant mixture was stirred for 5 minutes before 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (80 mg, 0.27 mmol) was added. The reaction vial was sealed, purged with nitrogen and irradiated in a microwave at 150° C. for 10 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (53 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.57 (d, J=0.9 Hz, 1H), 8.98 (dd, J=2.3, 0.8 Hz, 1H), 8.47 (dd, J=8.7, 2.3 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.89-7.83 (m, 2H), 7.77 (dd, J=9.1, 7.2 Hz, 1H), 7.65-7.61 (m, 2H). LCMS (Method B): RT=3.05 min, m/z: 381 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]#[N:13].C(N(CC)CC)C>CCOCC>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:11][C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: OCCC1CCNCC1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.7 %

Procedure:
The title compound was prepared according to general procedure G described in Scheme 3. 2-(Piperidin-4-yl)ethanol (1.2 g, 9.3 mmol) was treated with 2-chloroacetonitrile (1.4 g, 18.6 mmol), triethylamine (10.4 mL, 74.3 mmol) and stirred at RT for 14 h. The crude reaction mixture was diluted with Et2O (25 mL) and washed with H2O (3×10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a yellow oil (1.56 g, 100%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:4][N:3]=1
Reactant: C#CCCO
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(I)cnc(N)c34)cc2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(C#CCCO)cnc(N)c34)cc2)c1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A suspension of Example 144A (0.227 g, 0.45 mmol) in piperidine (3 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with 3-butyn-1-ol (0.069 mL, 0.91 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and CuI (5 mg, 0.023 mmol), then heated to 80° C. in a sealed tube for 30 minutes. The resulting homogeneous solution was cooled to room temperature and concentrated under a stream of nitrogen. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 164 mg (81%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.65 (t, J=6.78 Hz, 2H), 3.63 (q, J=6.73 Hz, 2H), 4.92 (t, J=5.59 Hz, 1H), 5.70 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25–7.28 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.49 (s, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.93 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 443 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]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>CC(N(C)C)=O>[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:45]1
Reactant: COC1(Cc2ccccc2F)CCCC(N)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.025 mmol, 12.4 mg), HCl salt of 3-(2-fluorobenzyl)-3-methoxycyclohexanamine (0.025 mmol, 6.8 mg), HATU (0.025 mmol, 9.5 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-methoxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:17][CH:16]4[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]4)[CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1>[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:17][CH:16]4[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]4)[CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1C2C=C(c3c[nH]c4cc(F)ccc34)CC1CC2
Agent: [Pd]
Solvent: CO
Product: CN1C2CCC1CC(c1c[nH]c3cc(F)ccc13)C2
Yield: 28.9 %

Procedure:
A mixture of 0.233 gm (0.91 mMol) 3-(6-fluoroindol-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene and 0.235 gm 10% palladium on carbon in 12 mL methanol was placed under an atmosphere of hydrogen at room temperature. After 8 hours the reaction mixture was filtered and then concentrated under reduced pressure. The residue was again hydrogenated with 0.23 gm 10% palladium on carbon in 7 mL ethanol. After several hours the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to basic alumina chromatography, eluting with dichloromethane containing 30% dichloromethane saturated with ammonia and 0.5-2% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.068 gm (29%) of the title compound as a colorless solid.
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:28])[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl:44])[NH:40][N:39]=[C:38]2[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[K+].[K+]>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].ClCCl>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([C:45]([OH:47])=[O:46])=[N:39][NH:40]2)=[CH:36][C:35]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:28])[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Temperature: 110 °C
Yield: 11.4 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (800 mg, 2.34 mmol), 1-(4-bromophenyl)cyclobutanol (500 mg, 2.20 mmol), potassium acetate (1.0 g, 10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (136 mg, 0.17 mmol) in 1,4-dioxane (12 mL) was degassed with N2 for 5 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through a cotton plug and concentrated in vacuo. The resulting dark solid was dissolved in 1:1 toluene/EtOH (10 mL) and to this solution was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (551 mg, 2.00 mmol) followed by 2N aqueous potassium carbonate solution (4.0 mL, 8.0 mmol). The reaction mixture was degassed with N2, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (98.0 mg, 0.12 mmol) under N2, and heated in a sealed pressure tube to 110° C. for 3 hours. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (20 mL) and 2N citric acid solution (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (Biotage C18 column, 20-60% MeCN/water) to give the title compound (78 mg, 10% yield) as a solid. MS (ES−) 341.5 (M−H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.88 (s, 1H), 7.59 (d, J=8.05 Hz, 2H), 7.42 (d, J=8.05 Hz, 2H), 5.55 (br. s, 1H), 2.39-2.46 (m, 2H), 2.23-2.35 (m, 2H), 1.89-2.01 (m, 1H), 1.64-1.76 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=[C:8]([CH:38]=1)[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:37])[C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)=[O:10])([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[NH2:22][C:20]1[CH:19]=[CH:18][C:17]([C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)=[C:16]([CH:21]=1)[C:15]([NH:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[C:8]1[CH:38]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=1[C:39]1[CH:40]=[C:41]([O:49][CH3:50])[C:42]([O:47][CH3:48])=[C:43]([O:45][CH3:46])[CH:44]=1)=[O:37]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)NCCNC(=O)c2cc([N+](=O)[O-])ccc2-c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(N)cc2C(=O)NCCNC(=O)c2cc(N)ccc2-c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 20 mg (0.028 mmol) of N,N′-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]ethylenediamine synthesized by the process of Example 52 in acetic acid-ethyl acetate (1:3, 2 ml) was added 20 mg of 10% palladium on carbon, and the mixture was stirred for 3 hours at room temperature under hydrogen. The catalyst was removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A solution of the resultant residue in chloroform was washed with a saturated solution of a sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, thereby obtaining 17 mg (quantitative) of crude crystals of the title compound. The crude crystals were recrystallized from methylene chloride-diethyl ether, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cccc(Br)c1
Reaction time: 8 h
Yield: 190.7 %

Procedure:
A mixture of 2-methoxyphenylboronic acid (4.3 g, 28.3 mmol), 3,5-dibromobenzene (20 g, 85.5 mmol, 3 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (100 mg) in ethyleneglycol dimethylether (25 mL) and a solution of sodium bicarbonate (8.2 g, 0.098 mol) in water (140 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic phase was washed with water (2×300 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica (150 g) with heptane (6 L) to afford pure 21 (14.2 g, 58%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[NH2:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 60 h

Procedure:
A 200 mL RBF was charged with (R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine (4.10 g, 10.1 mmol) and palladium, 10 wt. % on activated carbon wet (0.179 ml, 2.03 mmol) under nitrogen. MeOH was added via syringe, and the atmosphere replaced with hydrogen via one or more balloons. The reaction was stirred rapidly for 60 h. The reaction was flushed with nitrogen, filtered through celite rinsing with 100 mL MeOH, and concentrated in vacuo. The crude material was treated with hexanes and passed through a Redi-Sep® pre-packed silica gel column (80 g) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine as a brown oil. MS m/z=375 [M+H]−. Calc'd for C18H29F3N2OSi: 374.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1O>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][C:29]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)C1
Yield: 25 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 2-fluoro-5-(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 25%). MS (m/e): 490.4 (M+H+, 100%).
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([OH:16])=O)[CH:11]=3)[C:4]=2[NH:5][N:6]=1.[CH:17]1[CH:18]=[CH:19][C:20]2N(O)N=[N:23][C:21]=2[CH:22]=1.C(Cl)CCl.C1(N)CCCCC1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:21]1([NH:23][C:14]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[C:4]2[NH:5][N:6]=[C:2]([I:1])[C:3]=2[CH2:13]3)=[O:16])[CH2:22][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: NC1CCCCC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Yield: 49.6 %

Procedure:
A mixture of Example 84A (0.359 g, 1.07 mmol), HOBt (0.218 g, 1.61 mmol), EDC (0.308, 1.61 mmol), cyclohexylamine (0.18 mL, 1.61 mmol), and Et3N (0.22 mL 1.61 mmol) in DMF (8 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over MgSO4 filtered, concentrated, and triturated with ether to give 0.216 g (50%) of the desired product as yellow solid. MS (DCI/NH3) m/z: 408.0 (M+H)+; 1H NMR (300 MHz, DMSO46) δ ppm 1.09-1.44 (m, 5H) 1.58-1.91 (m, 5H) 3.48-3.67 (m, 2H) 3.77 (m, 1H) 7.61 (m, 1H) 7.86 (d, J=7.46 Hz, 1H) 8.02 (s, 1H) 8.23 (d, J=8.14 Hz, 1H) 13.27 (s, 0.5H) 13.58 (s, 0.5H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Br:13][C:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:5][C:2]([NH:1][C:17]([C:14]1([Br:13])[CH2:16][CH2:15]1)=[O:18])([CH3:6])[CH2:3][OH:4]
Reactant: O=C(Cl)C1(Br)CC1
Reactant: CC(C)(N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)C1(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
1.69 g of 2-amino-2-methyl-1-propanol is introduced into 85 ml of methylene chloride under nitrogen at room temperature, and 2.38 g of sodium carbonate is added to 38 ml of water and then 3.6 g of acid chloride 107. It is stirred overnight at room temperature and then treated with methanolic 2N sodium hydroxide solution. The organic phase is separated, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.83 g of 1-bromocyclopropanecarboxylic acid-1,1-dimethyl-2-hydroxy-ethylamide 108 is obtained as a colorless oil.
Reaction SMILES: C([S:4][CH:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:6]([NH:8][CH2:9][C:10]([N:12]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:7])(=O)C.[OH-].[Na+]>CO>[SH:4][CH:5]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[C:6]([NH:8][CH2:9][C:10]([N:12]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:7]
Reactant: CC(=O)SC(Cc1ccc(O)cc1)C(=O)NCC(=O)N1C(c2ccccc2)CC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCC(=O)N1C(c2ccccc2)CC[C@H]1C(=O)O)C(S)Cc1ccc(O)cc1
Yield: 97.6 %

Procedure:
450 mg of the compound obtained in Example 9 are dissolved in 5 ml of degassed methanol. 2 ml of 1M sodium hydroxide are added at 0° C., and the reaction is continued as described in Example 3. 400 mg of the expected compound are obtained in the form of a white solid.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Next, 0.73 g (1.37 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[(4-chlorophenyl)(methyl)phosphono]butanoate and 0.89 g (8.22 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.55 g (4.11 mmol) of aluminum trichloride. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was separated and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the eluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with 40% methanol at a flow rate of 6 mL/min and the fractions of the compound were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[(4-chlorophenyl)(methyl)phosphono]butanoic acid (0.24 g, yield 57%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:33])=[C:12]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+:37]>C(O)C>[F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O-:33])=[C:12]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[Na+:37]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
A solution of 7-(4-Fluorobenzyl)-4-hydroxy-N-(2-methoxyethyl)-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (693 mg, 1.436 mmol) in ethanol (20 mL) was treated with 1.009 M NaOH (1.423 mL, 1.436 mmol). The solution was evaporated in vacuo, triturated with Et2O, filtered and dried under high vacuum to provide the product as a white solid: 1H NMR (d6-DMSO) δ 10.65 (1H, s), 8.20 (1H, s), 7.73 (1H, s), 7.35 (2H, dd, J=5, 9 Hz), 7.11 (2H, t, J=9 Hz), 4.16 (2H, t, J=9 Hz), 4.02 (2H, s), 3.24-3.39 (8H, m), 3.25 (3H, s), 2.05 (2H, t, J˜9 Hz), 1.69-1.79 (2H, m); ES− MS: 483 (M−H+).