Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])/[C:22](=[N:24]/O)/[NH2:23].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:22]2[N:24]=[C:15]([C@@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]3)[O:17][N:23]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: N/C(=N\O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](c2nc(-c3ccc(Cl)c(Cl)c3)no2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.7 %

Procedure:
A microwave vial was charged with cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.24 g, 0.98 mmol), DMAP (0.12 g, 0.98 mmol) and Intermediate 33A (0.20 g, 0.98 mmol). The reactants were dissolved in DMF (1 mL) and DIC (0.15 mL, 0.98 mmol) was added. The reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted in 3 mL of pyridine. The vial was capped and the reaction mixture was heated in the microwave at 145° C. for 20 minutes, allowed to cool to rt, diluted with EtOAc and washed with water and brine. The solution were concentrated under reduced pressure and purified by flash chromatography with EtOAc/hexanes to give Intermediate 33B (233 mg, 0.565 mmol, 57.9% yield) as a white solid. LCMS=434.1 [M+1], RT=2.43 min (Method B); 1H NMR (500 MHz, chloroform-d) δ ppm 8.19 (1H, d, J=1.93 Hz), 7.92 (1H, dd, J=8.53, 1.93 Hz), 7.56 (1H, d, J=8.25 Hz), 4.59 (1H, br. s.), 3.71 (1H, d, J=9.63 Hz), 3.14-3.22 (1H, m), 2.07-2.17 (2H, m), 1.92-2.02 (2H, m), 1.84 (2H, td, J=8.67, 4.13 Hz), 1.62-1.73 (2H, m), 1.44 (9H, s).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[N:8]=[C:7]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:6]3=[C:5]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[C:3]=1[C:21]#[N:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].COCCOC.O>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[S:10][C:9]3[N:8]=[C:7]4[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:6]4=[C:5]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[C:4]=3[C:3]=2[C:21]#[N:22])=[CH:27][CH:26]=1
Reactant: N#Cc1c(Br)sc2nc3c(c(-c4cccs4)c12)CCCCC3
Reactant: COc1ccc(B(O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2sc3nc4c(c(-c5cccs5)c3c2C#N)CCCCC4)cc1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a Schlenk tube was added 2-bromo-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-3-carbonitrile (45 mg, 0.116 mmol), p-methoxyphenyl boronic acid (21 mg, 0.138 mmol), NaHCO3 (29 mg, 0.348 mmol), Bu4NBr (8 mg, 0.023 mmol) and 1 mL of DME/H2O (4/1). After evacuating and back-filling with nitrogen twice, a catalytic amount of Pd(PPh3)4 was added. The sealed mixture was heated to 80° C. overnight. After pouring into water, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography to provide 30 mg of the title compound, 2-(4-methoxyphenyl)-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-3-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]=3[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]3=[C:10]([O:25][CH3:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)cc(OC)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-(4-bromophenyl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4(7H)-one (200 mg, 0.51 mmol, 1.00 equiv) in tetrahydrofuran (2 mL), PPh3 (290 mg, 1.11 mmol, 2.17 equiv), methanol (18 mg, 0.56 mmol, 1.11 equiv). To the resulting mixture was then added DEAD (180 mg, 1.03 mmol, 2.03 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×10 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (Petroleum Ether-1:100) to yield 6-(4-bromo-phenyl)-3-ethyl-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine as a white solid. MS (m/z): 409 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=O)=[CH:2]1.C[S:30](C)(=O)=O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[S:30])=[CH:2]1
Reactant: O=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21
Reactant: CS(C)(=O)=O
Solvent: O
Product: S=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21

Procedure:
3-(1H-indol-3-yl)-3,3′-biindolin-2-one (728 mg, 2 mmol), crystalline P2S5.2C5H5N (228 mg, 0.6 mmol) and dimethylsulfone (3.05 g) were heated (165-170° C.) for 20 min. The melt was allowed to cool and then heated in water for 10 min. The solid formed was collected, 766 mg (94%), mp>260° C. 1H NMR (300 MHz, DMSO-d6) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 72.7 (s), 111.2 (d), 124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7 (s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s), 143.0 (s), 143.5 (s), 145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C24H17N3S; C, 75.96; H, 4.51; N, 11.07. Found C, 76.10; H, 4.46; N, 11.00.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
22.53 g of methyl isobutyrylacetate (0.15 mol, concentration 96%) and 18.54 g of 4-fluorobenzonitrile (0.15 mol, concentration 98%) were dissolved in 150 ml of toluene and treated with 43.32 g of tin tetrachloride (0.165 mol, concentration 99%) at room temperature over the course of 12 min. After half an hour at room temperature, the mixture was heated to 80° C. After 3 h, the suspension was cooled to room temperature and treated with 150 ml of water. It was diluted with 100 ml of ethyl acetate and the phases were separated. After extraction of the aqueous phase with ethyl acetate (2×100 ml), the combined organic phases were washed with 100 ml of saturated aqueous sodium hydrogencarbonate solution and 100 ml of 1N sodium hydroxide solution and dried over magnesium sulphate. After concentration in vacuo, 46.46 g of crude product were obtained in the form of a yellowish solid. The solid was dissolved in a mixture of 50 ml of n-hexane and 5 ml of toluene under reflux and filtered hot. The product precipitated from the filtrate on cooling. By filtering through a frit and washing the filter cake with 2×40 ml of n-hexane, 32.42 g of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were obtained in the form of a spectroscopically pure solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[OH:7][C:8]1[CH:40]=[CH:39][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:38])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:6]=[C:3]([CH2:4][CH3:5])[CH2:2][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:38])=[CH:39][CH:40]=1
Reactant: CCC(=O)CBr
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7.37 ml of 1-bromo-2-butanone, 20.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 21.18 g of cesium carbonate and 200 ml of anhydrous acetone was stirred at room temperature for 3 hours. At the end of this time, the acetone was removed by evaporation under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate, diethyl ether and diisopropyl ether, to give 19.36 g of the title compound, melting at 155.2° to 156.4° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.F[C:9]1[C:10]([CH3:29])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16]([C:19]1[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=1)[CH:15]=[CH:14][CH:13]=2.CO.C(Cl)Cl>CN(C=O)C.[NH4+].[Cl-]>[CH:3]1([O:7][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: OC1CCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1OC1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
NaH (60% w/w in mineral oil; 37.8 mg, 0.945 mmol) was added to a solution of of cyclobutanol (Aldrich; 0.074 mL, 0.945 mmol) in DMF (1.0 mL) and the resulting suspension was stirred at 25° C. for 10 min. 2-(3-Fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol) was added, and the resulting solution was heated at 60° C. for 3 h. The mixture was cooled to 25° C., diluted with half-saturated aq. NH4Cl (30 mL), and extracted with DCM (2×40 mL). The combined organic extracts were washed with water (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-cyclobutoxy-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (17.8 mg, 0.051 mmol, 38% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.07 (1H, br. s.), 7.99 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.2 Hz), 7.55 (1H, t, J=7.8 Hz), 7.18 (1H, d, J=2.0 Hz), 5.46 (1H, br. s.), 5.28 (1H, quin, J=7.4 Hz), 3.70 (2H, t, J=6.7 Hz), 3.02 (2H, t, J=6.8 Hz), 2.68 (3H, s), 2.59-2.67 (2H, m), 2.33-2.45 (2H, m), 2.01-2.13 (1H, m), 1.77-1.92 (1H, m). m/z (ESI, +ve) 349.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[CH2:41][N+:42]#[C-:43]>CN(C)C=O.O.C(O)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11]3[N:12]([CH:43]=[N:42][C:41]=3[C:40]3[CH:44]=[CH:45][CH:46]=[C:38]([Cl:37])[CH:39]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Cl)c2C(=O)N2CC[C@@H]12
Reactant: [C-]#[N+]Cc1cccc(Cl)c1
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3cccc(Cl)c3)c2[C@@H]2CCN12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A suspension of 11.83 g (50 mmol) of (S)-5-chloro-1,10a-dihydro-azeto[2,1-c][1,4]benzodiazepine-4,10-(2H,9H)-dione in 35 ml of dry N,N-dimethylformamide is treated at -30° to -20° with 2.18 g (50 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at the above temperature for a further 35 minutes, and then at -70° there is added dropwise a solution of 13.43 g (50 mmol) of phosphoric acid diphenyl ester chloride in 8 ml of dry N,N-dimethylformamide. After stirring for 20 minutes in an acetone/dry-ice bath there is added dropwise at -70° a solution of 7.58 g (50 mmol) of 3-chlorobenzyl isocyanide in 4 ml of dry N,N-dimethylformamide, and subsequently at -65° to -40° there is added dropwise a solution of 5.61 g (50 mmol) of potassium t-butylate in 9 ml of dry N,N-dimethylformamide. The mixture is left to warm to room temperature and neutralized by the addition of 2.5 ml of glacial acetic acid. The mixture is poured into 300 ml of water and extracted five times with methylene chloride. The combined organic extracts are washed three times with water, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel while eluting with ethyl acetate and recrystallized twice from ethyl acetate. There is obtained (S)-8-chloro-1-(m-chlorophenyl)-12,12a-dihydro-9H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one having a melting point of 221°-223°.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]3[CH2:16][CH:12]([CH2:13][NH:14]3)[CH2:11][CH:10]=2)[CH:4]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.CO.O1CCOCC1>[ClH:1].[ClH:1].[CH3:19][N:14]1[CH2:13][CH:12]2[CH2:16][CH:15]1[C:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)=[CH:10][CH2:11]2
Reactant: C1=C(c2cccnc2)C2CC(C1)CN2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC2CC=C(c3cccnc3)C1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene dihydrochloride (90 mg, 0.35 mmol) in 15 mL of dichloromethane was added a solution of formaldehyde (37% aqueous, 0.15 mL, ˜1.8 mmol). With vigorous stirring, solid sodium triacetoxyborohydride (300 mg, 1.4 mmol) was added in two portions. The reaction was allowed to stir overnight at ambient temperature. The reaction mixture was quenched by the addition of a sodium hydroxide solution (10% aqueous, approximately 1 mL), and the whole extracted with dichloromethane (2×10 mL). The organic extracts were washed successively with water and brine (10 mL each), and dried over sodium sulfate. Filtration and removal of solvent in vacuo gave a residue, which was dissolved in a small volume of methanol and treated with approximately 1 mL of 4M HCl in dioxane. The resulting solution was concentrated in vacuo, and the residue taken up in a minimum amount of warm isopropanol. After cooling briefly, ether was added to the point of cloudiness, and the solution cooled slowly to ambient temperature. A sticky solid precipitate formed which resisted crystallization. Solvents were removed in vacuo, leaving the product as a hygroscopic, gummy mass (30 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:13][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccc(OC)cc2)CC1
Yield: 1976.8 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50 g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) at room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 7.25-7.27 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (m, 2H), 1.15 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(NC(C)C)(C)C.O>C1COCC1.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.[Cu]I>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 4-ethynylanisole (700 mg, 5.30 mmol), 4-iodoanisole (1.30 g, 5.55 mmol), (PPh3)2PdCl2 (74.4 mg, 0.106 mmol), and CuI (10.1 mg, 0.053 mmol) in THF (7 ml), diisopropyl amine (1.13 g, 11.1 mmol) was added dropwise under ice cooling under argon atmosphere. After stirring at room temperature for 1 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water then saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=15/1) to give bis(4-methoxyphenyl)ethyne (95%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=O)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[C:7]([C:38]1[S:37][CH:41]=[CH:40][CH:39]=1)[CH:16]=[CH:15]2
Reactant: OB(O)c1cccs1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 73.7 %

Procedure:
Combine 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate (6.0 g, 11.4 mmol), Thiophene-2-boronic Acid (4.4 g, 34.3 mmol), tricyclohexylphosphine (1.1 g, 4.0 mmol), palladium (II) acetate (0.51 g, 2.3 mmol), cesium fluoride (15.6 g, 102.8 mmol) and acetonitrile (150 mL; degas with nitrogen for 30 minutes) to a round bottom flask under nitrogen. Warm the resulting mixture to 80° C. and stir for 40 minutes. Filter off solids and wash with acetonitrile. Combine the filtrate and washes and concentrate in vacuo. Dissolve the residue in methanol and load onto an SCX acidic ion exchange column. Flush the column with methanol then elute with 2M ammonia in methanol. Concentrate the ammonia containing eluent in vacuo to give a light brown solid. Purify the solid by silica gel flash chromatography to obtain the title compound (3.88 g, 8.4 mmol). 1H NMR (d6-DMSO) δ29 (dd, J=5.9, 11.2 Hz, 2H), 1.43-1.37 (m, 5H), 2.32 (s, 4H), 2.52 (t, J=5.9 Hz, 2H), 3.87 (t, J=6.1 Hz, 2H), 6.62-6.60 (m, 2H), 6.76-6.74 (m, 2H), 7.09-7.03 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.48-7.47 (m, 1H), 7.62-7.59 (m, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.[OH-].[Na+].O>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:23][NH:3][CH:4]2[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NC1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1cccc(CNC2CN3CCC2CC3)c1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A mixture of of 3-aminoquinuclidine dihydrochloride (2.0 g, 10.0 mmol), NEt3 (1.3 mL) and 3-chlorobenzaldehyde (1.5 g, 11.0 mmol) in THF (50 mL) was stirred at room temperature. To this was added Na(OAc)3BH 13.2 g, 15 mmol) and the reaction was stirred overnight. The reaction mixture was diluted with 3N NaOH and water and extracted with EtOAc. The organic extracts were combined, washed with water and then brine and dried over K2CO3. The solution was filtered and the solvent was evaporated in vacuo to give an oil which was chromatographed on silica (94/6 CHCl3/0.5 M NH3 in MeOH). The appropriate fractions were combined and the solvent was evaporated in vacuo to give N-[(3-chlorophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (0.75 g, 30%) as an intermediate, a light yellow semi-solid. MH+=251,253. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: [Bi](Cl)(Cl)Cl.CC1C=CC(S(O[CH2:16][C:17]2([C:20]([F:23])([F:22])[F:21])[CH2:19][O:18]2)(=O)=O)=CC=1.[CH3:24][C:25]1[CH:26]=[C:27]([NH2:40])[C:28]2[CH:29]=[N:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]=2[CH:33]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-]>ClCCl.C(Cl)(Cl)Cl.O1CCCC1.[Bi](Cl)(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27]([NH:40][CH2:16][C:17]2([C:20]([F:21])([F:22])[F:23])[CH2:19][O:18]2)[C:28]2[CH:29]=[N:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]=2[CH:33]=1
Reactant: Cc1cc(N)c2cnn(-c3ccccc3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CO2)cc1
Agent: Cl[Bi](Cl)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 698.8 %

Procedure:
Bismuth chloride (347 mg, 1.1 mmol) was added to a mixture of [2-(trifluoromethyl)-2-oxiranyl]methyl 4-methylbenzenesulfonate (3.41 g, 11.5 mmol) and 6-methyl-1-phenyl-1H-indazol-4-amine (2.45 g, 1.1 mmol) in dry dichloromethane (4.5 ml) and the mixture stirred at room temperature under nitrogen over the weekend. More bismuth chloride (173 mg, 0.55 mmol) and dichloromethane (0.5 ml) were then added and the mixture stirred overnight and then diluted with chloroform (50 ml) and dry tetrahydrofuran (25 ml). N,N-Diisopropylethylamine (0.38 ml, 2.2 mmol) was added followed by polymer supported carbonate resin (Fluka, ca. 3.5 mmoles carbonate/g resin, 9.4 g) and 4 A molecular sieves. After 6 hours LCMS indicated the reaction to be complete and the mixture was filtered. The filtrate was washed with water, the aqueous phase was back-extracted with dichloromethane and the combined organic phases were dried and evaporated to give crude product which was purified by silica gel chromatography using the Flashmaster II (100 g cartridge) eluting with a 0 to 100% cyclohexane:ethyl acetate gradient. Product containing fractions were combined with similar fractions from a parallel reaction (1.28 g input of Intermediate 9) to give the title compound (2.67 g).