Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([O:21][CH2:22]C)(=[O:20])C>N1C=CC=CC=1.[Cu-]=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:18]([O:21][CH3:22])=[O:20])=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Br)cc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccc(C)cc2)c2ccccc12

Procedure:
The title A indole (819 mg, 4.67 mmol, 1.0 eq.) and 4-bromotoluene (1.44 ml, 11.69 mmol, 2.5 eq.) were dissolved in pyridine (4.7 ml, 1M) in an argon atmosphere. Copper(I) oxide (668 mg, 4.67 mmol, 1.0 eq.) was added and heated at 130°±5° C. for 8.5 hours. Ethyl acetate was added and the solid was removed by filtration through celite. The filtrate was washed with water (3×40 ml), 0.5N hydrochloric acid (2×50 ml) and saturated sodium hydrogen carbonate solution (40 ml), dried over anhydrous magnesium sulfate and freed of solvent in vacuo. The remaining brown oil was chromatographed on silica gel, eluting with 10% ether in hexane to give the title B compound (1.165 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.O>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Reactant: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-n3ccnc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-methylsulfonylpyrazolo[3,4-d]pyrimidin-4-one (3.1 g, 0.01 mol) and imidazole (2.1 g, 0.03 mol) was heated at 165°-175° C. for 3.5 hours. The mixture was cooled to room temperature and water (25 ml), followed by acetic acid (3 ml) were added. A precipitate was obtained which was collected by filtration and washed with water. The product was recrystallized from ethanol/ether to afford 2.4 g (81%) of 1-cyclopentyl-3-ethyl-6-(1-imidazolyl)pyrazolo[3,4-d]pyrimidin-4-one as white crystals, m.p. 228°-230° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Reaction time: 4 h
Yield: 15.6 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 4-fluorobenzylamine (56 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(4-fluorobenzyl) pyrimidine-5-formamide (30 mg, 16% yield).
Reaction SMILES: [CH3:1][C:2](=[O:8])[C:3](=O)[C:4](=O)[CH3:5].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].C(#[N:19])C>>[CH3:5][C:4]1[NH:19][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:16][C:3]=1[C:2](=[O:8])[CH3:1]
Reactant: CC(=O)C(=O)C(C)=O
Reactant: NCc1ccccn1
Reactant: CC#N
Product: CC(=O)c1nc(-c2ccccn2)[nH]c1C

Procedure:
A mixture of 6.5 g of 2,3,4-pentanetrione, 3-oxime and 6.0 g of 2-pyridylmethylamine in 125 ml of acetonitrile was reacted as described in Example 1, giving 3.6 g of the desired compound, mp 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1.[C:22]([C:29]1[NH:30][CH:31]=[CH:32]N=1)([C:24]1NC=CN=1)=O.[N-:34]1C=C[N:36]=[CH:35]1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:19]2[O:21][N:36]=[C:35]([C:24]3[CH:22]=[CH:29][N:30]=[CH:31][CH:32]=3)[N:34]=2)=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC1=c2c(cc3c(c2C)N=c2ccccc2=3)N=C1C(=O)O
Reactant: c1c[n-]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=c2c(cc3c(c2C)N=c2ccccc2=3)N=C1c1nc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,4-Dimethylpyrrolo[3,2-b]carbazole-2-carboxylic acid (0.556 g, 2 mmol), (prepared as described in WO93/01512) and carbonyl diimidazole (0.37 g, 2.2 mmol) were dissolved in freshly distilled tetrahydrofuran (10 ml) in an oven-dried flask under a nitrogen atmosphere. The resulting orange solution was stirred at room temperature for 2 hours, by which time it was an orange suspension, and complete conversion of the acid to the imidazolide intermediate was verified by TLC. Meanwhile, in a second oven-dried flask, 4-pyridylamidoxime (0.557 g, 4.1 mmol) was dissolved in THF (20 ml). To this was added crushed 3 Å sieves (0.66 g) and the mixture was stirred at room temp for 1 hour. Sodium hydride (60% dispersion in mineral oil, 0.161 g, 4 mmol) was added and the mixture stirred for a further 1 hour. The contents of the two flasks were combined and stirred at room temp for 18 hours, by which time TLC showed complete consumption of the imidazolide intermediate. The yellow precipitate which had formed was filtered off and taken up into hot DMSO. This was filtered and water was added. On cooling, yellow crystals of the title compound formed, were filtered off and dried (vacuum oven/85° C.) (0.265 g, 35%) m.p. >300° C. (decomp.) (Found: C, 71.37; H, 4.49; N, 17.94. C23H17N5O.0.4H2O requires: C, 71.45; H, 4.64; N, 18.11%); δH [2H6 ]-DMSO 11.85 (1H, s, 1-NH), 10.70 (1H, s, 5-NH), 8.17 and 8.05 (4H, AB quart, J 5.5, pyridine), 8.13 (1H, d, J 7.5, 9-H), 7.95 (1H, s, 10-H), 7.48-7.32 (2H, m, 6-H, 7-H), 7.10 (1H, ddd, J 7.5, 5.5, 2, 8-H), 3.08 and 2.95 (2×3H, 2×s, 3-CH3 and 4-CH3); m/z (%) 379 (5, M+), 259 (42), 224 (61), 193 (100); νmax (KBr disc)/cm-1 3439, 3244, 1610, 1500, 1414, 1371, 1311, 1242.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.C([O-])(O)=O.[Na+]>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2n1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
DIPEA (0.21 mL, 1.2 mmol) was added to a solution of 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (268 mg, 0.815 mmol)) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (204 mg, 0.896 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with sat. aq. NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash silica gel chromatography (used DCM as loading solvent, eluted with Et2O/hexanes, gradient from 10% to 30% Et2O) to yield (1R,3S,5R)-3-(2-(6-bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (332 mg) as white solid. LC-MS retention time 4.283 min; m/z 476.88 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)C.CO.O.O[Li].O>C1COCC1>[C:15]1([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:21])=[CH:9][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred solution of 4-phenylamino-benzoic acid (3.0 g, 0.01401 mol) in DMF (10 mL), was added DIPEA (5.4 g, 0.04205 mol), HOBt (2.27 g, 0.01682 mol) and EDCI.HCl (6.69 g, 0.03504 mol) at ambient temperature. After 2 minutes amino-acetic acid ethyl ester hydrochloride (2.33 g, 0.01682 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration, washed with water followed by hexane and dried to afford 4 g (95%) of (4-phenylamino-benzoylamino)-acetic acid ethyl ester. To a stirred solution (4-phenylamino-benzoylamino)-acetic acid ethyl ester (4 g, 0.01337 mol) in a mixture of THF (15 mL), methanol (15 mL) and H2O (8 mL) was added LiOH.H2O (2.24 g, 0.0535 mol). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated. The residue was diluted with water and acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 3.3 g (91%) of (4-phenylamino-benzoylamino)-acetic acid.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.CCN(CC)CC.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][NH:29][CH2:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: C=C1Sc2ccccc2NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 2-methylene-4H-benzo[1,4]thiazin-3-one (5.14 mmol) in 10 mL of anhydrous DMF, Et3N (25.7 mmol) is added followed by O-benzylhydroxylamine hydrochloride (25.7 mmol). The mixture is stirred at 100° C. for 12 hours and then the solvent is evaporated. The crude is purified by column chromatography (hexane/EtOAc) to give 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one. Yield 58%. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.13 (m, 9H), 6.1 (bs, 1H), 4.64 (s, 2H), 3.86 (m, 1H), 3.3 (m, 1H), 2.9 (m, 1H). MS: (ES+): 301.2 [M+1].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[C:13]([F:16])([F:15])[F:14])[CH2:20]1
Reactant: CN(C)C1CCNC1
Reactant: COC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2CCC(N(C)C)C2)c(C(F)(F)F)c1
Yield: 59.6 %

Procedure:
A reactor is charged with 1.2 g (4.06 mmol) of the compound obtained in step 2, 0.55 g (4.88 mmol) of 3-dimethylaminopyrrolidine, 2.8 g (20.3 mmol) of potassium carbonate and 25 ml acetone. The mixture is heated for 6 hours at reflux. The solvent is evaporated under reduced pressure and 100 ml of water is then added. The obtained solution is extracted with 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and then evaporated under reduced pressure to give the expected product (0.8 g, 61%),
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:17][CH3:18])[C:6]=2[CH2:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:7]1[C:6]2[CH2:5][NH:4][CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:18]
Reactant: CCn1c2c(c3ccccc31)CCN(C(C)=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCn1c2c(c3ccccc31)CCNC2

Procedure:
A portion of the crude 2-acetyl-9-ethyl-1,2,3,4-tetrahydro-β-carboline (1.7 was heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water (2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-ethyl-1,2,3,4-tetrahydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-ethyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)cc1Sc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (i) (0.24 g), lithium hydroxide (0.036 g) in methanol (30 ml) and water (5 ml) was stirred at RT overnight then acidified with 2M hydrochloric acid. The mixture was extracted with ethylacetate, the organics dried and evaporated under reduced pressure, yield 0.23 g
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][OH:14])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:4]1(=[O:27])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane (6.75 g, 14.5 mM), dry dichloromethane (25 mL) and dry pyridine (10 mL), a solution of methanesulfonyl chloride (1.7 g) in dichloromethane (25 mL) is slowly added with stirring. The reaction mixture is kept at room temperature overnight, additional dichloromethane is added, and the reaction mixture is washed with 1N HCl (twice) and then washed with brine (twice). The resulting solution is dried (Na2SO4) and the solvent evaporated to yield an oil. Upon scratching this oil with eher/petroleum ether, the compound 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-methanesulfonyloxy-4-aza-octane is obtained as white crystals: 7.64 g (97%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C>CO.[OH-].[Na+]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:20])=[O:3])=[CH:17][CH:16]=1
Reactant: CCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(Sc1ccc(OC)cc1)C(=O)O

Procedure:
2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4-methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5].[Cl:24][CH2:25][C:26](Cl)=O>C(O)(=O)C>[C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:23])[N:1]=[C:26]1[CH2:25][Cl:24]
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1-c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Yield: 60.9 %

Procedure:
Prepared according to Procedure B with 1i (2.0 g, 6.20 mmol) and chloroacetyl chloride (1.5 mL, 18.6 mmol) in acetic acid (30 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 1.44 g of an off-white solid (61%). 1H NMR (CDCl3) δ: 7.61-7.64 (m, 1H); 7.58-7.59 (m, 1H); 7.54-7.57 (m, 2H); 7.52-7.53 (m, 1H); 7.45-7.52 (m, 2H); 7.24 (s, 5H); 3.92-4.03 (m, 2H). MS (ES): m/z 381.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Nc1cccc(B(O)O)c1
Product: COc1cc(Nc2cncc(-c3cccc(N)c3)n2)cc(OC)c1OC
Yield: 38.6 %

Procedure:
Using Method C with 1.0 g (3.4 mmol) 2a and 635 mg (4.1 mmol) 3-aminophenyl boronic acid, 463 mg pure title compound were obtained. The filtrate was submitted to purification by preparative HPLC (eluent:AcOEt) and another fraction of 412 mg was obtained. A total of 875 mg CJS 364 (72.9%) were obtained. Reaction time: 28 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.64 (s, 3H, CH3O(4′)), 3.81 (s, 6H, CH3O(3′+5′)), 5.19 (s, 2H, NH2), 6.66 (d, 1H, Harom 4′, J=7.70), 7.13 (t, 1H, Harom 5′, J=7.77), 7.22 (d, 1H, Harom 6′), 7.26 (s, 2H, Harom(2+6)), 7.29 (s, 1H, Harom 2′), 8.11 (s, 1H, HP5), 8.33 (s, 1H, HP3), 9.51 (s, 1H, NHamine);
Reaction SMILES: [CH3:1][C:2](=[CH2:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[OH-:22].[Na+].[C:24](#[N:26])[CH3:25]>C(O)(=O)C.O>[N:11]1([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([NH:26][C:24](=[O:22])[CH3:25])([CH3:1])[CH3:16])=[CH:10][CH:9]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: C=C(C)COc1ccc(-n2ccnc2)cc1
Reactant: CC#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC(C)(C)COc1ccc(-n2ccnc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 27 g (0.126 mol) of 1-[4-(2-methyl-2-propenyloxy)phenyl]-1H-imidazole in a solution of 78 mL of glacial acetic acid and 29 mL of acetonitrile. Cool this solution to 0° C. over an ice bath and add 29.0 mL of 95% sulfuric acid dropwise at a rate to keep temperature below 15° C. Upon completionof the addition, stir overnight at room temperature. After this time, make basic (pH=12-14) with 4 N sodium hydroxide. Dilute with 400 mL of water and extract with 3×400 mL of diethyl ether. Concentrate the combinedether extracts to 350 mL on the rotary evaporator and cool in the refrigerator for 1 h. Filter off the resulting precipitate to provide the title compound.
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][N:7]([CH3:17])[CH2:8][C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=32)=[N:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.S1(CCCC1)(=O)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]3[C:2]([N:18]4[CH2:23][CH2:22][C:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20][CH2:19]4)=[N:3][N:4]=[C:5]3[CH2:6][N:7]([CH3:17])[CH2:8][C:9]=2[CH:15]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: CN1Cc2cc(Cl)ccc2-n2c(Br)nnc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 14.3 %

Procedure:
A mixture of 1-bromo-8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene (50 mg, 0.16 mmol), tetrabutylammonium bromide (10 mg, 0.031 mmol) and 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (65 mg, 0.32 mmol) in sulfolane (0.5 ml) was stirred for 20 h at 160° C. The reaction mixture was poured on water and extracted with tert-butyl methyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Residual sulfolane was evaporated by kugelrohrdistillation (120° C., 1-2 mbar). Preparative HPLC with n-heptane/2-propanol (70:30) as eluent gave the title compound (10 mg, 14%) as light yellow solid. MS m/e: 436 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
To a solution of Example 154 (0.085 g, 0.218 mmol) in methanol (1.4 ml), lithium hydroxide (0.026 g, 1.09 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under to afford the title compound as a yellow solid (0.034 g, 38%). M.P.: >270° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (d, J=2.7 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (d, J=7.1 Hz, 1H), 7.82 (t, J=8.9 Hz, 2H), 7.52 (q, J=4.1 Hz, 1H), 6.10 (s, 2H), 4.48 (s, 2H). MS (m/z): 385.87 (M+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.O.CN([CH:21]=[O:22])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[O:16][CH2:15][O:14][C:11]2=[CH:12][C:13]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)OCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1C=O)OCO2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of phosphorous oxychloride (3.00 mL, 0.033 mol) in DMF (10 mL) was added a solution of 1-methoxy-3,4-methylenedioxybenzene (2.00 g, 0.013 mol) in DMF (2 mL) at 0° C. After stirring at 60° C. for 18 h the mixture was cooled to 0° C. and then poured into water (500 mL). The precipitate was filtered and dried. The title compound was collected as a yellow solid (2.20 g, 92%): 1H NMR (250 MHz, CDCl3) δ 10.22 (s, 1H), 7.20 (s, 1H), 6.52 (s, 1H), 5.98 (s, 2H), 3.85 (s, 3H); mp: 110°l C.