Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:59])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)C(O)=O)=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)=O)C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:48]([O:47][C:45]([N:44]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[C:40]1[C:41]2[C:36](=[CH:35][C:34]([NH:33][CH:29]3[C:26]4=[CH:27][CH:28]=[C:23]([CH:24]=[CH:25]4)[O:22][CH2:21][C:20](=[O:59])[NH:19][C:15]4=[CH:14][C:13](=[CH:18][CH:17]=[CH:16]4)[CH2:12][NH:11][C:9]3=[O:8])=[CH:43][CH:42]=2)[CH:37]=[CH:38][N:39]=1)=[O:46])([CH3:49])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC3C(=O)NCc4cccc(c4)NC(=O)COc4ccc3cc4)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A solution of 66D (55 mg, 0.082 mmol) in 10 mL DMF was added to a solution of PyBOP (88 mg, 0.17 mmol), DMAP (49 mg, 0.4 mmol), and TEA (40 mg, 0.4 mmol) in CH2Cl2 (30 mL) dropwise through syringe pump over 3 h. The solution was stirred at rt for 16 h. The solution washed with 1M H3PO4, sat NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc in hexanes) to give 66F (8.5 mg, 16%). MS (ESI) m/z 654.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:12](OC(OCC)OCC)C.CC(O)=O>C(Cl)Cl>[Cl:9][C:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]2[N:1]=[CH:12][NH:8][C:7]=2[CH:6]=1
Reactant: N#Cc1nc(Cl)cc(N)c1N
Reactant: CCOC(OCC)OCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1nc(Cl)cc2[nH]cnc12

Procedure:
A mixture of 3,4-diamino-6-chloropicolinonitrile (3.2 g), triethylorthoformate (16 ml) and AcOH (5.4 ml) was heated to 150° C. in DCM (16 ml) in a microwave for 15 minutes. Solvent was evaporated, residue was dissolved in EtOAc (250 mL) and washed with water (150 mL). Organic layer was dried over sodium sulphate. Solvent was evaporated under reduced pressure to yield 6-chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.Cl>[OH-].[Na+]>[N:1]1([C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CSCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was added benzyl chloridocarbonate (1.66 mL) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was neutrolized with 1N HCl and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to give benzyl 4-thiomorpholinecarboxylate as a colorless solid (4.8 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:10]=1[C:25]([F:28])([F:27])[F:26].S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35]>C(OCCCC)(=O)C>[N+:34]([C:22]1[CH:23]=[CH:24][C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[C:9]([Cl:8])[CH:14]=2)=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])([O-:36])=[O:35]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Agent: O=S(=O)(O)O
Solvent: CCCCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 85 %

Procedure:
Acetic anhydride (37.7 g) was added to 3-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-benzoic acid (86% strength, 45 g) in n-butyl acetate (85.8 g) at 35° C. Sulphuric acid (98%, 12.2 g) was added slowly and the mixture cooled to 0° C. Nitric acid (90%, 10.4 g) was then added slowly over about 3 hours such that the temperature was maintained at -5 to 0° C. On completion of the nitric acid addition the reaction was quenched with water (60 g) at 0° C. The mixture was warmed to 50-60° C. and the aqueous layer removed. The solvent layer was washed with water (2×100 g) at 60° C. and the aqueous layer removed. The solvent and acetic acid were removed by distillation to give 2-nitro-5-(2-chloro-α,α,α-trifluoro-4-tolyloxy) benzoic acid (85%), 2'-nitro isomer (7.5 to 8.5 pph), total dinitro's (~0.5 pph).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)sc2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)sc2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (15 mL), and then the solvent was distilled off. Benzene (15 mL) was added to the residue, and the benzene was distilled off again, followed by vacuum drying to yield 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:11])[NH2:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]1(=[N:10][N:9]([CH3:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)N
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CN(C)N=C1CCCCC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 87.4 %

Procedure:
To solution of cyclohexanone (2.00 g, 20.4 mmol) and N,N-dimethylhydrazine (1.50 ml, 20.4 mmol) in ethanol (20 ml) was added a catalytic amount of toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at 70° C. for 72 h. The solvent was evaporated, and the residue was purified by Kugelrohr distillation (60-80° C., 5 mbar) to give the title compound (2.50 g, 87%) as colorless oil. MS m/e: 141 ([M+H]+)
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CC#N>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(F)c2ccccc2c1O
Temperature: 23 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.50 g, 4.74 mmol) in CH3CN (37.5 mL) was cooled to 0° C. Selectfluor (1.70 g, 4.74 mmol) was added, and the reaction was allowed to warm to 23° C. After 2 h, the reaction was added slowly to a mixture of saturated Na2HPO4 (70 mL) and H2O (30 mL) at 23° C. More H2O (40 mL) was added, and the system was extracted with DCM (3×40 mL). The combined organic phases were treated with hexane (20 mL). The phase that separated was removed. The remaining organic phase was dried (Na2SO4), filtered, and concentrated. The filtrate was concentrated and dissolved in benzene. The solution was wet-loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.26 g, 79%). 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.51 (dd, J=6.9, 6.9 Hz, 1H), 7.45 (dd, J=6.9, 6.9 Hz, 1H), 5.46 (s, 1H), 4.23-4.14 (m, 2H), 2.49 (d, JHF=3.2 Hz, 3H), 1.31 (s, 9H), 1.20 (t, J=7.1 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−137.3 (app. s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].[CH:29]([NH2:31])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:29]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1)#[N:31]
Reactant: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Br)cc1
Reactant: NC=O
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-Bromo-4-nitro-4'-(N,N-diethylamino)azobenzene (1.9 parts), copper (I) iodide (0.95 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperatures is maintained at 110° C. for 31/2 hours when reaction is adjudged complete by thin layer chromatography. The solvent is removed at 80° C. under reduced pressure and the residue is slurried in water (250 parts), collected and dried. 2-Cyano-4-nitro-4'-(N,N-diethylamino)azobenzene is obtained in 75% yield and requires no purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=1)([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[C:7]([C:26]([F:28])([F:27])[F:29])[CH:6]=1)([CH3:2])[CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)cc1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.2 %

Procedure:
To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 17B, 0.225 g, 0.563 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.3 mL, 0.563 mmol) followed by osmium tetroxide (4% in water) (0.088 mL, 0.011 mmol) at room temperature. The contents were stirred at room temperature for 14 h. Sodium periodate (0.181 g, 0.845 mmol) dissolved in 1 mL of water was added at room temperature. The contents were stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (10 mL) and brine (5 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.222 g, 0.553 mmol, 98% yield). LC/MS M+1=402.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:11]([NH:12][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([CH3:1])[C:3]([O:4][CH2:5][C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
To a solution of crude (2-methyl-3-amino-4-chlorophenoxy)acetonitrile (11.53 g) in toluene (PhMe) (60 mL) was added methanesulfonyl chloride (MsCl) (4.5 mL, 6.7 g) and the resultant solution was warmed to 35-40° C. Pyridine (py) (4.7 mL, 4.6 g) was then added slowly over 2 h. The resultant mixture was permitted to cool to ambient temperature and stirred for 24 h. The crude product mixture was then partitioned between 1N hydrochloric acid (100 mL), and a mixture of ethyl acetate (300 mL) and tetrahydrofuran (100 mL). The organic phase was washed with water, then concentrated to ca. 200 mL, leading to crystallization of the desired product. The white crystalline product was collected, rinsed with toluene, and dried to afford 10.40 g (65.1% field) of N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (>97% pure by HPLC). This material could optionally be recrystallized from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.[O:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][C:28](Cl)=[O:29])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:16][C:28](=[O:29])[CH2:27][C:20]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=2[O:17][CH3:18])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: N#Cc1c(N)cc(N)nc1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
To a solution of 50 mg (0.24 mmol) of 4,6-diamino-2-phenyl-nicotinonitrile in 2 mL of CH2Cl2 was added 150 mg (0.70 mmol) of (2,5-dimethoxyphenyl)acetyl chloride (Example 68A), then 100 μL (1.23 mmol) of pyridine. The mixture was stirred at ambient temperature for 10 minutes then the solvent was removed under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, then extracted with 1 M HCl(aq.) (2×5 mL), saturated NaHCO3(aq) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 40% ethyl acetate:hexanes to provide 11 mg (12%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.43 (m, 1H), 7.75 (m, 2H), 7.51 (m, 4H), 6.99 (m, 2H), 6.91 (m, 1H), 6.81 (m, 2H), 3.69 (m, 8H); MS (ESI) m/e 389 (M+H)+, 387 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(Cl)Cl.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
38 g of ethoxy acrylate from Example 1 are initially introduced into 150 ml of methylene chloride. An aqueous solution of 15.4 g of ethyl 3-aminopropionate hydrochloride is added to this. A solution of 8.4 g of NaHCO3 in water is added dropwise to the two-phase system with vigorous stirring. After completion of the dropwise addition, the mixture is stirred for a further 2 hours, and the phases are subsequently separated.
Reaction SMILES: [C:1]([CH:5]1[C:18](=[O:19])[CH2:17][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:20])(=O)[CH2:2][CH3:3].Cl.[CH2:22]([O:24][NH2:25])[CH3:23].C([O-])(=O)C.[Na+].Cl>C(O)C>[CH2:22]([O:24][N:25]=[C:1]([CH:5]1[C:18](=[O:19])[CH2:17][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:20])[CH2:2][CH3:3])[CH3:23]
Reactant: CCON
Reactant: CCC(=O)C1C(=O)CC2(CCc3ccccc32)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1C(=O)CC2(CCc3ccccc32)CC1=O

Procedure:
4-Propionylspiro[cyclohexane-1,1'-indan]-3,5-dione (0.54 g), ethoxyamine hydrochloride (1.3 equiv), anhydrous sodium acetate (1.3 equiv) and absolute ethanol (20 ml) were stirred at room temperature for 3 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then immediately extracted with diethyl ether. The dried (MgSO4) organic fraction was evaporated to give 4-[1-(ethoxyimino)propyl]spiro[cyclohexane-1,1'indan]-3,5-dione (5) as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.09-1.41 (6H, 2×t); 2.06 (2H, t); 2.6-3.1 (8H, m); 4.12 (2H, q); 7.2 (4H, m); 14.93 (1H, brs).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]([CH2:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:26]=3)=O)[C:19]([OH:21])=[O:20])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1.FC1C=C2C(C=CN2CC2C=CC=CC=2)=CC=1.C(N1C2C(=CC=CC=2)C(C(CC(C2C3C(=CC=CC=3)N(CC)C=2C)=O)C(O)=O)=C1C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH:22]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:26]=4)[O:20][C:19]3=[O:21])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(C(=O)O)c1cn(Cc2ccccc2)c2cc(F)ccc12)c1cn(Cc2ccccc2)c2cc(F)ccc12
Agent: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Agent: Fc1ccc2ccn(Cc3ccccc3)c2c1
Agent: O=C1C=CC(=O)O1
Product: O=C1OC(c2cn(Cc3ccccc3)c3cc(F)ccc23)=CC1c1cn(Cc2ccccc2)c2cc(F)ccc12

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis(6-fluoro-1-benzyl-3-indolyl)-4-oxobutanoic acid prepared by interaction of maleic anhydride and 6-fluoro-1-benzylindole by a procedure similar to that described in Example 3, part A is used in place of 2,4-bis-(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid, there is obtained 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-2(3H)-furanone (Formula II: R=C6H5CH2 ; R1 =H; Y=6-F).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]
Reactant: C1COCCN1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (8.25 mL, 46.4 mmol) was added at 0° C. to a stirred solution of morpholine (1.62 g, 18.5 mmol) in tetrahydrofuran (40 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (5.0 g, 19 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4-(4-bromo-3-methyl-benzenesulfonyl)-morpholine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO3S [M+] 320.2, obsd. 321.9.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29].N12CCN(CC1)CC2.Cl>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[O:18][C:28](=[S:29])[N:27]([CH3:31])[CH3:26])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-7f, in 6.3 ml of anhydrous DMF was added 578 mg of dimethylthiocarbamoylchloride and 1.5 g of 1,4-diazabicyclo[2.2.2]octane. The mixture was stirred overnight at room temperature. The mixture was poured into 30 ml of 1 N HCl and extracted three times with 30 ml portions of ethyl acetate. The organic fractions were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to 1.9 g of product; MS (+) m/z 425.27 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)CCC2
Temperature: 85 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A solution of 7-nitro-3,4-dihydro-1(2H)-naphthalenone (10.0 g, 52.3 mmol) in ethanol/water (4:1 mixture, 200 mL) was treated with iron (10.3 g), and ammonium chloride (1.1 g), stirred at 85° C. for 4 hours, and filtered. The filtrate was concentrated and the concentrate was dissolved in 400 mL of ethyl acetate, washed with brine (5×), dried (Na2SO4), filtered, and concentrated. The concentrate was treated with diethyl ether and filtered. The filter cake was washed with diethyl ether and dried under vacuum to provide 7.56 g of the desired product. The filtrate was concentrated to provide 0.39 g of additional product. MS (DCI) m/e 162 (M+H)+, 179 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:24])[CH:23]=[N:16][C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Cl:1])[N:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15]
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 95 °C

Procedure:
To a solution of 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid amide (2.40 g, 0.00907 mol) in Toluene (40 mL) was added 1,1-Dimethoxy-N,N-dimethylmethanamine (4.82 mL, 0.0363 mol). The flask was sealed and heated to 95° C. for 8 h. The reaction was deemed complete by TLC. The solvent was removed in vacuo to give 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide which was used crude. MS (ESI+) 320.1
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1cncc2[nH]c3ccc(Cl)cc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)cc2c1[nH]c1cncc(F)c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
Sodium nitrate (1.5 eq, 53 mmol, 4.5 g) was added portionwise to a solution of Intermediate 65 (1.0 eq, 35 mmol, 7.8 g) in trifluoroacetic acid (200 mL) and the resulting mixture heated at 70° C. for 3 h. After cooling to RT the trifluoroacetic acid was removed on a rotary evaporator to afford a crude solid which was suspended in a small volume of methanol and added dropwise to a vigorously stirred mixture of saturated sodium bicarbonate solution (500 mL). The resulting slurry was stirred for 15 min then the precipitated solids were collected by suction filtration, washed with water (300 mL) and then dried in vacuo to afford 6-chloro-4-fluoro-8-nitro-9H-β-carboline (about 9.5 g) which was used in the subsequent step without further purification. Retention Time (LC, method: ammonium acetate standard): 1.79 min. MS (M+H+): 266