Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])=[O:4].[CH3:14][C:15](C)=[CH:16]C(Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:15]1[CH:16]=[C:6]([C:7]([F:10])([F:9])[F:8])[O:5][C:3](=[O:4])[CH:2]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(F)F)oc(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trifluoroacetic anhydride (10.63 g, 50.61 mmol) and 3,3-dimethylacryloyl chloride (5.0 g, 42 mmol) in chloroform (85 mL) at 0° C. was added triethylamine (12.91 mL, 92.60 mmol). The resulting reaction mixture was stirred at same temperature for 1 h, then allowed to warm to room temperature overnight. The reaction solution was washed with water (2×), saturated sodium bicarbonate, water, and brine, and then dried over Na2SO4, filtered and concentrated. The crude residue was used in next step.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-(2,4-Difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) was dissolved in a mixture of anhydrous THF (20 ml) and anhydrous DMF (2 ml). CDI (0.18 g, 1.1 mmol) was added and the solution stirred at RT for 2 h. 3-Amino-1-propanol (0.16 g, 2.2 mmol) was then added and the solution stirred for a further 15 h. The solvent was removed under reduced pressure and the residue partitioned between 2% MeOH/EtOAc and water. The organic fraction was washed with water ×2, NaHCO3, brine, dried (Na2SO4) and concentrated to give crude 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide. Further purification by flash chromatography on silica gel (5% MeOH/CH2Cl2) afforded 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.12 g, 68%) as a cream solid; m.p. (EtOAc/Hexane) 129-132° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.84 (br s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.22 (s, 1H), 7.51-7.37 (m, 2H), 7.16-7.10 (m, 1H), 5.32 (d, J=1.1 Hz, 1H), 4.47 (t, J=4.9 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.27 (dd, J=12.7, 6.8 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 336 (100%). Anal. Calcd for C16H17F2N3O3.0.25 H2O: C, 56.2; H, 5.2; N, 12.3. Found C, 56.4; H, 5.3; N, 12.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.Cl.Cl.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][NH:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:24]3[CH2:29][CH2:28][C:27]4([C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][NH:30]4)[CH2:26][CH2:25]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNC21CCNCC1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)NCc1ccccc12
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution of 0.10 g (0.51 mmol) 6-chloro-1H-indole-3-carboxylic acid in 5 ml dichloromethane were added 0.074 ml (0.56 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. The reaction mixture was concentrated in vacuo after 1 h. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A suspension of 0.147 g (0.56 mmol) 2,3-dihydrospiro[isoindole-1,4′-piperidine]dihydrochloride and 0.285 ml (2.04 mmol) triethylamine in 2 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 16 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane/methanol) to give the title compound (0.045 g; 24%) as an off-white solid. MS m/e (%): 366 (M+H+, 100).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(O[C:9](=[O:11])[CH3:10])(=O)C.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:9](=[O:11])[CH3:10])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirring suspension of AlCl3 (144 g, 1.08 mol) in CH2Cl2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes. A solution of 1-benzenesulfonyl-2,3-dihydro-1H-indole (46.9 g, 0.18 mol) in CH2Cl2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum to yield 1-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone (42.6 g, 79
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].NN.[BH4-].[Na+]>CO>[CH:19]1([NH:18][N:6]2[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[CH:9][C:8]=3[N:17]=[C:5]2[CH2:4][O:3][CH2:1][CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NN
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.4 %

Procedure:
2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine (0.900 g, 3.71 mmol) was placed in a 50 mL round bottom flask, dissolved in 1,2-dichloromethane, and placed under N2. Cyclohexanone (1.19 mL, 11.5 mmol), acetic acid (0.45 mL, 7.79 mmol) and sodium triacetoxyborohydride (1.65 g, 7.79 mmol) were added and the reaction was stirred under N2 at room temperature for 5 days. The reaction was quenched by slow addition of saturated NaHCO3 solution (25 mL) and dichloromethane (25 mL). The mixture was transferred to a separatory funnel and the phases separated. The aqueous portion was extracted with dichloromethane (25 mL). The combined organic portions were washed sequentially with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and then concentrated to yield a thick brown oil. Analysis by liquid chromatography/mass spectroscopy (LC/MS) of the crude product showed it to be a mixture of the hydrazone and hydrazine. The oil was dissolved in methanol (25 mL), chilled in an ice water bath and then treated with sodium borohydride (1.25 g). The reaction was quenched with water (25 mL) and the mixture concentrated. The residue was partitioned between dichloromethane 50 mL) and water (15 mL), transferred to a separatory funnel, and the phases were separated. The organic portion was washed sequentially with saturated NaHCO3 solution (20 mL), water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and then concentrated to yield a thick brown oil. The material was purified by column chromatography (35 g SiO2, 97:3 chloroform:methanol) to yield 0.51 g of N-cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine as a light brown oil/solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43]>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9])[CH3:47]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc(F)cc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 1-bromo-4-fluoro-2-methyl-benzene (5.00 g, 26.45 mmol), palladium acetate (0.59 g, 2.64 mmol), tri-o-tolylphosphine (1.61 g, 5.29 mmol), DIPEA (13.8 mL, 79.35 mmol) and ethyl acrylate (3.34 mL, 105.80 mmol) in propionitrile (106 mL) is stirred at 90° C. under nitrogen overnight. The mixture is ed off through Celite and washed with ethyl acetate. The mixture is concentrated under reduced pressure, purified by flash chromatography by eluting with hexane:ethyl acetate 10:1 to afford the title compound (5.50 g, 99%). Rf=0.49 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.33 (t, 3H, J=7.3 Hz), 2.41 (s, 3H), 4.26 (q, 2H, J=7.3 Hz), 6.28 (d, 1H, J=16.0 Hz), 6.88-6.91 (m, 2H), 7.48-7.53 (m, 1H), 7.88 (d, 1H, J=15.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)(=[O:3])[CH3:2].C([O:18][N:19]=O)(C)(C)C.CC(C)([O-])C.Cl>C1COCC1.CCOC(C)=O.O>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[N:19][OH:18])=[N:9]1)([CH3:11])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1ccc(=O)n(C(C)C)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)C=NO)ccc1=O
Temperature: 0 °C

Procedure:
A mixture of 6-acetyl-2-isopropyl-3(2H)-pyridazinone (74.0 g) and t-butylnitrite (73.3 ml) in THF (740 ml) was stirred at 0° C. Pottasium t-butoxide (55.3 g) was added to the reaction mixture. Then the reaction mixture was stirred at 25° C. for 1 hour. Water, 1N HCl and EtOAc were added to the reaction mixture. The organic layer was washed with 1N HCl, aq. NaHCO3 and brine. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain (1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)(oxo)-acetaldehyde oxime (15.0 g) as white powder.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]2[CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=[CH:19][C:18]=3[O:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[CH3:30][O:29][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][CH:15]([CH2:14][C@H:11]3[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]4[CH:41]=[CH:42][C:36]5[O:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:31])[CH2:13][CH2:12]3)[CH2:28][C:27]2=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CO4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 4 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid as starting material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[C:28](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>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>[CH3:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 94 %

Procedure:
1,1-dimethylethyl 4-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 28) (2.59 g, 5.47 mmol), potassium carbonate (1.513 g, 10.94 mmol) in 1,4-dioxane (80 ml) were stirred for 5 min then trimethylboroxin (1.523 ml, 10.94 mmol) and Pd(PPh3)4 (0.632 g, 0.547 mmol) were added and the reaction mixture heated at 100° C. for 1.5 h. Further trimethylboroxin (0.5 mL) was added and the mixture heated at 100° C. for 30 min before allowing to cool overnight. The mixture was concentrated under vacuum then EtOAc (150 ml) added, washed with 200 ml of water, dried on a phase separation cartridge and evaporated under vacuum. The crude material (3.1 g) was purified via Biotage (40+M silica column) using a gradient EtOAc/1-hex from 10/90 to 30/70. Desired fractions were collected and concentrated under vacuum to give the title compound (2.1 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C([O-])(=O)C.[Na+].O.[CH2:14]([O:18][CH2:19][CH:20]=O)[CH2:15][CH:16]=[CH2:17]>C(O)C>[CH2:14]([O:18][CH2:19][CH:20]=[N:6][OH:7])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCOCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCCOCC=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Hydroxylamine sulfate (20.5 g), sodium acetate (12.8 g) and water (20 ml) were added to a solution of 3-butenyloxyacetaldehyde (17.8 g; J. Chem. Soc., Perkin Trans. 1, 1999, 3143-3155) in ethanol (200 ml). The mixture was stirred at room temperature overnight and then water was added. The excess of ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (6.20 g).
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:17](O)=[O:18].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.C(O)(=O)C>C1COCC1.O>[CH3:20][C:2]1([CH3:21])[CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6]2[C:17](=[O:18])[NH:1]1
Reactant: CC(C)(N)CCn1c(C(=O)O)cc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CCn2c(cc3ccc(C(=O)O)cc32)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
To a solution of the crude 1-(3-Amino-3-methylbutyl)-1H-indole-2,6-dicarboxylic acid from the preceding step in THF (9.0 mL) is added 1,1′-carbonyldiimidazole (162 mg, 0.90 mmol) followed by 1,8-diazabicyclo[5.4.0] undec-7-ene (0.14 mL, 0.90 mmol). The mixture is stirred at room temperature for 2 h. Acetic acid (0.3 mL) and water (50 mL) are added and the mixture is extracted with EtOAc. The organic layers are dried (Na2SO4) and concentrated. The crude compound is purified by flash column chromatography using 10% methanol in CH2Cl2 to afford the title compound (17 mg, 16% for three steps).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=2[C:7]([O:9]CC)=O)[CH2:3][CH2:2]1.ClS([N:23]=[C:24]=[O:25])(=O)=O.C([O-])(=O)C.[Na+].CC(C)([O-])C.[Na+]>ClCCl>[CH:1]1([N:4]2[C:5]3[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=3[C:7](=[O:9])[NH:23][C:24]2=[O:25])[CH2:2][CH2:3]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(F)c(SC)nc1NC1CC1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc2c(cc1F)c(=O)[nH]c(=O)n2C1CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
A solution of 4.1 g (15.2 mmol) of ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in 125 mL of dichloromethane is cooled to −20° C. and treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 3 hours and allowed to come to room temperature overnight. The mixture is recooled to −20° C. and treated with 6.8 g (80 mmol) of solid sodium acetate. After stirring for 1 hour without cooling, the solvent is removed in vacuo without heating. The residue is triturated with a saturated solution of sodium acetate in brine and extracted with ethyl acetate (3±75 mL). The combined organic layers are dried (MgSO4), filtered and evaporated in vacuo. The residue is suspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at room temperature for 36 hours. The solvent is removed in vacuo, the residue triturated with 100 mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give a residue which is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 0.75 g of the title compound, mp 220-222° C.
Reaction SMILES: C(O[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][N:5]=1)C.Cl.[CH3:15][NH2:16]>C(O)C>[ClH:13].[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][NH:5][C:4]2=[N:16][CH3:15])=[CH:8][CH:9]=1
Reactant: CN
Reactant: CCOC1=NCc2ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Product: CN=C1NCc2ccc(Cl)cc21
Yield: 148.4 %

Procedure:
A suspension of 110.5 g of 1-ethoxy-6-chloro-3H-isoindole and 41.9 g of methylamine hydrochloride in 1100 ml of ethanol was heated to boiling under reflux for 4 hours under argon, whereupon it was cooled to 2°, the separated crystals were filtered off under suction and recrystallized from ethanol. There are obtained 91.0 g of 6-chloro-1-(methylimino)isoindoline hydrochloride as white crystals with a m.p. of >250°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 165° C.; 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J=1.8 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.02 (s, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 4.06 (app. q, J=8.0 Hz, 1 H), 3.15 (t, J=8.1 Hz, 2 H), 1.99-1.74 (m, 2 H), 1.11-0.99 (m, 1 H), 0.94 (t, J=7.5 Hz, 3 H), 0.88-0.73 (m, 1 H), 0.57-0.46 (m, 2 H), 0.39-0.27 (m, 1 H); HRMS (CI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9604.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[C:11]([CH3:37])[N:12]=[CH:13][CH:14]=3)[C:9]2=[O:38])=CC=1>C(#N)C.C(OCC)(=O)C.O>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]2[C:15]3[C:10](=[C:11]([CH3:37])[N:12]=[CH:13][CH:14]=3)[C:9](=[O:38])[NH:8][C:17]=2[CH:18]=1
Reactant: COc1ccc(Cn2c(=O)c3c(C)nccc3c3ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc32)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccc2c1c(=O)[nH]c1cc(OC[C@@H](N)CC(C)C)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(4-methoxybenzyl)-4-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.192 mmol) (prepared as described in Example 49), in acetonitrile (5 mL) and water (5 mL) was added ceric ammonium nitrate (527 mg, 0.962 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to afford (S)-8-(2-amino-4-methylpentyloxy)-4-methylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.154 mmol, 80% yield) as an off-white solid. LC/MS (ESI) m/e 326.2 [(M+H)+, calcd for C19H24N3O2 326.2] LC/MS retention time (method C): tR=1.56 min. HPLC retention time (method A): tR=6.98 min; HPLC retention time (method B): tR=6.96 min. 1H NMR (400 MHz, CD3OD) δ ppm 6.32 (m, 1H), 8.44 (m, 2H), 7.13 (m, 1H), 6.94 (d, J=2.4 Hz, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 3.75 (m, 1H), 3.2 (s, 3H), 1.75 (m, 3H), 1.10 (m, 6H).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:14]1[CH2:15][N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(ON2C(=O)c3ccccc3C2=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (1.72 g, 10.541 mmol), di-tert-butyl 4-hydroxypyrazolidine-1,2-dicarboxylate 141 (Journal of Antibiotics, 1993, Vol 46, (12), 1866-1882, 1.52 g, 5.27 mmol) and triphenylphosphine (2.76 g, 10.54 mmol) in THF (50 mL) was added DIAD (2.24 mL, 11.59 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 142 (1.8 g, 79%) as a white foam.