Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[NH2:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH:48]=O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH2:48][NH:33][C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25]([NH:24][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:35])=[O:34])=[CH:42][CH:41]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Oc2cccc(CNc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)C(=O)O)c2)cc1
Reaction time: 7 h
Yield: 76 %

Procedure:
Reductive amination was carried out using (2S)-(2-amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester (123 mg, 0.25 mmol), 3-(4-tert-butyl-phenoxy)-benzaldehyde (130 mg, 98%, 0.5 mmol), acetic acid (0.7 mmol), sodium triacetoxyborohydride (131 mg, 97%, 0.6 mmol) and DCE (2.5 mL). The mixture was stirred for 7 h. Purification by flash chromatography (ethyl acetate/hexanes 1:9) gave the title compound as colorless oil (139 mg, 0.19 mmol, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:32])([F:31])[F:30])[C:14]4=[O:33])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4]N=1.NC1C2C=C3C4(C5C(=CC=CC=5)N(C[C@H]5CCCO5)C4=O)COC3=CC=2ON=1>>[OH:4][C:5]1[C:6]([C:2]#[N:1])=[CH:7][C:8]2[C:13]3([CH2:12][O:11][C:9]=2[CH:10]=1)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:30])[F:31])[C:14]3=[O:33]
Reactant: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Agent: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21
Product: N#Cc1cc2c(cc1O)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 45 and making non-critical variations using 3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one to replace 3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (38%): mp 122-124° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.81-7.78 (m, 1H), 7.62-7.47 (m, 2H), 7.30-7.23 (m, 3H), 7.18 (s, 1H), 7.08-7.03 (m, 1H), 6.73-6.70 (m, 1H), 6.53 (s, 1H), 5.11-4.83 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 178.8, 165.7, 162.1, 141.6, 132.9, 132.7, 131.0, 129.8, 128.1, 127.7, 126.7, 124.7, 124.1, 120.9, 116.7, 110.0, 99.0, 93.2, 81.1, 57.2, 41.0; MS (ES−) m/z 435.1 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([CH3:9])=[N:7][CH:8]=1)#[CH:2].Cl.[CH3:14][NH:15][CH3:16].C([BH3-])#N.[Na+]>CCO>[CH3:14][N:15]([CH3:16])[CH2:2][CH2:1][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CNC
Reactant: C#Cc1cnc(C)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(CCN(C)C)cc1[N+](=O)[O-]
Yield: 40.7 %

Procedure:
To a solution of 5-ethynyl-2-methyl-3-nitropyridine (930 mg, 5.74 mmol) in EtOH (7 mL) were added dimethylamine hydrochloride (2.34 g, 28.7 mmol) and sodium cyanoborohydride (0.721 g, 11.5 mmol). The reaction mixture was allowed to stir at reflux for 24 h, concentrated, and treated with 4N NaOH (10 mL). The solution was extracted with DCM (2×200 mL). The organic solutions were combined, washed with brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N,N-dimethyl-2-(6-methyl-5-nitropyridin-3-yl)ethanamine (489 mg, 41%). LCMS (AA): Rt=1.35 min, m/z 210 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[C:6]([NH:8]C)[CH3:7])[CH3:2].O.[NH2:22]N>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH3:7])=[N:8][N:22]=[C:10]1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[O:20])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1c(F)cccc1Cl)=C(C)NC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1C(C)=NN=C1c1c(F)cccc1Cl

Procedure:
2-(2-Chloro-6-fluoro-benzoyl)-3-methylamino-but-2-enoic acid ethyl ester (500 mg, 1.6 mmol) was taken in acetic acid (10 mL) and was treated with hydrazine hydrate at 150° C. overnight. Acetic acid is removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed with water, (2×10 mL), brine (2×10 mL), dried over sodium sulfate, filtered and evaporated to yield the title compound (588 mg, crude).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:22].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:10]3[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=3[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=2[CH3:22])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: CC(C)c1ccc(O)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c(Oc3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Temperature: 140 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
A mixed solution of N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.36 mmol) obtained in Example 343, 4-isopropylphenol (556 mg, 4.08 mmol) and potassium carbonate (188 mg, 1.36 mmol) in pyridine (16 mL) was stirred at 140° C. under argon atmosphere for 1 hour. Copper iodide (259 mg, 1.36 mmol) was added to the reaction solution and the mixture was stirred at 140° C. for 60 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with 1 N hydrochloric acid and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) and Gilson HPLC to obtain 230 mg (yield: 40%) of the title compound. Melting point: 148-149° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[Na+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:22]=1)[CH:20]=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:20]([OH:21])[CH2:4][N+:1]([O-:3])=[O:2])[CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])CC(O)c1cc(OCc2ccccc2)ccc1Br
Reaction time: 18 h

Procedure:
A solution of nitromethane (2.02 mL, 37.3 mmol) in ethanol (10 mL) was treated with 10N NaOH (3.0 mL) at ambient temperature. A white solid precipitated immediately, and a solution of 5-benzyloxy-2-bromo-benzaldehyde (8.67 g, 29.8 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred for 18 h and quenched with water (100 mL). The mixture was extracted with CH2Cl2 (2×50 mL), dried (Na2SO4), and concentrated to a residue, which was then purified by silica gel chromatography (hexanes/EtOAc 8/2) to afford 1-(5-benzyloxy-2-bromo-phenyl)-2-nitro-ethanol as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[C:8](=[O:17])[N:9]2[CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[N:19]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]1[CH3:25].[OH-].[Li+]>O1CCCC1.O>[C:13]([CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N:19]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:25])=[C:2]([Cl:1])[CH:11]=2)[NH:6][C:7](=[O:18])[C:8]1=[O:17])([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3c(C)ccc3C)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
4.0 g (10.6 mmol) of 7-chloro-6-(2,5-dimethyl-1-pyrrolyl)-1-(methoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione (Example 44) were dissolved in 100 ml of tetrahydrofuran, and a solution of 0.76 g (31.9 mmol) of lithium hydroxide in 15 ml of water was added. The mixture was stirred at room temperature for 2 h and then the organic solvent was removed under reduced pressure, and the aqueous phase was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction to yield 3.1 g (84%) of the product. Melting point>265° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1>[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(OCc2cccc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCc4cccc(F)c4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 136 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.214 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-{4-[(3-fluorobenzyl)oxy]phenyl}pyridin-2-amine (200 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water, hexane and collected. The precipitate was sonicated in EtOAc and the insoluble material was collected to give 9-{4-[(3-fluorobenzyl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (317.7 mg) as an off-white solid. This was crystallized from MeOH-THF/IPE to give an off-white crystal.
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:24][C:25]1[CH:30]=[C:29]([C:12]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:22])[C:7](=[O:23])[CH2:6]3)[CH:28]=[N:27][CH:26]=1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2C1CC1
Temperature: 120 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 40d (50 mg, 0.16 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 113 mg, 0.479 mmol), 1,2-dimethoxyethane (1.5 mL), and 2 M aqueous sodium carbonate (0.2 mL, 0.4 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (43.5 mg, 4.79 μmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 343.0451 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.18-0.26 (m, 2H), 0.78-0.88 (m, 2H), 1.87-1.99 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: [O-:1]Cl.[Na+].[CH3:4][O:5][CH:6]([O:21][CH3:22])[C@@:7]1([CH3:20])[CH:12]=[CH:11][C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1>C(Cl)Cl>[CH3:22][O:21][CH:6]([O:5][CH3:4])[C@@:7]1([CH3:20])[C@H:12]2[O:1][C@H:11]2[C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1
Reactant: COC(OC)[C@@]1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To the pre-cooled solution of 0.55 M NaOCl (55 mL, 30.0 mmol) and of 0.05 M Na2HPO4 (21.5 mL) at 0° C., (2R)-2-dimethoxymethyl-2-methyl-6-nitro-2H-1-benzopyran n(2 g, 7.5 mmol) and (R, R) Jacobson's catalyst (477.5 mg, 0.75 mmol) in CH2Cl2 (10 mL) was added. The reaction mixture was stirred at rt for 8 hr and then filtered through Celite to remove the jacobson's catalyst. The layer was separated and the organic layer was washed with brine, dried (Na2SO4), filtered, then concentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1) to give the desired compound (1.64 g, 77%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[Cl:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>C1C=CC=CC=1>[ClH:17].[CH2:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Product: Cl
Temperature: 0 °C

Procedure:
11 gm (51.7 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were dissolved in 275 ml of hot benzene, and then a solution of 9.8 ml (103.4 millimols) of ethyl chloroformate in 70 ml of benzene were simultaneously added dropwise. After refluxing the resulting mixture for 2 hours, 150 ml of ice water were added to the cooled reaction mixture, and the aqueous mixture was made alkaline with 2 N sodium hydroxide. The benzene layer was separated and the aqueous layer was extracted with chloroform. The combined benzene and chloroform phases were dried over sodium sulfate, the solvents were distilled off, and the residual oil was admixed with ether, whereupon 11 gm (75% of theory) of the base, m. p. 126° C., crystallized out. For conversion into the hydrochloride, 11 gm of the base were dissolved in 60 ml of isopropanol, the solution was filtered, and 10 ml of isopropanolic hydrochloric acid were added. The hydrochloride crystallized out of the hot solution. Yield: 12 gm (72% of theory); m.p. 247° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][C@H:10]1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH3:27][S:28]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C@H:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:10]([O:18][CH3:19])[CH2:11]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1CN(CCO)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(CCOS(C)(=O)=O)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1

Procedure:
Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethanol (Intermediate 170, 740 mg, 2.1 mmol) was reacted with methanesulfonyl chloride (0.20 mL, 2.5 mmol) in the presence of triethylamine (0.41 mL, 2.9 mmol) as described for Intermediate 6. The crude product was presumed to be unstable and was used without further purification directly for the next step.
Reaction SMILES: Br[C:2]#[N:3].CC#N.[F:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([NH2:15])=[C:10]([NH2:16])[CH:9]=1>O.CO>[NH2:3][C:2]1[NH:16][C:10]2[CH:9]=[C:8]([F:7])[C:13]([F:14])=[CH:12][C:11]=2[N:15]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Reaction time: 2 h

Procedure:
To a stirred solution of 4.9 mL of 5M BrCN/MeCN in 50 mL of H2O, was added dropwise a solution of 3.515 g (24.389 mmole) of 10 in 50 mL of MeOH over 20 min. After the addition, stirring was continued at room temperature for 2 h. The reaction mixture was concentrated to ~50 mL and was extracted with EtOAc (50 mL×3). The combined EtOAc solution was back washed with 100 mL of H2O and then discarded. The combined H2O phase was basified with sat. NaHCO3 solution (precipitation occurred) and was extracted again with EtOAc (70 mL×3). The EtOAc solution was dried (Na2SO4) and evaporated to dryness. The residue was suspended in 50 mL of CHCl3 and filtered. The yellowish solid was washed with portions of CHCl3 to give 3.40 g of 11. The filtrate and washings were evaporated to dryness and the procedure was repeated to give an additional 0.355 g of 11. The total yield of 11 was 3.755 g (91%). 1H NMR (DMSO-d6) d 10.79 (br.s, 1,1-NH), 7.06 (dd, 2,4-H and 7-H, 3JF-H =11.0 Hz, 4Jf-H =7.5 Hz), 6.30 (br. s, 2,2-NH2).
Reaction SMILES: [C:1]([N:11]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][SH:36])=[CH:29][CH:28]=1.C(N([CH2:42][CH3:43])CC)C>C(OCC)C>[C:1]([N:11]([CH2:20][P:21]([O:25][S:36][CH2:35][CH2:34][CH2:33][C:43]1[CH:42]=[CH:29][CH:28]=[CH:27][CH:32]=1)([O:23][S:36][CH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=1)=[O:22])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCN(CC)CC
Reactant: SCCCc1ccccc1
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)OCc1ccccc1
Solvent: CCOCC
Product: CCCCOC(=O)CN(CP(=O)(OSCCCc1ccccc1)OSCCCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
n-Butyl N-carbobenzoxy-N-(dichlorophosphonomethyl)glycinate (9.5 g., 0.24 mole) was dissolved in 150 ml. of diethyl ether. To this solution was added 3-phenylpropylthiol (7.3 g., 0.48 mole) and then triethylamine (4.8 g., 0.048 mole) dissolved in 100 ml. of diethyl ether. This mixture was then stirred for 16 hours at ambient temperature, filtered to remove the triethylamine hydrochloride, washed with a 3% solution of ammonium hydroxide and then 5% hydrochloric acid and then with brine. The ether solution was dried over sodium sulfate, filtered and then concentrated under vacuum to yield a crude product. The crude product was chromatographed on a silica gel column employing methylene chloride and diethyl ether. Concentration of the ether eluant yielded n-butyl N-carbobenzoxy-N-[di(3-phenylpropylthio)phosphonomethyl]glycinate as a light yellow oil, ND25 =1.5685 and having the following analysis.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([N+:17]([O-])=O)[CH:11]=1.CC1C=CC(O)=C([N+]([O-])=O)C=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:12]([NH2:17])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: Oc1ccc(S)cc1
Agent: Cc1ccc(O)c([N+](=O)[O-])c1
Product: Nc1cc(Br)ccc1Sc1ccccc1

Procedure:
5-bromo-2-(phenylthio)benzenamine was prepared according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-bromo-2-nitrophenol for 4-methyl-2-nitro phenol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[Li]CCCC.[Br:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28](N(OC)C)=[O:29]>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]([C:28]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(Br)c(NC(=O)C(C)(C)C)cc1OC
Reactant: CON(C)C(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(C)(C)C)c(C(=O)c2cccc(Br)c2)cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flamed dried 500 mL three-necked flask was charged N-(2-bromo-4,5-dimethoxyphenyl)-2,2-dimethylpropanamide (30 g, 95 mmol) and dry THF (200 mL) under N2. n-BuLi (114 mL, 2.5 mol/L, 285 mmol) was added dropwise at −78° C. After the mixture was stirred at −78° C. for 1 hour, 3-bromo-N-methoxy-N-methylbenzamide (23.2 g, 94.9 mmol) in dry THF (30 mL) was added dropwise slowly at −78° C. The resulting mixture was stirred at −78° C. for 3 hours, then quenched with saturated NH4Cl (100 mL). The mixture was exacted with EtOAc (100 mL×3). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (30:1 hexanes/ethyl acetate) to afford a N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2,2-dimethylpropanamide as a yellow solid. MS (M+H)=420 and 422.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:9][S:10](Cl)(=[O:12])=[O:11].[C:16]([O:20][C:21]([NH:23][C@H:24]1[C@H:27]([CH2:28][CH3:29])[NH:26][C:25]1=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.O>[CH2:25]([N+:1]([CH2:2][CH2:17][CH2:16][CH3:18])([CH2:6][CH2:5][CH2:4][CH3:3])[CH2:29][CH2:28][CH2:27][CH3:24])[CH2:24][CH2:27][CH3:28].[C:16]([O:20][C:21]([NH:23][C@H:24]1[C@H:27]([CH2:28][CH3:29])[N:26]([S:10]([O-:9])(=[O:12])=[O:11])[C:25]1=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: c1ccncc1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: CC[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2 ml of absolute pyridine in 20 ml of dry dichloromethane is added trimethylsilyloxysulfonyl chloride (3.7 ml) in 5 ml of dry dichloromethane. The addition is accomplished at -30° C., under nitrogen, over a 10 minute period. After stirring at ambient temperature for 30 minutes, the flask is evacuated to yield a pyridine-sulfur trioxide complex. (trans)-3-t-Butoxycarbonylamino-4-ethyl-2-azetidinone (2.67 g) and 20 ml of dry pyridine are added to the flask which is then placed in an oil bath preheated to 90° C. After 15 minutes a clear solution is obtained and poured into 200 ml of a 1M solution of dibasic potassium phosphate. After the addition of 27 g of dibasic potassium phosphate and 100 ml of water a clear solution is obtained. The solution is extracted with two 60 ml portions of ethyl acetate. Tetrabutylammonium hydrogensulfate is added to the aqueous layer, and the aqueous solution is extracted with three 100 ml portions of dichloromethane and the combined organic layers are dried over MgSO4. Concentration in vacuo yields 6.9 g of the title compound.