Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:36][CH3:37])[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:36]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:37]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 64.4 %

Procedure:
A mixture of 0.33 g (1.70 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.61 g (1.70 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 535 mg of N-ethyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-benzenesulfonamide as a yellow solid (yield 64.4%).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([CH2:16][C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[C:28](C1C2C=C(F)C=C(F)C=2C(=O)OC=1N[C@@H](C1CCC1)C1C=CC=C(F)C=1)(=[O:30])[CH3:29].C1([C@H](NC(C2C3C=C(F)C=C(F)C=3C(=O)OC=2C)=O)C2C=CC=C(F)C=2)CCC1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O1CCCC1>[CH:1]1([C@H:5]([NH:13][C:14]([CH:16]([C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])[C:28](=[O:30])[CH3:29])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1cc(F)cc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CCC1
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CCC2)oc(=O)c2c(F)cc(F)cc12
Agent: Cc1oc(=O)c2c(F)cc(F)cc2c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cc(F)cc(F)c1C(=O)O
Reaction time: 0.5 h
Yield: 42 %

Procedure:
2-({[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4,6-difluoro-benzoic acid (3.4 g, 9.0 mmol in acetic anhydride (60 mL) was stirred at 100° C. overnight then evaporated and co-evaporated with toluene twice in vacuo to give a mixture of 4-acetyl-3-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amino}-6,8-difluoro-2-benzopyran-1-one and 6,8-difluoro-3-methyl-1-oxo-1H-2-benzopyran-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide. The obtained residue was dissolved in tetrahydrofuran (15 mL), allowed to cool on an ice-water bath and 2M aqueous NaOH (18 mL) was added. The cold bath removed and the reaction mixture was stirred for 30 min. The obtained mixture was diluted with water (20 mL) and extracted with isopropyl acetate (40 mL) which was washed with water (40 mL). The combined aqueous phase was cooled on ice bath and the pH was adjusted to 1 with conc. HCl. The title product was separated by extraction with isopropylacetate (2×40 mL) and purified by flash chromatography (50 g SiO2, the product was eluted with 1:1 ethyl acetate-heptane, 1.58 g, yield 42%). LC-MS (m/z) 420.6 (MH+); tR=1.35.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl.O>[N:28]([CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[N+:29]=[N-:30]
Reactant: OCc1cccc(Oc2ncccn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCc1cccc(Oc2ncccn2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
To a mixture of 3-(pyrimidin-2-yloxy)-phenyl-methanol (500 mg, 2.47 mmol) and triethylamine (625 μL, 4.5 mmol) in dichloromethane (40 mL) was added MsCl (2.33 uL, 3.0 mmol) at 0° C. The reaction was kept at 0° C. for 15 min. Removal of the solvent, the residue was dissolved in N,N-dimethylformamide (30 mL) and then treated with sodium azide (803 mg, 12.4 mmol). The reaction mixture was heated at 80° C. for 4 hr. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (2:1) to give the title compound (483 mg, 86%). MS (DCI/NH3) m/z 228 (M+1)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.49 (s, 2H) 7.19 (dd, J=8.11, 2.18 Hz, 1H) 7.21 (t, J=1.87 Hz, 1H) 7.26 (d, J=7.18 Hz, 1H) 7.27 (t, J=4.68 Hz, 1H) 7.47 (t, J=7.80 Hz, 1H) 8.64 (s, 1H) 8.65 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:24][CH2:25][C:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CN1C(=O)CCC1.C(OCC)(=O)C>O>[NH2:32][C:26]1([CH2:25][NH:24][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Reactant: NCC1(N)CCCCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1NCC1(N)CCCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (150 mg), 1-(aminomethyl)cyclohexaneamine (163 mg) and NMP (1 mL) was heated at 180° C. for 20 minutes using a microwave reaction system. The reaction liquid was cooled, and ethyl acetate and water were added and stirred for 30 minutes. Thereafter, the precipitated powder was collected by filtration. This powder was heated with ethanol-water (1:1) and washed to give 5-{[(1-aminocyclohexyl)methyl]amino}-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (112 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-Benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (365 mg, 0.97 mmol) was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (328 mg) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CNN(CC)NC>O1CCCC1.CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN(NC)NC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hrs, then heated at 60°-65° C. for 2 hrs. N,N-Dimethylaminoethylamine (1.06 g, 0.012 mole) was added and the reaction mixture was allowed to stir at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum overnight. The solid was treated with ice water, collected by filtration, washed with water, and dried under high vacuum at 50° overnight. The solid was dissolved in acetone and acidified with ethanolic hydrogen chloride. The crystalline precipitate was collected by filtration, washed with cold acetone, and dried under high vacuum to give 3.61 g. The solid was dissolved in 1.2 liters of acetone and concentrated to 600 ml to initiate crystallization. The solid was collected by filtration, washed with acetone, and dried under high vacuum overnight at 50° C. to give 1.9 g of title compound, mp 120°-122° C.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[F:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([F:27])[C:17]=1C(O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[C:17]1[C:16]([F:15])=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=1[F:27])([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)OC(C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
N,N-dimethylformamide di-tert-butyl acetal (75 ml, 0.31 mol) in toluene (60 ml) was added dropwise over 1.5 hours to 2,6-difluoro-4-methoxy-benzoic acid (15 g, 80 mmol)(Mol. Cryst. Liq. Cryst. 1989, 172) in toluene (120 ml) at 80° C. under a nitrogen atmosphere. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. Ethyl acetate (100 ml) was added and the organic solution was washed with saturated sodium hydrogen carbonate solution (2×150 ml), brine (150 ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using diethyl ether in pentane as eluant (10:90) to give the title compound as an oil (17.91 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:20])[C:5](=[O:19])[C:6]1[C:7](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([N:10]([CH2:12][CH2:13][OH:14])[CH3:11])=[O:9].C(N(CC)CC)C.[O:28]1[CH2:32][CH2:31][CH2:30]C1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)(Cl)Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:33]([O:1][CH2:2][CH2:3][N:4]([CH3:20])[C:5](=[O:19])[C:6]1[C:7](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([N:10]([CH2:12][CH2:13][O:14][C:32](=[O:28])[CH:31]=[CH2:30])[CH3:11])=[O:9])(=[O:36])[CH:34]=[CH2:35]
Reactant: C1CCOC1
Reactant: C=CC(=O)Cl
Reactant: CN(CCO)C(=O)c1ccccc1C(=O)N(C)CCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCN(C)C(=O)c1ccccc1C(=O)N(C)CCOC(=O)C=C
Yield: 43 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of N,N'-di(hydroxyethyl)-N,N'-dimethyl phthalamide (0.36 mol.), 67.8 g of triethylamine (0.72 mol.), 500 ml of tetrahydrofuran and 2 g of phenothiazine. Next, 68 g of acryloyl chloride (0.75 mol.) was slowly added to the flask over one hour. The reaction was stirred for an additional hour. The triethylamine hydrochloride salt was removed by filtration and the remaining mother liquor was evaporated with a rotoevaporator to yield a light brown liquid. The liquid was dissolved in chloroform and washed with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was removed with a rotoevaporator to yield 60 g (43%) of a light brown liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: [C:1]([C:5]1C=C(C2C=CC=C(C3N=C(C)C4C(C=3)=CC([O:27]C)=C(OC)C=4)C=2)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[O:32]1[CH2:37][CH2:36]O[CH2:34][CH2:33]1>>[CH3:34][CH2:33][O:32][C:37]([CH3:36])=[O:27].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: COc1cc2cc(-c3cccc(-c4cccc(C(C)(C)C)c4)c3)nc(C)c2cc1OC
Reactant: C1COCCO1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 58 %

Procedure:
3-(3′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxy-1-methylisoquinoline (92 mg) and SeO2 (25 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (55 mg, 58% yield). 1H NMR (400 MHz) (CDCl3) δ 10.39 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 8.07 (d, J=4 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.53 (t, J=12 Hz, 1H), 7.46-7.44 (m, 1H), 7.36-7.35 (m, 2H), 7.11 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 196.86, 153.26, 152.79, 151.71, 149.69, 147.04, 142.67, 141.02, 139.21, 135.42, 129.29, 128.54, 127.80, 125.81, 125.52, 124.61, 124.54, 124.47, 122.19, 120.07, 104.99, 103.52, 56.31, 56.07, 34.89, 31.47.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:31]([CH:33]4[CH2:35][CH2:34]4)=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:25]=2)O)=[C:18]([F:45])[N:17]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:39]1([S:36]([N:26]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([CH:33]4[CH2:34][CH2:35]4)[C:32]=3[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][C:8]4[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)=[N:17][C:18]=3[F:45])=[CH:25]2)(=[O:38])=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To {5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (75, 0.290 g, 0.448 mmol) in 9.93 mL of 1,2-dichloroethane, triethylsilane (0.31 mL, 2.0 mmol) and trifluoroacetic acid (0.16 mL, 2.0 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (76, 170 mg). MS (ESI) [M+H+]+=530.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:3]=12.[OH2:16]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:16])=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:3]=12
Reactant: O
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
A solution of 12.7 g (0.065 mol) of 4-methyl-5H-indeno[3,2-b]-pyridin-5-one in 550 ml of chloroform was added dropwise at 25° C. to a solution of 13 g (0.066 mol) of water-moist 3-chloroperbenzoic acid in 500 ml of chloroform. After stirring at room temperature for 12 hours, the mixture was washed twice with 50 ml each of a saturated aqueous sodium hydrogen carbonate solution and then with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was crystallized at 0° C. using 20 ml of diethyl ether. 12.4 g (90.5% of theory) of 4-methyl-5H-indeno[3,2-b]pyridin-5-one-N-oxide were obtained as white crystals of m.p. 218°-220° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24].CCOC(C)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:25]1([C:23]2[N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C:3]3[C:2]([CH:24]=2)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C#CC1CCCCC1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a mixture containing N-(2-iodo-4-nitrophenyl)methanesulfonamide (13.5 g; 39.5 mmol), triethylamine (17.9 ml; 129 mmol), ethynylcyclohexane (8.55 g; 79 mmol) in DMF (60 ml), CuI (1.5 g; 7.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) [Cl2(PPh3)2Pd] (2.77 g; 3.95 mmol) were added. The reaction mixture was left under stirring at 70° C. for 18 hours. After cooling to room temperature, EtOAc (100 ml) was added, the inorganic precipitate was filtered off and the solution was transferred into a separating funnel and washed with NaHCO3 (saturated solution, 3×200 ml) and water (2×150 ml). The organic phase was dried over Na2SO4, the solvent was removed by evaporation under reduced pressure. The so obtained crude product was crystallized (isopropyl ether) to give 2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (11.7 g)
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:30]1[CH:31]=[CH:32][C:33]2[NH:34][C:35]3[C:40]([C:41]=2[CH:42]=1)=[CH:39][C:38](Br)=[CH:37][CH:36]=3.C([O-])([O-])=O.[K+].[K+].Br[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.O.CCO.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>[C:51]1([N:34]2[C:35]3[CH:36]=[CH:37][C:38]([C:11]4[CH:10]=[CH:9][C:8]5[NH:7][C:19]6[C:14]([C:13]=5[CH:12]=4)=[CH:15][C:16]([C:4]4[CH:3]=[CH:2][C:1]5[N:7]([C:19]7[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=7)[C:8]7[C:13]([C:6]=5[CH:5]=4)=[CH:12][CH:11]=[CH:10][CH:9]=7)=[CH:17][CH:18]=6)=[CH:39][C:40]=3[C:41]3[C:33]2=[CH:32][CH:31]=[CH:30][CH:42]=3)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Reactant: Brc1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccc(-c7ccc8c(c7)c7ccccc7n8-c7ccccc7)cc6c5c4)ccc32)cc1
Yield: 65.4 %

Procedure:
A solution of 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)carbazole (7.1 g, 19.2 mmol), 3,6-dibromo-9H-carbazole (2.6 g, 8.0 mmol), K2CO3 (11.0 g, 79.7 mmol) in toluene (120 mL), water (40 mL) and EtOH (40 mL) was bubbled for 30 minutes with nitrogen. Then, Pd(PPh3)4 (0.9 g, 0.8 mmol) was added. The mixture was bubbled with nitrogen for 15 minutes and refluxed for 10 hours, after which bromobenzene (0.9 mL, 8.6 mmol) was added. The resultant mixture was refluxed for 6 hours. After cooling, the reaction mixture was extracted with CH2Cl2 and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by flash chromatography using 40-60% CH2Cl2/hexane to afford 3,6-bis(9-phenylcarbazol-3-yl)carbazole (3.4 g, 65% yield) as a white solid.
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH3:7].Br[C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1(C)C(C)=CC=CC=1>[CH3:7][C:6]1[CH:5]=[CH:4][N:3]=[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[C:10]=12
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Reactant: C/C=C/C=NN(C)C
Solvent: Cc1ccccc1C
Product: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 57.3 %

Procedure:
(E)-2-Butenal N,N-dimethylhydrazone, (3.70 g, 0.033 mol) in dry xylene (10 mL, Fisher) was added to a xylene solution (50 mL) of 2-bromo-1,4-naphthoquinone, (6.00 g, 0.025 mol) in a 200-mL, round-bottomed flask fitted with a condensor. The dark mixture was then heated at reflux for 6 h under a nitrogen atmosphere before decanting the solution into a 500-mL separatory funnel. The solids coating the wall of the flask were washed thoroughly with ethyl acetate (6×25 mL) and these washings added to the separatory funnel. The combined organic solutions were extracted with 2N sulfuric acid solution (1×100 mL followed by 2×75 mL). The acid layers were then combined, chilled in ice, and made basic (~pH 10 test paper) with sodium hydroxide before extracting with ethyl acetate (4×100 mL). The latter organic layers were dried over potassium carbonate and concentrated to dryness on a rotary evaporator. This material was applied to a 4×70 cm column of Silica gel (Merck 230-400 mesh) and the product eluted with ethyl acetate. Concentration of the appropriate column fractions yielded pure cleistopholine (3.20 g, 57%); mp 202°-204° C. (lit. mp 198°-201° C.). IR(KBr) 1680, 1660, 1590, 1300, 980, 720 cm-1 ; 1H NMR (CDCl3) δ 8.86 (d, J=4.9 Hz, 1 H), 8.34-8.30 (m, 1 H), 8.24-8.19 (m, 1 H), 7.82-7.76 (m, 2 H), 7.47 (dd,J=4.9, 0.7 Hz, 1 H), 2.88 (br s, 3 H); 13C NMR (CDCl3) 184.7 (0), 181.9 (0), 153.4 (1), 151.5 (0), 150.0 (0), 134.5 (1), 134.1 (1), 133.8 (0), 132.5 (0), 131.2 (1), 129.1 (0), 127.3 (1), 127.1 (1), 2.28 (3) ppm.
Reaction SMILES: [CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([OH:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OC(C)=O)(C)(C)C>[CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:5]([CH3:10])([CH3:6])[CH3:1])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of (S)-ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-hydroxy-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.50 g, 1.13 mmolo, 1 equiv) in t-BuOAc (18 mL) was added 70% HClO4 (0.48 mL, 5.64 mmol, 5 equiv). A white precipitate formed. DCM (5 mL) was added to aid solubility. After 1 h, the reaction was carefully added to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to provide the product (0.16 g, 28%) as a white foam. In addition, starting material (0.38 g) was recovered. 1H NMR (400 MHz, CDCl3) [note: major rotamer transcribed, 3:2 mixture of rotamers] δ8.23 (s, 1H), 7.33 (s, 1H), 6.06 (s, 1H), 5.97-5.81 (m, 1H), 5.17-4.97 (m, 2H), 4.53-4.42 (m, 2H), 3.71 (s, 3H), 3.69-3.64 (m, 1H), 3.57-3.50 (m, 1H), 3.17-3.07 (m, 1H), 2.88 (d, J=12.0 Hz, 1H), 2.46-2.44 (m, 3H), 2.18-2.08 (m, 2H), 1.71-1.58 (m, 6H), 1.48-1.43 (m, 3H), 1.25 (s, 9H), 1.16 (s, 3H); LCMS (ESI, M+1): 500.35.