Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Si:7]([O:14][CH2:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=O)[CH:19]=[CH:18][CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C1COCC1>[Si:7]([O:14][CH2:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:19]=[CH:18][CH:17]=1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a suspension of 420 mg of LiAlH4 in 20 mL of THF, the solution of 1.9 g of 3-[6-(t-butyldimethylsilanyl-oxymethyl)pyridin-2-yl]-1-morpholin-4-ylpropan-1-one in 30 mL of THF was added dropwise at ice temperature. After the reaction mixture was stirred at room temperature for 3 hours, the excess LiAlH4 was quenched with water, and the solution was filtrated through Hyflo Super-Cel (Nacalai Tesque) and partitioned. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by chromatography on silica gel (methylene chloride-ethanol 40:1) to give 760 mg of 4-{3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]propyl}morpholine.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]3[CH:19]=[CH:20][S:21][C:11]=23)[CH2:5][CH2:4]1>[Pd].CO>[F:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][N:13]=[C:12]3[CH:19]=[CH:20][S:21][C:11]=23)[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CF)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CF)CC1
Reaction time: 1 h

Procedure:
A mixture of N-[trans-4-(fluoromethyl)cyclohexyl]-6-nitrothieno[3,2-b]pyridin-7-amine (0.20 g, 0.65 mmol) and 10% palladium on carbon (0.07 g) in methanol (7 mL) was hydrogenated under balloon pressure of H2 at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated, diluted with dichloromethane, and then dried over MgSO4 and concentrated to give the desired product (0.11 g, 61%). LCMS calculated for C14H19FN3S (M+H)+: m/z=280.1. Found: 280.1.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13](=[O:20])[C:14]4[C:19]([C:10]=3[O:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22]NC.O1CCOCC1>>[CH3:22][N:8]=[C:7]([C:11]1[C:10](=[O:9])[C:19]2[C:14]([C:13](=[O:20])[C:12]=1[OH:21])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=O)c2c(-c3ccccc3)noc2-c2ccccc21
Reactant: CNC
Solvent: C1COCCO1
Product: CN=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
A solution of 3-phenyl-4,5-dihydronaphtho[2,1-d]-isoxazole-4,5-dione (500 mg) in 8 % dimethylamine-dioxane solution (100 ml) is irradiated by light of a high-pressure mercury lamp (1 KW) through a pyrex filter at room temperature (20- 30°C) in argon atmosphere for about 1.5 hours. After removal of the solvent, the residue is dissolved in methylene chloride, washed with water, dried with anhydrous sodium sulfate, and evaporated. The residue is washed with benzene to give 2-(N-methylbenzimidoyl)-3-hydroxy-1,4-naphthoquinone (158 mg), which is identical with the product of Example 16.
Reaction SMILES: [Li]CCCC.[CH:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl[Si:20]([CH:23]1[C:31]2[C:26](=[C:27]([CH3:33])[CH:28]=[C:29]([CH3:32])[CH:30]=2)[CH:25]=[C:24]1[CH3:34])([CH3:22])[CH3:21].[Li]>CCCCCC.CCOCC.C1COCC1.C1(C)C=CC=CC=1>[CH3:34][C:24]1[CH:23]([Si:20]([CH:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:18]2=[CH:6][CH:7]=[CH:8][CH:9]=3)([CH3:22])[CH3:21])[C:31]2[C:26]([CH:25]=1)=[C:27]([CH3:33])[CH:28]=[C:29]([CH3:32])[CH:30]=2
Reactant: CC1=Cc2c(C)cc(C)cc2C1[Si](C)(C)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2c(C)cc(C)cc2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 2.5 M n-BuLi solution in hexane (9.6 mL) was added dropwise at 0° C. under stirring to a solution of 3.78 g of fluorene in 40 ml of Et2O in a 100 mL Schlenk flask. After 30 min the resulting orange solution was allowed to warm up to room temperature and stirred for 3 days. A solution of chloro(2,4,6-trimethylindenyl)dimethylsilane (22.60 mmol) in 20 mL of THF was cooled to 0° C. and slowly added to the lithium salt solution, also previously cooled to 0° C. At the end of the addition a light brown suspension was obtained. The latter was allowed to warm up to room temperature and stirred for 24 h. Then the reaction mixture was evaporated under reduced pressure to give a brown sticky solid, which was treated at r.t. with 50 mL of toluene and then filtered to remove LiCl. The filtrate was dried in vacuo to give 8.54 g of a brown oil. The product was characterized by 1H-NMR spectroscopy: there are the signals of two isomeric species: allylic and vinylic (2:1). The product was used as such in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:20])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:20][C:13]1[C:12]([C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[C:17]([OH:18])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2-(2-chloro-6-methoxyphenyl)quinazoline (300 mg, 0.98 mmol) in 10 mL CH2Cl2 was added dropwise 5 equivalents of a 1 M BBr3 solution in CH2Cl2 at −78° C. The reaction was warmed to room temperature and was complete in 30 minutes. The reaction was quenched with a saturated aqueous NaHCO3 solution to pH 7. The aqueous layer was extracted with CH2Cl2, and the combined extracts were dried over Na2SO4, filtered, and concentrated to obtain 3-chloro-2-(4-chloroquinazolin-2-yl)phenol. LC/MS: m/z 291.3 (M+H)+ at 3.16 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][C:5]([CH2:10][Br:11])([CH2:8][Br:9])[CH2:6][OH:7].[CH2:12](Br)[CH:13]=[CH2:14]>>[Br:3][CH2:4][C:5]([CH2:10][Br:11])([CH2:8][Br:9])[CH2:6][O:7][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCC(CBr)(CBr)CBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOCC(CBr)(CBr)CBr
Temperature: 22 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Sodium hydride (1.67 g, 42 mmol) was added carefully to 3-bromo-2,2-bis(bromomethyl)propanol (9.75 g, 30 mmol) and allyl bromide (12.9 ml, 150 mmol) in dry and degassed DMF (40 ml) under nitrogen at 0° C. The temperature was then increased to room temperature (22° C.) and the reaction mixture was stirred for another 3 h. The reaction mixture was then carefully added to an aqueous saturated NH4Cl (50 ml). The H2O-phase was then extracted with diethyl ether (2×50 ml) and the combined organic phases were washed with H2O (5×50 ml) and then brine (50 ml). The organic phase was dried with Na2SO4 followed by filtration. The volatile materials were removed at reduced pressure to give a pale yellow oil (9.7 g). Column chromatography on silica (heptane:EtOAc 9:1) gave 6.6 g (62%) of the product as a clear oil. 1H-NMR (CDCl3); 5.93 (m, 1H), 5.28 (m, 2H), 4.05 (d, 2H), 3.58 (s, 6H), 3.52 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[C:6]#[N:7])([O-])=O.[OH2:22].NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[C:6]([NH2:7])=[O:22]
Reactant: O
Reactant: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: NC(=O)c1c(N)cccc1OCCOc1ccccc1
Yield: 50.2 %

Procedure:
The crystallized 2-nitro-6-(2-phenoxyethoxy)benzonitrile (5.82 g, 0.0205 mole) is stirred in 116 ml absolute ethanol at 50°C. and 3.62 ml (0.0615 mole) 85 percent hydrazine hydrate is added, followed by small scoops of Raney nickel. The temperature is kept at 50°-60°C. while the Raney nickel is added, and after gas evolution and the exotherm ceases, the mixture is filtered through diatomaceous earth. The filter cake is washed with hot ethanol and the filtrate is concentrated, giving 2.804 g of 2-amino-6-(2-phenoxyethoxy)benzamide m.p. 127°-150°C.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.CC([O-])(C)C.[K+].[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH:43]=O>C1COCC1>[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH:43]=[CH:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Yield: 90.8 %

Procedure:
To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (448 mg; CAS 473659-21-1) at r.t. in THF (7 ml) under an argon atmosphere were added potassium tert-butylate (109 mg) and 2-chlorobenzaldehyde (114 mg). The mixture (clear brown orange solution) was heated to 80° C. over night. The reaction mixture was cooled to r.t and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:2) to give 4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329 mg) as off-white solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:13][CH:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][NH:10][C@@H:9]1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:49]1([CH:55]2[CH2:59][CH2:58][NH:57][CH2:56]2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH:12]1[CH2:11][NH:10][C@H:9]([C:19]([N:57]2[CH2:58][CH2:59][CH:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:56]2)=[O:21])[C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]1
Reactant: COC(=O)CC1CN[C@H](C(=O)O)[C@@H](C(=O)OC(C)(C)C)C1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC1CN[C@H](C(=O)N2CCC(c3ccccc3)C2)[C@@H](C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 104.9 %

Procedure:
To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: (2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylic acid (50 mg, 0.166 mmol), anhydrous DMF (2 mL), BOP reagent (100 mg, 0.226 mmol), 3-phenyl-pyrrolidine (25 mg, 0.17 mmol), and N,N-diisopropyl ethylamine (0.086 mL, 0.49 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo to afford 75 mg of crude product that was used directly in the following hydrolysis. LCMS (ESI): 431 (M+H), 375 (M−t-Bu+2H+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:22](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:4]([C:5]2[O:6][CH:22]=[N:8][N:7]=2)[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[CH3:21]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc(I)ccc1Nc1c(-c2nnco2)ccc(F)c1F
Yield: 79 %

Procedure:
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt)3 was added along with approximately 3 mg of pTsOH> The reaction was heated to reflux for 3 h, cooled and concentration on a rotary evaporator. The reaction was purified (SiO2, 4:1 Hexane/EtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder. M.p. =144.4-145.5° C. 1H NMR (400 MHz, CDCl3) δ8.89 (s, 1H), 8.44 (s, 1H), 7.66 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1 H), 6.83 (m, 1H), 6.14 (dd, J=8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H).
Reaction SMILES: [CH:1]1[NH:2][C:3](=[O:12])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2.[CH3:13]I>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:13][N:2]1[C:3](=[O:12])[CH:4]=[C:5]2[C:10]([C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2)=[CH:1]1
Reactant: O=C1CCCc2cc(=O)[nH]cc21
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cn1cc2c(cc1=O)CCCC2=O

Procedure:
The novel intermediates of the present invention originate from a novel process which utilizes dihydro=resorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cyanoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarboni=trile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl, trialkylsilyl or cycloalkyl halide produces the corresponding 6-alkoxy, 6-trialkylsilyloxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetra=lone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. The reaction of the keto group of the latter tetralone with vinyl magnesium chloride results in 7-aza-6-methoxy-1-vinyl-1-tetralol, which is contacted with a 2-(lower alkyl)cyclopentane-1,3-dione, such as 2-methylcyclopentane-1,3-dione, in the presence of a basic catalyst such as triethylamine to afford 5,6,7,8-tetrahydro-3-methoxy-8-[(2-methyl-1,3-dioxocylopent-2-yl)ethylidene]isoquinoline. Alternatively, the tetralol is converted to the iso-thiouronium salt, which is reacted with the dione to afford the latter product. Cyclization of the latter diketone, suitably in the presence of p-toluenesulfonic acid, results in dl-2-aza-3-methoxyestra-1,3,5(10), 8,14-pentaen-17-one. Catalytic hydrogenation, using a palladium-on-calcium carbonate catalyst effects saturation of the 14-double bond, thus producing dl-2-aza-3-methoxyestra-1,3,5(10),8-tetraen-17-one, while chemical reduction, for example with sodium borohydride, converts the 17-keto group, thus yielding dl-2-aza-3-methoxyestra-1,3,5(10),8,14-pentaen-17β-ol. The 14-double bond of the latter substance is catalytically reduced, using a palladium-on-calcium carbonate catalyst, to yield dl-2-aza-3-methoxy=estra-1,3,5(10),8-tetraen-17β-ol, which is allowed to react with sodium in liquid ammonia to afford dl-2 -aza-3-methoxyestra-1,3,5(10)-trien-17β-ol.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[S:10][C:9]2[C:11]([CH2:15]O)=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1>ClCCl>[Cl:3][CH2:15][C:11]1[C:9]2[S:10][C:6]([CH3:5])=[CH:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc2cccc(CO)c2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2cccc(CCl)c2s1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Thionyl chloride (0.415 mL, 5.69 mmol) was added slowly to an ice cold solution of the alcohol (510) (0.203 g, 1.14 mmol) in dichloromethane (6.0 mL). The reaction mixture was stirred and warmed to room temperature for 1 h. The resulting solution was quenched slowly with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the intermediate 7-(chloromethyl)-2-methylbenzo[b]thiophene (511) (0.150 g, 67.0%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Br[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=2[S:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=1>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29][C:30]([CH3:32])([CH3:31])[CH3:33])(=[O:27])=[O:28])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Brc1ncc[nH]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 2-bromoimidazole (68.9 mg, 0.469 mmol; see step (a)) in DMSO (1 mL) and NaOH (32.8 mg, 0.82 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (173.6 mg, 0.391 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 99% yield as a colourless syrup (197.3 mg, 0.387 mmol).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Oc1cc(O)cc(C=Cc2ccccc2)c1
Temperature: 165 °C

Procedure:
For demethylation, a homogeneous mixture of 54.0 g (0.22 mol) of 3,5-dimethoxystilbene and 40.0 g (0.35 mol) of pyridine hydrochloride is heated at about 165° C. for 3 hours. The cooled, oily reaction mass is then introduced into 1.2 liters of 2N hydrochloric acid and the crude product is isolated by extraction with diethyl ether. Recrystallisation from toluene yields 3,5-dlihydroxystilbene in the form of a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([N:28]=[C:29]=[O:30])=[O:27].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:30]=[C:29]1[NH:28][C:26](=[O:27])[CH2:25][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:6][CH:7]=1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Reactant: O=C=NC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4CC(=O)NC4=O)cc3)n(CC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) was treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution was warmed to 60° C. overnight. The solution was cooled, and DBU (0.20 mL, 1.31 mmol) was added. This mixture was stirred at ambient temperature overnight, and then was partitioned between water and ethyl acetate (50 mL each). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was triturated with ether, and the resulting solid was collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 200 mmole) in dry THF (250 ml) was added to a solution of 4-fluorophenylmagnesium bromide in dry THF at 60° C. The mixture was allowed to warm to 25° C. and quenched with saturated NH4Cl solution and extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo. The residue was crystallized from hexane to give the product (89%, mp: 133°-135° C). Calc'd for C14H17FO3 : C, 66.66%; H, 6.80%. Found: C, 66.54%; H, 7.12%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:26][CH:27]=[N:28][CH:29]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)=[CH:19][N:20]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Product: COc1ncc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)cn1
Yield: 54 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 54% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.05 (s, 2H), 8.55 (s, 2 H), 7.98-8.11 (m, 1 H), 7.79-7.88 (m, 1 H), 7.70-7.77 (m, 1 H), 7.67 (d, J=7.58 Hz, 1 H), 7.41-7.57 (m, 4 H), 6.96 (br s, 2 H), 3.87 (s, 3 H); MS (ESI) m/z 395 [M+1]+.
Reaction SMILES: [OH:1][C:2]1([CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]2=[O:26])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[Cl-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[OH:1][C:2]1([CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]2=[O:26])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: COc1ccc2ncc(=O)n(CCC3(O)CCC4(CC3)OCCO4)c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCC3(O)CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
To 8 mL of a dioxane suspension containing 0.25 g of 1-(2-(8-hydroxy-1,4-dioxaspiro(4.5)decan-8-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was dividedly added at room temperature, and the mixture was stirred for 5 hours and 15 minutes. An aqueous saturated sodium hydrogen carbonate solution was added with the reaction mixture, and then added with ethyl acetate and sodium chloride. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 1:3] to obtain 0.10 g of a colorless oily substance, 1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxyquinoxalin-2(1H)-one.