Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3][CH2:2]2)=[O:36])[CH2:34][CH2:33]1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Reactant: O=C(Cl)C1CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[O:16][C:15]([N:17]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:18][C:19]([O:21]CC)=[O:20])=[N:14][CH:13]=2)[CH3:11])=[CH:5][CH:4]=1.CO.O.[OH-].[Li+]>C1COCC1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[O:16][C:15]([N:17]([CH2:24][C:25]([OH:27])=[O:26])[CH2:18][C:19]([OH:21])=[O:20])=[N:14][CH:13]=2)[CH3:11])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NOCc2ccc(C(F)(F)F)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=NOCc1ccc(C(F)(F)F)cc1)c1cnc(N(CC(=O)O)CC(=O)O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of the product of step 3 (295 mg, 0.62 mmoles) in a mixture of THF (6 ml), methanol (2 ml) and water (2 ml), lithium hydroxide (105 mg, 1.25 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl. White solid seperated was filtered and washed with water & dried over P2O5 under vacuum to give 250 mg (82%) of title product as off white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:39]([O:38][C:36]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) in THF (0.5 mL) at room temperature was treated with triethylamine (28.4, 0.2 mmol) followed by ethyl chloroformate (19 μL, 0.2 mmol). The reaction mixture was stirred for 2 h then diluted with EtOAc (2 mL) followed by a saturated aqueous NaHCO3 solution (1 mL). The organic phase was isolated and further washed with an additional portion of a saturated aqueous NaHCO3 solution (1 mL) followed by a brine solution (1 mL). The organic component was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 10% then 30% EtOAc/hexane as eluant to afford product as an oil (30 mg, 34%). 1H NMR (CDCl3) 1.25 (t, J=7.2, 3H), 1.60-1.65 (m, 2H), 1.79-1.89 (m, 3H), 1.92-2.00 (m, 2H), 2.60-2.72 (m, 2H), 2.95 (dd, J=12.9, 4.8, 1H), 3.20-3.28 (m, 2H), 3.33-3.42 (m, 2H), 3.79 (s, 3H), 4.08-4.13 (m, 3H), 4.40 (br s, 1H), 4.69-4.72 (m, 1H), 6.39 (dd, J=8.6, 2.4, 1H), 6.47 (s, 1H), 6.77 (d, J=8.6, 1H), 7.22-7.34 (m, 5H) LC/MS 7.81 min, [M+1]+ 439.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6](=O)[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8].ClC1C(C(F)(F)F)=CC=CC=1CNCC(C1C=CC=CC=1Cl)C>>[Cl:1][C:2]1[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH3:8]
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Agent: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Yield: 94 %

Procedure:
The titled compound was prepared from N-(2-chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propionamide in 94% yield in the same manner as the preparation of N-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine in Example 184c. MS (ESI) 362 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH3:14])=[C:3]1[C:15]([O:17][CH3:18])=[O:16]>C1COCC1.[C].[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[CH3:14]
Reactant: COC(=O)c1c(C)c2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c2cc(N)ccc2n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
To a solution of methyl 1,3-dimethyl-5-nitro-1H-indole-2-carboxylate (5.27 g) in THF (105 mL) was added 10% palladium carbon (50% water wet, 2.25 g), and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere (balloon). The insoluble material was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=7:3-hexane:ethyl acetate=3:2 (volume ratio)] to give the title compound (4.63 g, yield 98%) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([CH3:8])[C:6]1=[O:9])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1CC(c2ccccc2)=C(C)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of the diketoester 20a (12 g, 45.8 mmol) in dry ethanol (150 ml) was added dropwise to a solution of sodium hydroxide (1.83 g, 45.8 mmol) in dry ethanol (75 ml) with vigorous stirring. The solution was heated to 50° C. and stirred overnight at that temperature. Ether (1.5 L) was added and the organic phase was washed with 2 N HCl (3×300 ml) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give an oil that was purified by flash column chromatography (6% EtOAc/hexane) to give the cyclic β-ketoester 21a (8.7 g, 78%) as a yellow oil: TLC Rf=0.40 (silica gel, 25% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.50-7.42 (m, 3H), 4.26 (q, J=7.2 Hz, 2H), 3.58 (dd, J=3.2 Hz, 7.6 Hz, 1H), 3.38-3.31 (m, 1H), 3.15-3.07 (m, 1H), 1.99 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 202.6, 169.6, 166.5, 135.8, 134.9, 130.2, 128.9, 127.9, 61.9, 51.3, 33.7, 14.5, 10.5; HRMS calcd for C15H16O3+Na+ 267.0997; found 267.0974 [M+Na+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([O:11][CH:12]([F:14])[F:13])[CH:6]=1)=[O:4].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[Cl:15][C:6]1[C:7]([O:11][CH:12]([F:14])[F:13])=[N:8][N:9]([CH3:10])[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(OC(F)F)nn1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.94 mmol) of methyl-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 10 ml of N,N-dimethylformamide is admixed at 0° C. with 389 mg (2.91 mmol) of N-chlorosuccinimide and then stirred for 8 hours at 80° C. The reaction solution is poured onto water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. This gives 466 mg of methyl 4-chloro-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (99%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N)CN>[Cu]I.O1CCOCC1>[O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 40 h
Yield: 45.5 %

Procedure:
To a sealed-vial was added (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (162 mg, 0.756 mmol), potassium phosphate (321 mg, 1.51 mmol), iodobenzene (0.101 mL, 0.907 mmol), ethylenediamine (0.020 mL, 0.30 mmol), dioxane (3 mL) and molecular sieves followed by copper(I) iodide (57.6 mg, 0.302 mmol). The vial was purged with nitrogen gas and sealed. Then the reaction was stirred at 110° C. for 40 hr. The reaction was diluted with EtOAc (30 mL) and washed with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give (S)-tert-butyl 2-oxo-1-phenylpiperidin-3-ylcarbamate (100 mg, 0.344 mmol, 45.6% yield) as a white solid. Anal. Calcd. for C16H22N2O3 m/z 290.3. found: 291.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.40 (t, J=7.70 Hz, 2H), 7.33-7.20 (m, 3H), 5.56 (br. s., 1H), 4.37-4.20 (m, 1H), 3.78-3.66 (m, 2H), 2.63 (dd, J=12.37, 5.77 Hz, 1H), 2.16-1.97 (m, 2H), 1.81-1.661 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].Cl.[F:36][C:37]([F:49])([F:48])[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH2:44][NH:43][CH2:42][CH2:41]2.[CH2:50]([O:52][C:53](=[O:64])[NH:54][C:55]1[C:60]([CH3:61])=[CH:59][C:58](Br)=[CH:57][C:56]=1[CH3:63])[CH3:51]>C1(C)C=CC=CC=1>[CH2:50]([O:52][C:53](=[O:64])[NH:54][C:55]1[C:60]([CH3:61])=[CH:59][C:58]([N:43]2[CH2:42][CH2:41][C:40]3[C:45](=[CH:46][CH:47]=[C:38]([C:37]([F:36])([F:48])[F:49])[CH:39]=3)[CH2:44]2)=[CH:57][C:56]=1[CH3:63])[CH3:51]
Reactant: CCOC(=O)Nc1c(C)cc(Br)cc1C
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1c(C)cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (17 mg, 0.03 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (35 mg, 0.09 mmol) were added to dry toluene (5 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (166 mg, 1.48 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (176 mg, 0.74 mmol) and (4-Bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester (200 mg, 0.74 mmol) were then added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature filtered through silica gel and purified by preparative thin layer chromatography (DCM 100%) to give the desired compound as a solid.
Reaction SMILES: [NH:1]=[C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])[CH3:3].ClN1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:3][C:2]1[C:4]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=2[O:13][N:1]=1
Reactant: CC(=N)c1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1noc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a stirred suspension of 2-(1-iminoethyl)-4-nitrophenol (Step 33.1) (2.94 g, 16.32 mmol) in THF (40 mL) was added N-chlorosuccinimide (3.27 g, 24.48 mmol) and K2CO3 (4.51 g, 32.6 mmol) under Ar. The reaction mixture was stirred for 3 hr at rt, quenched with brine, and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude product was purified by silica gel column chromatography (hexane/EtOAc 5-15%) to afford the title product (2.8 g, 15.72 mmol, 96% yield) as a white solid. tR: 4.31 min (HPLC 1); tR: 0.86 min (LC-MS 2); ESI-MS: 179 [M+H]+ (LC-MS 2); Rf=0.85 (hexane/EtOAc 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:34])=[O:22])[CH:17]([C:35]([O:37]CC)=[O:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:34])=[O:22])[CH:17]([C:35]([OH:37])=[O:36])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1sc(-c2ccncc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To a solution of ethyl 4-(6-chloronaphthalene-2-sulfonyl)-1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]-piperazine-2-carboxylate (100 mg) in methanol (20 ml) was added 1 N sodium hydroxide aqueous solution (5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and 1 N hydrochloric acid aqueous solution (5 ml) was added to the residue. The precipitate was filtered and dried to give a colorless solid of the title compound (17 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[K+].[NH2:8][C:9]1[N:14]=[C:13](Br)[C:12]([C:16]#[N:17])=[C:11]([S:18][CH3:19])[N:10]=1>COCCOCCOC>[NH2:8][C:9]1[N:10]=[C:11]([S:18][CH3:19])[C:12]([C:16]#[N:17])=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:14]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CSc1nc(N)nc(-n2cccn2)c1C#N
Temperature: 60 °C
Yield: 27.4 %

Procedure:
To a stirred solution of 500 mg (7.34 mmol) pyrazole in 15 ml diglyme at room temperature under argon was added 0.90 ml (7.34 mmol) potassium hydride (35% dispersion in oil) and the reaction mixture heated at 60° C. for 2 hours. 1.50 g (6.12 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile was then added and the reaction mixture heated at 60° C. for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/3) afforded 390 mg (27%) 2-amino-4-methylsulfanyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 232 (M+, 61), 231 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC.O1CCOCC1.CN1C(=O)N(C)CCC1>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(-c3cccs3)cc2c1O
Reaction time: 0.08 h

Procedure:
A deoxygenated mixture of 0.75 g of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40, 0.75 g of 2-(tributylstannyl)thiophene, 60 mg of bis(triphenylphosphine)palladium(II)dichloride, 7.5 mL of dioxane and 2.5 mL of DMPU is stirred for 2 h at 100° C. The cooled mixture is diluted with 20 mL of hexanes and 60 mL of distilled water. The mixture is stirred for 5 minutes and then filtered. The solid is washed with two 50 mL portions of distilled water and then with two 25 mL portions of methyl t-butyl ether. It is then dissolved in 20 mL of refluxing acetic acid, treated with 2 g of activated carbon and filtered through celite. The volume of the filtrate is reduced to 10 mL and the hot solution diluted with 10 mL of distilled water. Upon cooling, 0.3 g of the title compound precipitates and is collected by filtration.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([NH2:23])=O)[O:3]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:8]=2)[C@@H:4]([C:21]#[N:23])[O:3]1
Reactant: NC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#C[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Yield: 68.2 %

Procedure:
To a solution of (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxamide (80 mg, 0.261 mmol) in dichloromethane (2 mL) was added phosphorus oxychloride (0.243 mL, 2.61 mmol). The reaction was heated to reflux for 4 h and sodium bicarbonate (sat) was added until pH 7. The reaction mixture was back extracted with dichloromethane (3×5 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield a yellow wax that was purified by Preparative HPLC Method 6 providing (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonitrile (53 mg, 0.178 mmol, 68.3% yield) 1H NMR (500 MHz, DMSO-d6) δ ppm 5.36 (d, J=4.27 Hz, 1H) 5.63 (d, J=4.27 Hz, 1H) 7.39-7.49 (m, 4H) 7.52 (t, J=7.93 Hz, 1H) 7.56-7.64 (m, 4H) 8.76 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[C:20]([CH2:22][C:23](O)=O)[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2>>[S:17]1[CH:21]=[C:20]([CH2:22][CH2:23][N:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:14][CH2:15][CH3:16])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)Cc1csc2ccccc12
Reactant: CCCNC1CCc2cccc(OC)c2C1
Product: CCCN(CCc1csc2ccccc12)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 3-benzo[b]thienyl acetic acid (A3-11: R=OMe, Cy=3-benzo[b]thienyl) (purchasable from Alfa Aesar, Karlsruhe (Germany); order number: LO 5855 or Maybridge, Tintagel, Cornwall (UK); order number: S11080) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: C(OC(C1C(=O)OC2C(C=1)=CC(Cl)=C(O)C=2[N+:18]([O-:20])=[O:19])=O)C.[CH2:22]([O:24][C:25]([C:27]1[C:28](=[O:41])[O:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[C:31]=2[O:39][CH3:40])=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1[C:28](=[O:41])[O:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([N+:18]([O-:20])=[O:19])=[C:32]([O:37][CH3:38])[C:31]=2[O:39][CH3:40])=[O:26])[CH3:23]
Reactant: CCOC(=O)c1cc2ccc(OC)c(OC)c2oc1=O
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])c(OC)c(OC)c2oc1=O

Procedure:
Compound 227 was prepared following the preparation of compound 241, except that 3-ethoxycarbonyl-7,8-dimethoxycoumarin was nitrated to give the title compound 227.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2]>O.NN.C(O)C>[NH2:7][CH2:6][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)OCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CN)CC(CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
3 g (6.4 mmol) of benzyl 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4- methylvalerate were dissolved in 39 ml (12.8 mmol) of a 0.33 M solution of hydrazine hydrate in ethanol. The solution was stirred at room temperature overnight. The solvent was removed by evaporation and traces of hydrazine were removed by treatment with toluene followed by evaporation. The residue was taken up in 50 ml of dichloromethane and stirred at room temperature for 45 minutes in the presence of 5 ml of glacial acetic acid. The solid was removed by filtration and the filtrate was evaporated to give 2.56 g of benzyl 2(RS)-[[(RS) -(aminomethyl)(ethoxy)phosphinyl]methyl]-4-methylvalerate in the form of a gum.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[Br:12][CH:13]([CH3:17])[C:14]([NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])=[O:15]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(Br)C(=O)Br
Product: CCc1cccc(CC)c1NC(=O)C(C)Br
Yield: 80 %

Procedure:
Following the procedure described in Example 8A using 2,6-diethylaniline and 2-bromopropionyl bromide the desired intermediate was obtained in 80% yield. Recrystallized from abs. methanol it melted at 197°-199° C.
Reaction SMILES: [BrH:1].N[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([Cl:12])=[CH:5][N:4]=1.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:1][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([Cl:12])=[CH:5][N:4]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cnc1Br
Yield: 51.5 %

Procedure:
To a stirred, ice bath cooled solution of HBr (48%, 214 mL, d=1.49, 1.89 mol) was added 2-amino-5-chloro-3-nitropyridine (2) (66.0 g, 376 mmol). The mixture was stirred until the internal temperature was less than 0° C., and then bromine (65 mL, d=3.102, 1.3 mol) was added dropwise. The resulting orange mixture was stirred at a temperature below 0° C. A solution of NaNO2 (91.3 g, 1.32 mol, used as received) in water (125 mL) was added slowly to the mixture so as to maintain the internal temperature below 0° C. The mixture was stirred for an additional 45 min at below 0° C., and then NaOH (139.3 g, 3.482 mol) in water (200 mL) was slowly added to the mixture to maintain the internal temperature below 20° C. The mixture was stirred at below 20° C. for an additional hour, and then gravity filtered. The recovered brown solid was dried at 25° C. under vacuum for 6 h. It was purified by recrystalization from 95% ethanol to obtain 103 as a yellow solid (46.0 g, 51.5%), mp 68°-73° C. (Lit., 75° C., Berrie et al., J. Chem. Soc. 2042 (1952)); 1H NMR (CDCl3): δ8.15 (d, J=2.1 Hz, 1H), 8,57 (d, J=2.1 Hz, 1H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O.O>[N+:10]([C:6]1[N:5]=[C:4]2[CH2:3][CH2:2][O:1][C:9]2=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2c(c1)OCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2c(n1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2,3-dihydrofuro[3,2-b]pyridine (32.9 g, 271 mmol) in sulfuric acid (50 mL) was added dropwise a mixed solution of fuming nitric acid (20 mL) and sulfuric acid (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was neutralized with 8M aqueous sodium hydroxide solution and diluted with water. The resulting crystals were collected by filtration to give the title compound (37.5 g, yield 83%).