Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]n1
Yield: 63.8 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.
Reaction SMILES: C(S[CH:4]=[CH2:5])=C.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.O=O.C(S[C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)[O:33][O:32]1)C.[O:51]1[CH2:54]CO1>C(Cl)Cl>[OH:50][C:46]1[CH:45]=[C:44]([C:31]2([O:51][CH2:54][CH:4]=[CH2:5])[C:34]3([CH:35]4[CH2:43][CH:39]5[CH2:38][CH:37]([CH2:42][CH:41]3[CH2:40]5)[CH2:36]4)[O:33][O:32]2)[CH:49]=[CH:48][CH:47]=1
Reactant: C1COO1
Reactant: CCSC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Reactant: C=CSC=C
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: O=O
Solvent: ClCCl
Product: C=CCOC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: -78 °C

Procedure:
The vinyl sulfide of Example 1(b) (0.100 g) was irradiated in 20 mL of CH2Cl2 containing a few crystals (<1 mg) of methylene blue with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. TLC indicated that the vinyl sulfide was consumed after 10 min. N-Chlorosuccinimide (0.0446 g) was added and the mixture maintained at -78° C. for 15 minutes. Allyl alcohol (50 uL) was added and the solution warmed to room temperature. Progress of the reaction was monitored by the appearance of a new material by TLC (20% ethyl acetate in hexane) which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 1 was gradually replaced by the blue emission of dioxetane 8. The solution was concentrated to dryness and the residue extracted with ether. The ether was evaporated and the resulting residue chromatographed on a silica prep. TLC plate with 20% ethyl acetate in hexane. The major band contained 47 mg of dioxetane 8: 1H NMR (CDCl3) δ1.09 (m, 1H), 1.26 (m, 1H), 1.471 (dq, 1H), 1.51-1.96 (m, 9H), 2.195 (br s, 1H), 3.127 (br s, 1H), 3.72-3.82 (m, 1H), 4.02-4.12 (m, 1H), 5.14-5.22 (m, 1H), 5.32-5.44 (m, 2H, vinylic H and phenolic-OH), 5.90-6.03 (m, 1H), 6.86-6.93 (m, 1H), 7.19 (br s, 2H), 7.26-7.34 (m, 1H).
Reaction SMILES: Cl[C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C-:7]1(Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1.[Zr+2:13].COC>C(OCC)C>[CH3:7][C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Zr+2:13]
Reactant: Cl[c-]1cccc1
Agent: [Zr+2]
Agent: COC
Solvent: CCOCC
Product: C[c-]1cccc1
Product: c1cc[cH-]c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
First of all, the polysilane to be employed in this example was synthesized as follows. Namely, a mixture comprising 60 mL (milliliter) of dried diethyl ether and 5.34 g of dichlorozirconocene were stirred in an argon atmosphere at a temperature of −20° C., during which 1.6 μm methyl ether was added little by little to the mixture. After continuing the stirring for 70 minutes, the mixture was further stirred at 0° C. for another 30 minutes. Thereafter, diethyl ether was removed and a white solid thus produced was allowed to sublimate to obtain methylzirconocene.
Reaction SMILES: CO[NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:12].ClCl.[C:15]([OH:18])(=O)C>O>[Cl:12][C:10]1[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=1[O:18][CH3:15])[CH2:5][CH2:4][NH2:3]
Reactant: CONCCc1ccccc1
Reactant: CC(=O)O
Reactant: Cl
Agent: ClCl
Solvent: O
Product: COc1ccc(CCN)cc1Cl
Yield: 26.4 %

Procedure:
Methoxyphenethyl amine (39.4 g, 0.261 mol) was dissolved in water (300 mL) and concentrated HCl(22mL). To this solution was added chlorine gas (20.3 g, 0.287 mol) in glacial acetic acid (300 mL) OVcr a 15 minute period while maintaining the temperature below 35° C. After standing for ten minutes, the volatiles were removed in vacuo and the dark solid residue was dissolved in absolute ethanol (100 mL) and allowed to crystallize at -10° C. The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL). The organic layer was separated and dried over anhydrous sodium sulfate. It was condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg) to give 12.8 g (26.4%) of a clear oil. 1R (neat) 3600-3310 (br,NH2), 1600, 1500, 1250 and 1060 cm-1 ; 1H NMR(CDCl3)δ,d 7.36-6.71 (m, 3H, ArH), 3.85 (S, 3H, OCH3), 3.15-2.48 (m, 4H, (CH2)2), 1.12(S, 2H, NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22](O)=[S:23])=[N:14]1.C(N(CC)CC)C.C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:46]=[N+:47]=[N-:48])=[S:23])=[N:14]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Temperature: 5 °C
Yield: 90.9 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole-3-carboxylic acid (5.6 g) was dissolved in dry N,N-dimethylformamide (50 ml) and triethylamine (1.33 g) added. After cooling to 5° C., a solution of diphenylphosphorylazide (3.63 g) in N,N-dimethylformamide (20 ml) was added. When the solution had reached ambient temperature, it was heated to 35° C. for 21/2 hours. After evaporation in vacuo at a temperature kept below 40° C., a solution of sodium chloride (5 g) in water (100 ml) was added, and the suspension extracted with ether (3×100 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulphate and evaporated to give 1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole-3-carboxylic acid azide (5.4 g). A solution of this in dry toluene (200 ml) was heated under reflux with stirring for 1.5 hours, tert-butanol (35 ml) was added, and reflux continued for 4 hours. After evaporation in vacuo the residue was purified by chromatography eluting with dichloromethane to give the title compound (3.3 g) as an off-white solid, m.p. 122°-125° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:15]=[C:16]([Cl:29])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([Cl:29])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:31]([O:33][CH3:34])=[O:32])[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)c1sc2nc(Cl)nc(Cl)c2c1-c1ccccc1
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
A solution of diisopropylamine (0.755 mL, 5.33 mmol) in dry tetrahydrofuran (10 mL) was cooled with an acetone/cardice bath to −55° C. under a nitrogen atmosphere. Butyllithium in hexanes (2.0 mL, 4.98 mmol, 2.5 M) was added and the temperature was allowed to rise to 0° C. for 10 min. The mixture was cooled to −55° C. and a solution of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1.00 g, 3.56 mmol) in dry tetrahydrofuran (10 mL) was added. The mixture was stirred for 1 hr, maintaining the temperature at −55° C. Methyl chloroformate (0.561 mL, 7.11 mmol) was added and the mixture was allowed to rise to room temperature. It was stirred for 4 hr. Water (20 mL) was added to quench the reaction. The layers were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown solid. (1.63 g). This was purified by silica chromatography (50 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 10%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the target compound as a yellow solid (1.24 g). m/z [M+H]+338.9/340.9. Retention time 4.89 min (LCMS method+ve 6 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24]>C1(C)C=CC=CC=1>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:24][CH2:23][CH2:22][O:9]1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(C)OCCO2)cc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 4-methylacetophenone (1.00 g, 7.45 mmol), p-toluenesulfonic acid (133 mg, 0.745 mmol) and ethylene glycol (1.20 mL, 22.4 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxolane (23) as a colourless oil (1.05 g, 59%). 1H nmr (200 MHz, CDCl3) 1.65 (s, 3H, CH3), 2.35 (s, 3H, ArCH3), 3.74-3.86 (m, 2H, OCH2), 3.94-4.06 (m, 2H, OCH2), 7.15 (d, J=8.2 Hz, 2H, 2×ArH), 7.37 (d, J=8.2 Hz, 2H, 2×ArH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)n1nc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccc3[nH]ccc3c2)c2c(N)ncnc21
Yield: 74.6 %

Procedure:
Tert-butyl 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-1-carboxylate (BA86, 9 mg, 0.022 mmol) was dissolved in 50:50 CH2Cl2:TFA and stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA89 (4.8 mg, 75% yield). ESI-MS (M+H)+ m/z calcd 293.1, found 293.0.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:18](O)=[O:19])(=[O:15])=[O:14].C(N(CC)CC)C.[CH2:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH3:35][N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][CH:17]([C:18]([N:48]1[CH2:49][CH2:50][CH:45]([CH2:43][CH3:44])[CH2:46][CH2:47]1)=[O:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NC(CCCNC(=O)OCc3ccccc3)C(=O)O)cccc12
Reactant: CCC1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1CCN(C(=O)C(CCCNC(=O)OCc2ccccc2)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2d (48.90 g, 0.098 mol), triethylamine (25.0 mL, 0.18 mol) and 4-ethylpiperidine (20.0 g, 0.18 mol) in anhydrous dimethylformamide (160 mL) was added dropwise diphenylphosphoryl azide (21.1 mL, 0.098 mol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ether (150 mL) and water (80 mL). The ethereal layer was separated and the aqueous layer was extracted four additional times with ether (80 mL). The combined ethereal extracts were then washed with saturated sodium bicarbonate solution and brine prior to drying (Na2SO4) and solvent concentration. Two identical reactions were performed in tandem. Purification of the combined residues by HPLC on silica gel (elution with 50% ethyl acetate in hexane) furnished 53.09 g (45%) of 3d as a yellow foam, m.p. 56°-62° C. (dec.); 1H NMR (CDCl3) δ 8.47 (d, 1H), 8.30 (t, 1H), 8.16 (d, 1H), 7.58 (m, 1H), 7.56-7.36 (m, 6H), 7.15 (d, 1H), 6.17-5.96 (dd, 1H), 5.10 (s, 2H), 4.75-4.62 (bm, 1H), 4.10-3.91 (bm, 2H), 3.42-3.30 (bm, 1H), 3.16-2.92 (bm, 2H), 2.85-2.83 (d, 6H), 2.68-2.41 (dt, 1H), 2.24-1.97 (m, 1H), 1.57-0.76 (m, 3 H), 0.16-0.08 (m, 1H); 13C NMR (CDCl3) ppm 168.50, 156.40, 151.62, 136.50, 135.00, 134.70, 130.56, 130.44, 129.80, 129.35, 129.18, 128.50, 128.41, 128.07, 128.00, 123.01, 122.93, 119.33, 115.58, 115.47, 66.60, 52.29, 52.19, 45.70, 45.43, 45.37, 45.13, 42.02, 42.21, 40.35, 40.18, 37.48, 37.34, 32.17, 31.92, 31.06, 30.79, 30.65, 29.67, 28.77, 28.58, 25.12, 11.08; IR (KBR, cm-1) 33,50 2975, 2975, 2950, 1725, 1650, 1550, 1475, 1350, 1275, 1180, 1160; MS m/z (MH+) 595.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:9]#[N:10].[Na+].Cl[CH:13]1[C:16]([CH3:18])([CH3:17])[C:15]([CH3:20])([CH3:19])[C:14]1=[O:21]>CN(C)C=O>[CH3:20][C:15]1([CH3:19])[C:16]([CH3:17])([CH3:18])[CH:13]1[C:14]([O:8][CH:1]([C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1(C)C(=O)C(Cl)C1(C)C
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(C(=O)OC(C#N)c2ccccc2)C1(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 100 mmol of benzaldehyde, 100 mmol of sodium cyanide and 50 ml of N,N-dimethylformamide was stirred at a temperature of 80° C for 30 min. Then, an amount of 100 mmol of 2-chloro-3,3,4,4-tetramethylcyclobutanone was added over a period of 30 min and stiring was continued for six hours. At the end of this period the reactants were fully converted and alpha-cyanobenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate was obtained in a yield of 65%.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[CH2:43][C:44](O)=[O:45]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:44](=[O:45])[CH2:43][C:37]4[C:36]5[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=5)[NH:39][CH:38]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)N3C[C@@H]4[C@H](C3)C(c3ccccc3)(c3ccccc3)CC[C@@]4(O)c3ccccc3OC)c2c1
Yield: 61.3 %

Procedure:
By working in accordance with Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.41 g of (5-methoxy-3-indolyl)acetic acid, 0.66 g of (3aS,4S,7aS)-7,7-diphenyl-2-[(5-methoxy-3-indolyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol is obtained in the form of a beige foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][NH:45][C:46]([C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=1)=[O:47].C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl.CO>COCCOC.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>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:42]=[CH:43][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:52]3[CH:51]=[CH:50][CH:49]=[C:48]([C:46](=[O:47])[NH:45][CH3:44])[CH:53]=3)[C:11]=12
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)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: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c23)c1
Reaction time: 6 h
Yield: 35.6 %

Procedure:
A stirred mixture of N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.144 mmol; prepared as in Example 7, Step C), 3-(N-methylaminocarbonyl)phenyl boronic acid (51.47 mg, 0.288 mmol), Pd(PPh3)4 (8.31 mg, 0.0072 mmol) dissolved in 3:1 DME:aqueous 2N Na2CO3 (8 mL) was heated at 70° C. Reaction was monitored by TLC (90/10 CHCl3/MeOH). After stirring for 6 hours, the reaction mixture was partitioned between ethyl acetate (25 mL) and water (50 mL). The organic layer washed with brine, dried over sodium sulfate, filtered and evaporated to afford crude product. The crude was purified by silica gel column chromatography (Biotage 12M) eluting with 2% MeOH/DCM to give the product as pale orange glass (36 mg, 35%). LRMS (APCI pos) m/e 703.2 (M+H).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[C:13]([O:17][CH3:18])(=[O:16])C=C.[C:19](C1C=CC=C(O)C=1O)(C)(C)[CH3:20]>COCCOCCOC>[CH:5]1([C:6]([O:8][CH3:9])=[O:7])[CH2:20][CH2:19][CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:3][CH:4]1[C:13]([O:17][CH3:18])=[O:16]
Reactant: C=CC(=O)OC
Reactant: COC(=O)/C=C/C=C/C(=O)OC
Reactant: CC(C)(C)c1cccc(O)c1O
Solvent: COCCOCCOC
Product: COC(=O)C1CCC(C(=O)OC)C(C(=O)OC)C1
Temperature: 150 °C

Procedure:
In a 75 ml sealed tube, a stirred suspension of trans,trans dimethyl muconate (10.0 g, 58.8 mmol), two equivalents of methyl acrylate (10.6 ml, 117.6 mmol), neutral Al2O3 (300 mg of Aldrich 199974, 3 mass percent), and tert-butyl catechol (25 mg, 0.2 mol percent) in diglyme (20 ml, 2.9 M) is heated to 150° C. for 24 hours. After cooling to room temperature, the reaction mixture is filtered, transferred to a flask, and concentrated (0.5 M). Pd/C catalyst is added (856 mg (0.3 mol percent) of Johnson-Matthey 5 percent Pd/C #6) at room temperature. The flask is equipped with a reflux condenser, fritted gas dispersion tube, and internal T probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux for 27 hours whereby trimethyl trimellitate (46 percent over 2 steps) is formed. Some trimethyl cyclohexane-1,2,4-tricarboxylate is also produced.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[N:9]#[C:10][Br:11]>CCO.O.CCO.O>[BrH:11].[N:1]1[N:2]=[C:10]([NH2:9])[N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12
Reactant: N#CBr
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: O
Product: Br
Product: Nc1nnc2ccccn12

Procedure:
2-Hydrazinopyridine (654 mg) was dissolved in a mixture of EtOH and water (7.5/1.5 ml) at RT while stirring. Subsequently, cyanogen bromide solution (666 mg dissolved in a mixture of EtOH/water 1.5/0.3 ml) was added dropwise while stirring. After stirring at RT for 6 h, the solvent was drawn off, and the residue was taken up in water and freeze-dried. 1.3 g of the title compound were obtained. LC-MS rt: 0.15 min [M+H]+: 135.3 (met. a)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=2[N:10]=1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)#[CH:28].C(N(CC)CC)C>O1CCCC1.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)I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:28]#[C:27][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH:7]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3Br)n(CC3CCCCC3)c2cc1F
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (600 mg, 1.36 mmol) in tetrahydrofuran (20 ml) was added 4-ethynyl-benzonitrile (173.4 mg, 1.36 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (57.2 mg, 0.08 mmol), copper iodide (7.7 mg, 0.04 mmol) and triethyl amine (20 ml) at 25° C. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite and solvents were removed under reduced pressure. The residue was purified by column chromatography over silica gel (10% ethyl acetate/n-hexane) to afford the desired compound as a yellow solid (18%). MS (Turbo Spray): m/z=485.6 (M+H).