Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36]2.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>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1[NH:38][C:39]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH:32][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30])=[CH:41][CH:40]=2)=[O:43])[CH3:46]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.321 mmol), ethyl 5-amino-1H-indole-2-carboxylate (114 mg, 0.558 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 159 mg, 0.417 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by RP-HPLC chromatography (20-95% acetonitrile/water) to afford 5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid ethyl ester (37 mg, 17.6%) as an off-white powder. LCMS (ES+) m/z Calcd for C34H32Cl2F2N4O3+H [(M+H)+]: 652.18. found: 6512.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=CC(C2(C=O)CCC2)=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]([OH:17])[C:1]#[N:2])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [C-]#N
Agent: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of sodium cyanide (19.5 g) in water (50 ml) was added dropwise over a period of 30 minutes to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbaldehyde [(62.16 g) prepared in a similar manner to that described in Example A for 1-(4-chlorophenyl)-cyclobutanecarbaldehyde] in methanol (70 ml) whilst the temperature was maintained at 20° C. by cooling. A saturated aqueous solution of sodium metabisulphite (81 ml) was added over a period of 20 minutes at 20° C. and the mixture was stirred for 16 hours and then poured into a mixture of ice and water. The resulting mixture was extracted with ether and the extracts were washed and dried. Evaporation of the solvent gave 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile as a yellow oil which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])(=[O:9])=[O:8])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:16][C:5]([S:7]([CH2:10][CH2:11][C:12]([F:14])([F:15])[F:13])(=[O:9])=[O:8])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
2-Methyl-2-(3,3,3-trifluoro-propane-1-sulfonyl)-propionic acid ethyl ester (1.3 g, 4.63 mmol) is dissolved in THF/water (14 mL, 4:1 ratio) and LiOH (0.2 g, 9.27 mmol, 2 eq.) is added. The mixture is stirred for 18 h at room temperature, then concentrated under reduced pressure to remove the organic solvent. The aqueous residue is further diluted with water, washed with DCM and then acidified to pH ˜2 and extracted with DCM. The combined acidic organic extracts are concentrated to afford 0.97 g of title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.72 (3H, s), 2.64-2.81 (2H, m), 3.46-3.6 (2H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)CC(Br)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)Cc1cnc(-c2ccc(OC)cc2)s1
Yield: 66.5 %

Procedure:
4-Methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give ethyl [2-(4-methoxyphenyl)-1,3-thiazol-5-yl]acetate (1.79 g, yield: 67%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[N:29][C:5]2[O:6][CH2:7][CH2:8][C@@H:9]3[C@@:14]([CH3:15])([C:4]=2[CH:3]=1)[N:13]=[C:12]([NH:16]C(=O)OC(C)(C)C)[C:11]1([CH2:26][CH2:25][CH2:24]1)[S:10]3(=[O:28])=[O:27].C(O)(C(F)(F)F)=O>>[NH2:16][C:12]1[C:11]2([CH2:26][CH2:25][CH2:24]2)[S:10](=[O:27])(=[O:28])[C@@H:9]2[CH2:8][CH2:7][O:6][C:5]3[N:29]=[CH:30][C:2]([Br:1])=[CH:3][C:4]=3[C@@:14]2([CH3:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Br)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12N=C(N)C3(CCC3)S(=O)(=O)[C@@H]1CCOc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A flask was charged with tert-butyl ((4a′R,11b′R)-10′-bromo-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′: 6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.0306 g, 0.061 mmol) followed by the addition of TFA (1.0 ml, 13.46 mmol). The resulting mixture was stirred at rt for 15 min, quenched with water and the pH was brought to >10 using saturated NaHCO3 and 1 N NaOH, and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to afford a white solid as (4a′R,11b′R)-2′-amino-10′-bromo-11b′-methyl-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′: 6,7]oxepino[4,5-b][1,4]thiazine]-4′,4′-dioxide (0.0192 g, 0.048 mmol, 78% yield). LC/MS (ESI) m/z=399.8 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 33.9 %

Procedure:
A mixed solution of 2 g of 1,6-dibromopyrene, 1 g of 4-methylphenylboronic acid, 2.4 g of tripotassium phosphate, 0.4 g of tetrabutylammonium bromide, 22 mg of palladium acetate and 60 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 130° C. for 6 hours. After cooling the solution to room temperature, 30 ml of water was injected, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 0.7 g of 1-bromo-6-(4-methylphenyl)pyrene.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>CN(C=O)C.O1CCOCC1.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>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH2:29])=[O:31])=[CH:33][CH:34]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(Nc2ccc(-n3cc(-c4ccccn4)nn3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cnc(Nc3ccc(-n4cc(-c5ccccn5)nn4)cc3)c3nccn23)cc1

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-phenyl]-amine (40 mg, 0.0923 mmol), 4-(aminocarbonyl)phenylboronic acid (30.5 mg, 0.185 mmol) 1.5 M Na2CO3 (0.492 mL, 0.738 mmol), and Pd(PPh3)4 (26.7 mg, 0.023 mmol) in (2:1) DMF-dioxane (1.5 mL). The crude material is purified by Isolute FlashSilicaII Cartridge chromatography eluting with 98:2 DCM:NH3 (7M in MeOH) followed by 97:3 DCM:NH3 (7M in MeOH). The title compound is obtained as a white solid (23.5 mg, 54%). LCMS: Rt 2.67 min (95%) m/z (ES+) 474 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 7.41-7.47 (1H, d), 7.53 (1H, d), 7.66 (1H, br s), 7.81 (1H, s), 7.84-7.90 (2H, d), 7.96-8.07 (3H, m), 8.08-8.20 (5H, m), 8.36-8.44 (2H, d), 8.70 (1H, d), 9.30 (1H, s), 10.15 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](SC)=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[NH2:27]O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][N:27]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: NO
Reactant: COc1cc(NC(=CC(=O)c2ccccc2)SC)ccc1-c1cnco1
Solvent: CCO
Product: COc1cc(Nc2cc(-c3ccccc3)on2)ccc1-c1cnco1
Reaction time: 8 h
Yield: 0 %

Procedure:
To an oven dry flask was added acetophenone (0.4 mL, 3.33 mmol) followed by 10 mL of anhydrous DMF. The flask was cooled to 0° C. and to it was added sodium hydride (0.084 g, 3.33 mmol) over a 10 min. The flask was stirred at RT for 10 min. 1E (0.772 g, 3.33 mmol) was added over a 10 min. period and the reaction mixture was stirred at RT for 1 hour. Iodomethane (0.2 mL, 3.33 mmol) was added and the reaction mixture was stirred at RT for an additional hour, concentrated under reduced pressure and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield 3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-(methylthio)-1-phenyl-2-propen-1-one (1.3 g), which was used for the subsequent step without further purification. To a solution of 3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-(methylthio)-1-phenyl-2-propen-1-one (1.2 g, 3.32 mmol) in 10 mL of ethanol was added hydroxylamine (50% solution in water, 0.3 mL, 4.98 mmol) and the contents refluxed for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was left at RT overnight and the solid that separates out (700 mgs) was filtered. 100 mgs of this solid was purified using preparative HPLC (YMC S5 ODS 30×250 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA). The fraction having a retention time of 4.61 min. was collected, concentrated under reduced pressure, neutralized with 10% aqueous sodium carbonate and extracted into ethyl acetate. The ethyl acetate layer was concentrated to yield 0.015 mgs of the title compound. m.p. 173-175° C. (LC/MS retention time=4.61 min.; M+=334.22 Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[N:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:38])[CH:5]=1.[Li+].[OH-].O>O1CCOCC1>[CH:25]([C:24]1[CH:23]=[N:22][N:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[C:20]=1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:39])=[O:2])=[C:13]([CH3:38])[CH:14]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)cnn3-c3ccccc3C(F)(F)F)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2ccccc2C(F)(F)F)ccc1C=Cc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 3-(2-{4-[4-isopropyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-vinyl)-benzoic acid methyl ester (136 mg, 0.25 mmol) in 1,4-dioxane (7 mL) is added 2N LiOH/H2O (3 mL). The reaction mixture is stirred at 50° C. overnight. The solvent is evaporated and the residue is partitioned between EtOAc and 1N HCl. The layers are separated and the organic phase is washed with water and concentrated to give the title compound (129 mg, 97%). LC-ES-MS m/e 521 (M+1), 100%.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.O>CN(C=O)C>[N:24]1([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cn2ccnc2)cc1)c1ccccc1
Yield: 90 %

Procedure:
Prepared from 3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 1.5 equivalents of 4-(imidazol-1-yl)methyl-aniline (melting point: 128-130° C.) in DMF (120° C., 1 hour), pouring into water and washing the precipitate with MeOH and ether. Yield: 90% of theory;
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([OH:23])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)([O-:28])=[O:27].O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([O:23][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N+:26]([O-:28])=[O:27])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(O)ccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4[N+](=O)[O-])ccc3c21
Reaction time: 0.17 h

Procedure:
To a suspension of Compound 141a (1.00 g, 3.03 mmol) in dry THF (20 mL) cooled in an ice-water bath was added NaH (60 percent, 128 mg, 3.19 mmol) followed by stirring for 10 minutes. To the resultant solution was added 2-nitrobenzyl bromide (0.689 g, 3.19 mmol), and tetra-n-butylammonium iodide (0.11 g, 0.3 mmol), and the mixture was then stirred at 25° C. for one hour. Water was added to the reaction mixture followed by extraction with ethyl acetate (50 mL), washing with brine, dry over anhydrous Na2SO4, and concentration in vacuo to give a crude product. Flash column chromatography of the crude product (silica gel, 20 percent ethyl ether in benzene) afforded Compound 143a (1.27 g, 90 percent(: pale-yellow solid; mp 150°-152° C.; Rf =0.33 (silica, 20 percent ethyl ether in benzene); IR (CHCl3) νmax 2953, 2933, 1623, 1528, 1343, 1090, 1027, 838 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1 H, H6), 8.21 (dd, J=8.0, 0.9 Hz, 1 H, aromatic), 8.01 (d, J=9.2 Hz, 1 H, H1), 7.92 (d, J=7.8 Hz, 1 H, aromatic), 7.68 (dt, J=7.8, 0.9 Hz, 1 H, aromatic), 7.50 (t, J=8.0 Hz, 1 H, aromatic), 7.44 (d, J=2.6 Hz, 1 H, H4), 7.32 (dd, J=9.2, 2.6 Hz, 1 H, H2), 5.66 (s, 2 H, benzylic), 5.42 (t, J=3.1 Hz, 1 H, H10), 2.97 (br dd, J=14.0, 4.0 Hz, 1 H, H7), 2.86-2.72 (m, 1 H, H7), 2.25-2.15 (m, 2H, H8 or H9), 1.90-1.80 (m, 2 H, H8 or H9), 0.85 (s, 9 H, SiC(CH3)3), 0.22 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity 465 (N+Cs, 100), 407 (19), 330 (26), 198 (17), 136 (18); HRMS for C26H32N2O4SiCs (M+Cs), calcd 465.2210, found 465.2210. Anal. Calcd for C26H32N2O4Si: C, 67.21; H, 6.94; N, 6.03. Found: C, 67.31; H, 6.91; N, 5.96.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:36]=[CH:35][C:24]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[F:38][C:19]([F:18])([F:37])[O:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:28][CH2:27]2)=[CH:35][CH:36]=1
Reactant: OCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(COCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 47.2 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethanol (305 mg, 1.0 mmol) as crude materials, 125 mg title compound was generated and yield was 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2N(C3C=CC=CN=3)N=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[N:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:31]([C:27]3[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)[N:32]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1cncc(Cl)c1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1

Procedure:
785 mg (2.25 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 608 mg (3.38 mmol) of 5-chloropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 270 mg (34% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:10]([OH:37])[CH2:11][C@H:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[CH2:11][C@H:10]([OH:37])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
A solution of the product from Example 1D (2.6 g, 4.4 mmol) in a mixture of methanol (22 mL) and ethyl acetate (22 mL) was treated with Pd(OH)2 on carbon (0.8 g, 20% Pd by wt.) and HCl solution (1.0 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through celite®, rinsed with methanol and concentrated to give the title product (1.7 g) as the hydrochloride salt.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[Cl:11][C:12]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(Br)C.[Br-]>>[Cl:11][C:12]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(OCCCCCCBr)c(Cl)c1
Agent: [Br-]
Solvent: CCBr
Product: CCOP(=O)(CCCCCCOc1ccc(OC)cc1Cl)OCC
Temperature: 158 °C
Yield: 79.2 %

Procedure:
Triethyl phosphite (185 g, 230 ml, 1.1 mole) was placed in a flask equipped with a thermometer, dropping funnel, stirrer and 8 inch Vigreux column with condenser set for downward distillation. The phosphite was heated to 158° C. thereby inducing mild reflux. 6-(2-Chloro-4-methoxyphenoxy)hexyl bromide (320 g, 1 mole) was then added dropwise over a period of 50 minutes. The reaction mixture was heated for an additional 90 minutes at which time distillation of ethyl bromide ceased. The remaining reaction mixture was distilled in vacuo and the fraction (250 g) boiling at 183°-197° C. (0.2-0.3 mm) was collected. The latter was combined with 79 g of product obtained from another run starting from 100 g of bromide and redistilled to give 300 g of diethyl [6-(2-chloro-4-methoxyphenoxy)-hexyl]phosphonate, b.p. 202°-204° C. (0.02 mm).