Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]([N:8]1[C:12]2[N:13]=[CH:14][C:15]([C:24]3[O:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:25]=3)=[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:11]=2[CH:10]=[N:9]1)[CH3:7].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][C:26]2[N:25]=[C:24]([C:15]3[CH:14]=[N:13][C:12]4[N:8]([CH2:6][CH3:7])[N:9]=[CH:10][C:11]=4[C:16]=3[NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[O:28][N:27]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(C)=O)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, a further quantity of acetyl chloride (0.04 mmol) and diisopropylethylamine (0.1 mmol) were added to the reaction mixture. After 3.5 h the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 175 LCMS showed MH+=454, TRET=2.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[SH:11][CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CBr
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)NC(Nc1c(Cl)cccc1Cl)=[SH]CC(C)C
Yield: 92 %

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 2.1 g (0.015M) of ground potassium carbonate, 3.3 ml (0.03M) of isobutylbromide and 50 ml of acetone were heated together under stirring and reflux for 4 hours. The acetone was then distilled off. The residue in the flask was washed with water and then filtered. 5.9 g (92% of theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-isobutyl-thiourea melting at 106° to 112° were obtained. After recrystallization from benzene the product melted at 114° to 116° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:29][O:28][C:24]1[N:23]=[C:22]([C:20]([C:12]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[S:15][C:11]=2[CH2:10][CH2:9][N:8]([CH3:30])[CH3:7])=[CH2:1])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C(=O)c2c(CCN(C)C)sc3ccccc23)n1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cccc(OC)n1)c1c(CCN(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Anhydrous THF (8 mL) was added to a mixture of potassium t-butoxide (140 mg, 1.27 mmol) and methyltriphenylphosphonium bromide (0.45 g, 1.27 mmol) under N2 atmosphere. The reaction was stirred for 30 min at room temperature. A solution of [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(6-methoxy-pyridin-2-yl)-methanone (0.29 g, 0.85 mmol) in THF (8 mL) was added and the reaction was stirred for 1 hour at room temperature. The reaction was quenched by the addition of 0.1N HCl until the pH was <3 and extracted with 0.1N HCl. The aqueous layers were made basic with NH4OH and extracted with EtOAc. The organic layers were washed with water and concentrated in vacuo. Mass triggered preparative HPLC afforded 190 mg of (2-{3-[1-(6-methoxy-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 15-1) as a TFA salt.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[CH:21][C:22]2([CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC1(C=C2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Yield: 97.3 %

Procedure:
28.62 g of crude 4-(4-tert-butyl-phenyl)-2-(1-methylcyclo-hexylmethylene)-indan-1-one (GC: ˜83% purity) are dissolved in 286 ml of ethyl acetate in a flask with gas inlet and stirrer. 2 g of palladium on activated carbon (10 wt-% palladium) are added. The system is evacuated and refilled with argon three times to remove oxygen and then evacuated and refilled with hydrogen three times. The stirrer is started and the reaction mixture is vigorously stirred to help the diffusion of hydrogen gas into the liquid reaction mixture. The hydrogen uptake is monitored and stirring is continued until the hydrogen uptake ceases. Filtering the crude reaction mixture over a paper filter and removing the solvent in a vacuum leaves crude 4-(4-tert-butyl-phenyl)-2-(1-methyl-cyclohexylmethyl)-indan-1-one (yield 27.99 g, GC: ˜84% purity). The obtained crude product was used without further purification for the subsequent reduction/elimination-sequence.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[C:13]3[NH:20][CH:19]=[C:18]([C:21](O)=[O:22])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:21]([C:18]2[C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:13]=3[NH:20][CH:19]=2)=[O:22])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A78) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]1>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: NCCC1CCOCC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CS(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Temperature: 150 °C
Yield: 44.1 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.0 g, 2.95 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (0.381 g, 2.95 mmol) were placed in a microwave vial, dimethylsulfoxide (2 mL) was added and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 3600 s. The crude reaction mixture was purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (0.5 g, 1.3 mmol, 44% yield). MS (ESI) m/z 387.1 [M]+, 389.1 [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:24])([F:25])[F:26])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH:22][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)CC(F)(F)F
Reactant: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH2:20])[CH3:19]>CN(C)C=O>[CH2:18]([NH:20][C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CC(C)c1nnc2c(Cl)nc3ccccc3n12
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2c(C(C)C)nnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A slurry of 1.0 g. (0.004 mole) of 4-chloro-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 6) in N,N-dimethylformamide (15 ml.) was saturated with monoethylamine gas and stirred at room temperature for 4 hours. The precipitate was separated by filtration and washed with N,N-dimethylformamide to afford 220 mg. (22% yield) of 4-ethylamino-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 209°-211° C. Mass spectrum: m/e, 255 (P).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)=O.C(N(CC)CC)C>C(#N)C>[CH2:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[N:5]=[C:3]([NH:2][CH3:1])[S:4][C:8]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: O=C(c1ccc2c(c1)CCC2)C(Br)c1cccnc1
Reactant: CNC(N)=S
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc(-c2ccc3c(c2)CCC3)c(-c2cccnc2)s1
Reaction time: 2 h
Yield: 80 %

Procedure:
In 40 ml of acetonitrile was dissolved 661 mg. of N-methyl thiourea. In the solution was suspended 2.9 g of 2-bromo-1-(5-indanyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added dropwise slowly 1 ml of triethylamine. The mixture was then stirred for 2 hours at refluxing temperature, followed by being left standing for cooling. The solvent was then evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. Recrystallization was conducted from ethyl acetate-isopropylether afforded 1.8 g (80%) of 4-(5-indanyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole, m.p. 169°-170° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:13])([F:14])[F:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1-Methylsulfonyl-2-trifluoromethoxybenzene (15.7 g, 65 mmol) was dissolved in concentrated sulfuric acid (27 mL) and the solution was heated to 40° C. Nitric acid (100%, 27 mL) was added dropwise over 45 min. The reaction mixture was allowed to stand overnight at 60° C., cooled, and then poured on crushed ice (300 mL). The precipitated product was isolated by filtration, washed with water (10×50 mL) and dried (magnesium sulphate), affording 17.5 g of 3-methylsulfonyl-4-trifluoromethoxynitrobenzene.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].Br[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1>C1COCC1.C(OCC)C>[CH2:8]([C:7]1[CH:6]=[CH:11][C:1]([Br:4])=[CH:2][CH:3]=1)[CH:9]=[CH2:10]
Reactant: C=CCBr
Reactant: Brc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
At 5° C., a solution of allylbromide (5.64 g, 46.6 mmol) in THF (40 mL) is slowly added to the Grignard reagent freshly prepared from 1,4-dibromobenzene (10.0 g, 42.4 mmol) and Mg-turnings (1.13 g, 46.6 mmol) in THF. The reaction mixture becomes slightly warm and a fine precipitate forms. Upon completion of the addition, the suspension is stirred at rt for 1 h before it is diluted with diethyl ether and washed with two portions of 1 N aq. HCl and one portion of water. The wash solutions are extracted twice with diethyl ether. The organic extracts are combined, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 1-allyl-4-bromo-benzene (5.50 g) as a colourless oil.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:17]I>C(#N)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[CH3:17].[I-:1]
Reactant: CN1C=C[NH+](C)C1C=Cc1ccccn1
Reactant: CI
Agent: [I-]
Solvent: CC#N
Product: CN1C=C[NH+](C)C1C=Cc1cccc[n+]1C

Procedure:
1,3-Dimethyl-2-[2-(2-pyridinyl)ethenyl]-1H-imidazolium iodide (6.5 g) and 10 ml of methyl iodide are refluxed in 20 ml of acetonitrile for one hour. The resulting solid is filtered off and crystallized from methanol to yield 5.5 g of the title compound, melting point 75° C.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=C(O)C(O)=O)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:18]>O=[Mn]=O>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Agent: O=[Mn]=O
Product: CC(C)(C)c1ocnc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxazole alcohol 3 (9.9 g, 64 mmol) in acetone (200 mL, Aldrich, Cat. No. 179124) was added MnO2 (27.7 g, 319 mmol, 5 equiv., Wako Pure Chemical, Osaka, Japan, Cat. No. 138-09675), and the mixture was stirred at room temperature overnight. After celite filtration to remove MnO2, the solvent was removed by evaporation, and the residual pale brown oil was dissolved in CHCl3 and applied to silica-gel column chromatography (prepared with CHCl3), then eluted with CHCl3:MeOH (100:1 to 50:1), to give an pale yellow oil of aldehyde 4 (5.54 g, 57% (38% in two steps)). Rf 0.65 (CHCl3:MeOH=10:0.5), 1H NMR (300 MHz CDCl3) δ 10.10 (s, 1H), 7.77 (s, 1H), 1.47 (s, 9H); HRMS(EI): m/z 153.0794 (M+) (Calcd for C8H11NO2: 153.0790).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[C:17]([C:16]1[CH:22]=[N:1][C:2]2[C:7]([C:15]=1[OH:14])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1O
Temperature: 165 °C

Procedure:
A mixture of 30.6 g of 4-aminoveratrole and 43.2 g of diethyl ethoxymethylenemalonate was heated at 100 for 2 h and at 165° C. for 0.75 h. The intermediate thus obtained was dissolved in 600 ml of diphenyl ether, and the resulting solution was heated at reflux temperature for 2 h, cooled, and diluted with hexane. The resulting solid was filtered, washed with hexane followed by ether, and dried to provide the title compound as a brown solid, mp 275-285° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31]([O-:33])=[O:32])[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:34](=[O:38])(=[O:37])([OH:36])[OH:35].[CH3:39]O>>[S:34]([OH:38])([OH:37])(=[O:36])=[O:35].[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][NH:22][C@H:21]([C:31]([O:33][CH3:39])=[O:32])[CH2:20]3)=[O:17])[C:11]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CN1

Procedure:
850 mg 1-tert.butyl (2S,4R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylate and 60 μl sulphuric acid are placed in 12 ml abs. methanol. The reaction mixture is then refluxed for 48 hours with stirring and then evaporated to dryness. 1.0 g product is obtained as a foam. Analytical HPLC-MS (method B): RT=1.80 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH2:9][O:10][CH2:11]3)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(O)C.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:12]12[N:7]([C:5]3[S:6][C:2]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)=[C:3]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[N:4]=3)[CH:8]([CH2:14][CH2:13]1)[CH2:9][O:10][CH2:11]2
Reactant: Clc1ccc(-c2nc(N3C4CCC3COC4)sc2Br)cc1
Reactant: NS(=O)(=O)c1ccc(B(O)O)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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2sc(N3C4CCC3COC4)nc2-c2ccc(Cl)cc2)cc1
Temperature: 92.5 °C
Yield: 42 %

Procedure:
To a solution of 8-(5-bromo-4-(4-chlorophenyl)thiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step 3 of compound 56, 0.26 g, 0.67 mmol) in a mixture of toluene:ethanol (2.5 ml:7.5 ml) were added 4-aminosulfonylbenzene boronic acid (0.15 g, 0.74 mmol) and potassium carbonate (0.23 g, 1.68 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.039 g. 0.034 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 2-3% methanol in DCM as an eluent to obtain the title compound (0.13 g, 41.7%). MS: m/z 462 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([OH:35])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[N+](=[CH2:38])=[N-]>>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:38])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Reactant: C=[N+]=[N-]
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2

Procedure:
Asiatic acid (2) is treated with diazomethane to obtain methyl asiatate (3, R3 =methyl) quantatively, which is then oxidized to give a compound of lactol structure (4, R3 =methyl) in which A-ring have been modified. The compound is treated with catalytic amount of acetic acid/piperidine to obtain methyl A(1)-norursa-2,12-diene-23-hydroxy-2-formyl-28-oate (5, R3 =methyl). [See Scheme 1]
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>C(OCC)C.CCCCC>[CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccccc2CC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: OB(O)C1=Cc2ccccc2CC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 3-bromo-1,2-dihydro-naphthalene (7.7 g, 37 mmol) (Adamczyk, M.; Watt, D. S.; Netzel, D. A. J. Org. Chem. 1984, 49, 4226-4237) in diethylether (370 ml) was cooled in a dry ice bath and tert.-butyllithium solution (50 ml of a 1.5 M solution in pentane) was added maintaining T<−65° C. At this temperature stirring was continued for 30 min, then triisopropylborate (17.3 ml, 75 mmol) was added. The reaction mixture was brought to rt and treated with 3N HCl (100 ml). After 15 min the organic phase was dried (Na2SO4), evaporated and precipitated with pentane to provide the title compound (3.83 g, 60%) as a white solid material. MS: m/e=173 (M−H−).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CC(C)N1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CC(C)N1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 34.1 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-isopropylpiperidine (0.312 g, 2.0 mmol) of according to the procedure used for Example 2 to give 0.135 g of the title compound as a white solid.