Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[O:7])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13]([O:15][CH3:16])=[O:14])=[O:7])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: Nc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 85 °C
Yield: 67.4 %

Procedure:
Methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate (1.60 g, 5.14 mmol) and 4-aminophenyl boronic acid (1.07 g, 6.17 mmol) were combined in a dry flask under argon. Toluene (25 mL), EtOH (10 mL), and 3 M aqueous Na2CO3 (8.50 mL, 25 mmol) were added and resulting solution was degassed for 30 minutes by using a flow of argon. Then [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (419.9 mg, 0.51 mmol), was added and the resulting mixture was heated at 85° C. for 16 h. The mixture was cooled to rt, diluted with EtOAc, and passed through a Celite® pad. The solvent was removed by rotary evaporation. Water and EtOAc were added and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Flash 40M) using 29 to 33% ethyl acetate in hexane to afford methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (1.12 g, 67%). 1H NMR (400 MHz, CD2Cl2) δ 1.71-1.97 (m, 4H), 2.17 (m, 2M), 3.44 (m, 1H), 3.65 (s, 3H), 4.12 (m, 1H), 6.84 (m, 2H), 7.51 (m, 2H), 7.66 (m, 2H), 8.00 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:14]=[C:12]([C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][CH:10]=2)[S:13][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(C(N)=S)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(CCl)cs2)cc1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
To a solution of 1,3 dichloroacetone (0.84 g, 6.62 mmol) in toluene (5 ml) was added 4-methylthiobenzamide (0.50 g, 3.31 mmol) and the reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.49 g, 67%). The other derivatives were also prepared by the same general method.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:11].[Na+].C1OCCOCCOCCOCCOC1>C(#N)C>[C:1]1([O:7][C:8]([F:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [F-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)Oc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of phenylchloroformate in acetonitrile is charged sodium fluoride. To this mixture is charged the 15-crown-5(“15C5”) at ambient temperature. The reaction mixture is then heated to 40° C. for approximately 16 hrs. Reaction completion is monitored by gas chromatography (“G.C.”).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(Br)c1
Temperature: 75 °C
Yield: 85.3 %

Procedure:
3-Bromophenol (20.4 g, 118 mmol) dissolved in dry N,N-dimethylformamide was carefully treated with sodium hydride (4 g, 167 mmol). t-Butylbromoacetate (23 g, 118 mmol) was added and the mixture heated to 75° C. for 90 minutes. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated ammonium acetate and concentrated in vacuo to yield 28.9 g of tert-butyl(3-bromophenoxy)acetate.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:33].C([SiH2][O:39][C:40](C)(C)[C:41]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[CH:43][C:42]=1[N:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[C:61]([CH:66]3[CH2:68][CH2:67]3)[CH:62]=2)[C:57]1=[O:69])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O.ClCCl>CN(C=O)C.O1CCOCC1>[CH:66]1([C:61]2[CH:62]=[C:63]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:69])[N:56]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]6)=[O:25])=[CH:20][N:19]=5)[C:3](=[O:33])[N:2]([CH3:1])[CH:7]=4)[C:41]=2[CH2:40][OH:39])[CH:65]=[CH:64]3)[CH2:68][CH2:67]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Reactant: CN1CCN(C(=O)c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3cc(-c4cccc(-n5ccc6cc(C7CC7)ccc6c5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (104 mg, 0.256 mmol), 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (124 mg, 0.233 mmol), 2 mL dioxane, 200 μL DMF, and a 0.86 mg/μL solution of cesium carbonate in water (450 μL, 1.2 mmol) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged mixture with nitrogen for 5 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (10 mg, 0.012 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature and filtered the reaction mixture through a 300 mg C18 cartridge. Washed the cartridge with 4 mL EtOAc, 4 mL water, and 4 mL EtOAc. Separated filtrate phases and washed the organic phase with 5 mL of water and 5 mL of brine. Dried the solution over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one as an off-white solid. (80 mg, 0.13 mmol). MS (ESI) 617 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCC(F)(F)F)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.11 g) as a light yellow solid (0.1 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
4-Chloro-7-methylquinoline-2-carbonitrile (1-5, 2.47 g, 12.2 mmol, 1.0 equiv.), 4-fluorophenylboronic acid (2.05 g, 14.63 mmol, 1.2 equiv.), Pd(PPh3)4 (0.7 g, 0.61 mmol, 0.05 equiv), and 1M aqueous Na2CO3 (12.2 ml, 2.39 mmol) was added into 1,4-dioxane (40 mL). The mixture was degassed and stirred at 100° C. for 16 hours, until disappearance of the starting material. The mixture was cooled, saturated aqueous sodium hydrogen carbonate (2 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was treated with 50 ml of MeOH, stirred vigorously at rt for 1 h, the mixture was filtered and washed with MeOH. The solid was collected and dried under vacuum. The filtrate was concentrated and retreated with MeOH to get a second crop of white solid that was combined to the first to give 2.75 g of 4-(4-fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6). LRMS m/z (M+H)+ 263.3 found, 263.3 required.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[CH:17][C:16]=3[CH3:31])=[C:11]([CH3:32])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.C>CN(C=O)C.[Pt]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:10][C:11]=3[CH3:32])=[C:16]([CH3:31])[CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1-c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Pt]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(N)cc2)ccc1-c1ccc(Oc2ccc(N)cc2)cc1C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
4,4'-Bis(4-nitrophenoxy)-2,2'-dimethylbiphenyl (80 g) was dissolved in 350 ml of DMF and added carefully to a hydrogenation bottle containing 8 gm of 5% Pt/C. The solution was subjected to hydrogenation at 100° C. for 3 hours. Then 100 ml of water and 3 g of decolorizihg charcoal were added and heated for 5 min. The solution was then filtered through a Celite pad and 1000 ml of water was added. The reaction mixture became a mixture of fluffy solid and a sticky resin and was stirred for 1 hour to give a tan colored solid. The solid was removed by filtration, crushed with a mortar and pestel and then stirred with 1000 ml of water for 1 hour. The solid was collected by filtration and dried to afford 59.2 g (85%) of the product mp=140° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:43]C1C=C(C=CC=1)C(O)=O>>[Cl:43][C:38]1[CH:42]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:32](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:11][CH2:12][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:9]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:33]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: O=C(O)c1cccc(Cl)c1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(Cl)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 37.4 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-chlorobenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-chloro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (37.4% yield). MS m/z=567.4 [M+H], calc 567.12 for C30H39ClN6O3.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:21][C:22](=[O:24])[CH3:23])=[CH:15][C:16]=3[CH3:20])[O:11][CH:10]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:21][C:22](=[O:24])[CH3:23])=[CH:15][C:16]=3[CH3:20])[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)cc(C)c3c2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C2COc3cc(OC(C)=O)cc(C)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
Palladium on barium sulfate (5%, 0.06 g) was added to a solution of 4′,7-diacetoxy-5-methylisoflavone (0.30 g, 0.8 mmol) in ethyl acetate (50 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 h. The catalyst was removed by filtration through Celite and the resulting filtrate was evaporated in vacuo. The residue was recrystallised from ethanol to yield 4′,7-diacetoxy-5-methylisoflavan-4-one (0.20 g, 67%) as colourless plates. m.p. 143-45° C., 1H NMR (CDCl3): δ 2.29 (s, 3H, OCOCH3), 2.30 (s, 3H, OCOCH3), 2.62 (s, 3H, Me), 3.95 (t, 1H, J 7.2 Hz, H3), 4.62 (d, 2H, J 6.8 Hz, H2), 6.59 (d, 1H, J 2.2 Hz, H8), 6.66 (d, 1H, J 2.2 Hz, H5), 7.07 (d, 2H, J 8.3 Hz, ArH), 7.28 (d, 2H, J 8.3 Hz, ArH).
Reaction SMILES: [CH2:1]=[C:2]1[C:15](=[CH2:16])[CH:14]2[O:17][CH:3]1[C:4]1[CH2:5][CH:6]3[CH:11]([CH2:12][C:13]=12)[C:10](=O)[CH:9]=[CH:8][CH:7]3[O:19]S(C)(=O)=O>O1CCCC1>[CH2:16]=[C:15]1[C:2](=[CH2:1])[CH:3]2[O:17][CH:14]1[C:13]1[CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([OH:19])[C:6]=3[CH2:5][C:4]=12
Reactant: C=C1C(=C)C2OC1C1=C2CC2C(OS(C)(=O)=O)C=CC(=O)C2C1
Solvent: C1CCOC1
Product: C=C1C(=C)C2OC1C1=C2Cc2c(O)cccc2C1

Procedure:
876 mg of potassium tert.butylate were added under a nitrogen atmosphere to a solution of 2.37 g of 1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-mesyloxyanthracen-5-one in 40 ml of tetrahydrofuran, there being formed 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracen-5-ol. After stirring at room temperature for 1 hour, a further 877 mg of potassium tert.butylate were added. The mixture was stirred for a further 45 minutes, 1.32 ml of methyl iodide were added and the resulting mixture was stirred for a further 1 hour. The mixture was treated with 100 ml of aqueous ammonium chloride and extracted three times with 100 ml of diethyl ether each time. After washing with three 100 ml portions of ammonium chloride solution, the combined organic phases were dried over magnesium sulphate. There were obtained 1.56 g (87%) of crude 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene of melting point 145°-147° C. (from methanol).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1SC#N)CCN2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc2c(cc1SC#N)CCN2S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared in Example JJ; 4.5 g, 19 mmol) was taken in CH2Cl2 (50 mL) and treated with 4-cyanophenylsulfonyl chloride (3.91 g, 19.4 mmol) and pyridine (5 mL). The reaction mixture was stirred overnight, quenched with saturated NaHCO3 solution, and diluted with EtOAc. The organic layer was separated, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography (20%-75% EtOAc in hexanes as eluents). MS(APCI): 397 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][Mg]Cl)=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:21]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]([NH:13][CH3:12])=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At 0° C., (4-methoxybenzyl)magnesium chloride (0.25 M in THF) (37 ml, 9.3 mmol) was added to 2-methylisoindoline-1,3-dione (1.00 g, 6.2 mmol) in THF (3.0 mL) (Reference: Synthetic Comm. 2004, 34 (7), 1301-1308). The mixture was stirred at 0° C. for 5 minutes, then quenched with 10 mL of water. The reaction was warmed to RT and concentrated to yield 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide as a white solid (crude). The material was carried on to next step without further purification. MS m/z=284 [M+1]+. Calc'd for C17H17NO3: 283.33.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:39]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]([CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[O:24])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:8][C:7]=2[CH:39]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCOC(=O)C3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc(OCCOC(=O)C2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 48 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(cyclohexanoyloxyethoxy)phenyl]methanone (1.25 g, 2.3 mmol) was converted to the title compound by the procedure of Example 3 using 400 mg (7.0 mmol) of ethanethiol and 920 mg (7.00 mmol) of aluminum chloride (0.92 g, 7.00 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][NH:38][CH2:39]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][N:38]([C:8](=[O:10])/[CH:7]=[CH:6]/[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:39]2
Reactant: O=C(O)/C=C/c1cccs1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)/C=C/c3cccs3)CC21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a solution of (E)-3-(2-thienyl)-2-propenoic acid (200 mg, 1.08 mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (225 mg, 1.47 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg, 1.71 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 7 d and then concentrated in vacuao. Attempted partition between water (15 ml) and ethyl acetate (20 ml) produced a buff solid which was collected by filtration. Sonication for 5 min at room temperature in dichloromethane (5 ml) followed by filtration afforded the title compound as an off-white solid (337 mg, 77%).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1[C:10]1[CH:11]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:13]=[N:14][CH:15]=1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:3]1[C:2]([C:10]2[CH:11]=[C:12]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:13]=[N:14][CH:15]=2)=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: CC(C)(O)c1cncc(-c2cc3ccccn3n2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(O)c1cncc(-c2nn3ccccc3c2Cl)c1

Procedure:
A solution of the title compound from Example 2 Step A (0.099 g, 0.391 mmol) and N-chlorosuccinimide (0.063 g, 0.469 mmol) in acetonitrile (1.95 ml) was stirred at room temperature for 2 hours. The reaction was then concentrated under reduced pressure, diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1)[CH:2]=[CH2:3].O.C([O-])(O)=[O:39].[Na+].OO>C1COCC1>[OH:39][CH2:3][CH2:2][CH2:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1
Reactant: C=CC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 39.2 %

Procedure:
Compound 37 (0.74 g, 2 mmol) was treated with BH3Me2S (0.388 g, 5.12 mmol) in THF (10 ml). The reaction mixture was quenched with MeOH (0.7 mL). H2O (3 mL) and NaHCO3 (1.11 g, 13.3 mmol) were added to the reaction mixture followed by H2O2 (30%, 1.91 mL, 16.92 mmol). After work-up, the residue was purified by silica gel chromatography. The product was crystallized from ether/hexane to furnish 0.41 g of the product as white needles. mp 150-151° C.