Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21]C(=O)C)[CH:15]=[CH:14]3)=[CH:7][C:6]=1[O:41][CH3:42])(=[O:4])=[O:3].C([O-])(O)=O.[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][C:6]=1[O:41][CH3:42])(=[O:4])=[O:3]
Reactant: COc1cc(-c2ccc3cc(OC(C)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Yield: 76.1 %

Procedure:
Dissolve the compound of Example 81 (210 mg, 0.36 mmol) in MeOH (4 mL). Add NaHCO3 (60 mg, 0.72 mmol) and stir the reaction mixture for 12 hours at room temperature. Filter and remove the solvent under reduced pressure. Purify the residue by flash column chromatography (silica gel, 2 to 10% MeOH—NH4OH (10/1, v/v)/CH2Cl2) to give 150 mg of 6-(4-methanesulfonyl-3-methoxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol (75%). Dissolve the free base (150 mg, 0.27 mmol) in CH2Cl2 (5 mL) and cool to −78° C. Add 2M HCl in diethyl ether (0.2 mL) and stir the solution for 5 minutes. Remove the solvent under reduced pressure to give a solid. Dry the solid at room temperature overnight in vacuo to give 140 mg of the title compound (87%): mass spectrum (ion spray): m/z=548.1 (M+H−HCl).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Br:7][C:8]1[C:17]2[C:16]([CH3:19])([CH3:18])[CH2:15]CCC=2[CH:11]=[C:10]([CH:20]([O:22][C:23](=[O:25])[CH3:24])[CH3:21])[C:9]=1[O:26][CH3:27]>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Br:7][C:8]1[C:17]2[C:16]([CH3:18])([CH3:19])[CH2:15][CH2:4][C:1](=[O:5])[C:3]=2[CH:11]=[C:10]([CH:20]([O:22][C:23](=[O:25])[CH3:24])[CH3:21])[C:9]=1[O:26][CH3:27]
Reactant: COc1c(C(C)OC(C)=O)cc2c(c1Br)C(C)(C)CCC2
Reactant: CC(C)(C)OO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(C(C)OC(C)=O)cc2c(c1Br)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of chromium (VI) oxide (160 mg, 1.6 mmol) in dichloromethane (40 mL) at 0° C. was added tert-butyl hydroperoxide (13 mL, 96 mmol). After stirring at room temperature for 5 min, a solution of acetic acid 1-(4-bromo-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl ester (Compound A-97, 11.4 g, 32 mmol) in dichloromethane (10 mL) was added. The mixture was stirred at room temperature for 6 days and then quenched with 10% sodium bisulfite.). Organic phase was washed with 10% sodium bisulfite and brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from ethyl acetate and flash column chromatography of the mother liquid (silica gel, 10% ethyl acetate in hexane) afforded the title compound as a yellow solid.
Reaction SMILES: [CH:1]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[C@@H:7]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
tert-Butyl (2R)-4-sec-butyl-2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]piperazine-1-carboxylate (75 mg) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added and the mixture stirred at room temperature overnight. The mixture was partitioned between dichloromethane (75 ml) and saturated aqueous sodium bicarbonate (15 ml) and the organic layer concentrated in vacuo and adsorbed onto silica for purification by chromatography eluting with 0-20% methanol/dichloromethane. This gave the product as a brittle white solid (41 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCc1ccc(F)cc1
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCO)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) and N,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl N-(2-hydroxyethyl)benzenesulfonamide. The resulting oil was dried in vacuo (3.7 g, 68%). ES-MS m/z 250 (M+H) and 294 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=[O:27])([CH3:24])([CH3:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4n3C(=O)OC(C)(C)C)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-ylboronic acid (320.0 mg, 1.40 mmol), K3PO4 (440.0 mg, 2.08 mmol), Pd(PPh3)4 (40.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in dichloromethane (50 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.1%-1% ethyl acetate in petroleum ether to afford methyl 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (280.0 mg, 81%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.CC([Si](C)(C)O[CH:26]1[CH2:34][CH:29]2[O:30][C:31](=[O:33])[CH2:32][CH:28]2[CH:27]1CCC(O[Si](C(C)(C)C)(C)C)CCCCC)(C)C.[CH3:53][Si:54]([CH3:57])([CH3:56])Cl>O1CCCC1>[CH3:53][Si:54]([CH3:57])([CH3:56])[O:33][C:31]1[O:30][C:29]2=[CH:34][CH:26]=[CH:27][CH:28]2[CH:32]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCC(CCC1C(O[Si](C)(C)C(C)(C)C)CC2OC(=O)CC21)O[Si](C)(C)C(C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[Si](C)(C)OC1=CC2C=CC=C2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.5 ml of diisopropylamine in 50 ml of dry THF (tetrahydrofuran) cooled to 0° C. was added dropwise over a period of twenty minutes 19.6 ml of n-butyllithium (1.5M in hexane). After stirring an additional five minutes at 0° C. the solution was cooled to -40° C. (dry ice/acetone) after which time a solution of 13.1 g (0.0263 mol) of [3aR-[3a alpha,4alpha(3S*), 5beta,6a alpha]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl)-2H-cyclopenta[b]furan-2-one dissolved in 100 ml of THF was added slowly while maintaining the temperature at -40° C. After five minutes at this temperature 4.5 ml of trimethylchlorosilane was added rapidly. The cooling bath was then removed and the reaction allowed to warm to 15 C. The solvent was then removed under vacuum and the residue treated with 50 ml of dry ether. The mixture was then filtered through a cintered glass filter and the solvent evaporated under high vacuum to produce [3aR-[3a alpha, 4alpha (3S*), 5 beta, 6a alpha]]-4,5,6,6a-tetrahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[1,1-dimethylethyl)dimethylsilyl]oxy]-octyl]-2-[(trimethylsilyl)oxy]-3aH-cyclopenta[b]furan. This compound was then dissolved at 0° C. in 50 ml of dry CH2Cl2 containing 5.26 g of KHCO3, followed by the slow addition of 5.0 g of xenon difluoride. The mixture was then stirred for an additional 0.5 hr at 0° C. and then poured into 500 ml of ice water followed by extraction with CH2Cl2. The organic layer was separated, dried, and the solvent removed under reduced pressure. The residue (9.1 g) was then chromatographed on 500 g of silica gel (2% by volume ethyl acetate/98% by volume petroleum ether to 10% ethyl acetate/90% by volume petroleum ether) and afforded 2.2 g of starting material and 7 g (51.5% yield) of [3S-[3alpha,3a alpha,4alpha(3S*),5beta,6a alpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-one as a colorless liquid [α]D25 -29.35 (CHCl3, C=0.726).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([C:24](=[O:37])[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:12]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].CN(C1C=CC=CN=1)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>C(O)(=O)C.O1CCCC1.O.C(OCC)(=O)C.CCCCCC>[CH3:52][S:53]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([C:24](=[O:37])[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:12]1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2C[C@@H](CCO[Si](C)(C)C(C)(C)C)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2C[C@@H](CCOS(C)(=O)=O)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
3.95 g (6.92 mmole) of 2-[(5R)-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)oxazolidin-5-yl]ethanol t-butyldimethylsilyl ether [prepared as described in step (f) above] were dissolved in 70 ml of a 3:3:1 by volume mixture of acetic acid, tetrahydrofuran and water. The mixture was then heated under a nitrogen atmosphere at 80° C. for 8 hours. At the end of this time, the solution was neutralised by the addition of a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 30 ml of pyridine. 70 mg (0.57 mmole) of dimethylaminopyridine and 0.66 ml (8.53 mmole) of methanesulfonyl chloride were added, whilst ice-cooling, to the resulting solution, and the mixture was then stirred under a nitrogen atmosphere at 0° C. for 2 hours. At the end of this time, the reaction mixture was poured into 200 ml of ice-cooled 10% w/v aqueous hydrochloric acid and then extracted three times, each time with 100 ml of ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 5:1 to 1:1 by volume as the eluent, to obtain 3.02 g (yield 82%) of the title compound as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:31])[NH:7][C:6]=2[CH:32]=1.O>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][N:26]5[CH2:27][CH2:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:31])[NH:7][C:6]=2[CH:32]=1
Reactant: O=C1Cc2cnc(Nc3ccc(C#CCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cnc(Nc3ccc(CCCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of 9-chloro-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H benzo[b]pyrimido[4,5-d]azepin-6-one (I-47) (0.082 g, 0.19 mmol) in EtOH (5 mL) was added Pd/C (10% wt, ˜50% H2O, 0.01 g) and the mixture was placed under H2 (1 atm) and stirred for 12 h at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. Purification by C-18 RP LC-MS chromatography afforded I-66 (0.046 g, 56%):
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1>>[CH:1]1([CH2:6][O:7][C:13]2[CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH:10]=[CH:9][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCCC2)c1

Procedure:
Coupling of cyclopentylmethanol (0.22 g, 2.4 mmol) with compound 58 (0.56 g, 2 mmol) following the method used in Example 2 gave 2-(3-(3-(cyclopentylmethoxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.29 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.78-7.83 (m, 2H), 7.66-7.72 (m, 2H), 7.13 (t, J=7.8 Hz, 1H), 6.71-6.77 (m, 2H), 6.66 (ddd, J=0.6, 2.5, 8.0 Hz), 3.78 (d, J=7.0 Hz, 2H), 3.74 (t, J=7.0 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.28-2.38 (m, 1H), 1.98-2.07 (m, 2H), 1.77-1.87 (m, 2H), 1.52-1.66 (m, 4H), 1.30-1.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Se](=O)=[O:14]>C(O)(=O)C>[CH:1]([C:2]1[O:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: O=[Se]=O
Reactant: CCOC(=O)C1=C(C)OCCC1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C=O)OCCC1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of ethyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate (6.0 g, 35.3 mmol) and selenium dioxide (4.3 g, 38.8 mmol) was stirred in acetic acid (141 mL) 5 hours at 110° C. The reaction was then cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated down and purified by silica gel chromatography with 0 to 15% ethyl acetate/heptane gradient, followed by 15% to afford the title compound (1.710 g) as an amber oil in about 90% purity. MS (ESI) [m/e, (M+H)+]=185.3. 1H NMR (400 MHz, chloroform-d) δ ppm 10.22 (s, 1H), 4.28 (q, J=7.24 Hz, 2H), 4.12-4.19 (m, 2H), 2.54 (t, J=6.57 Hz, 2H), 1.88-1.98 (m, 2H), 1.30-1.38 (m, 3H).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2[nH]ncc2F)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 92 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methylazetidin-1-yl)-5-iodonicotinamide (Stage 90.1) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole to afford a white solid. HPLC (Condition 7) tR=5.813 min, UPLC-MS (Condition 8) tR=0.98 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 3H) 3.54-3.74 (m, 4H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.58-7.71+7.94-8.01 (m, 1H) 7.83-7.92 (m, 2H) 8.05 (br. s, 1H) 8.78 (br. s, 1H) 10.23 (s, 1H) 13.03 (br.s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[OH-].[Na+:23]>O>[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[Na+:23]
Reactant: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
A 22 L, Pyrex glass, five-neck, round bottom flask was equipped with an overhead stirrer, thermocouple temperature read out, and heating mantle. The flask was charged with 2099.7 g of N-(5-chlorosalicyloyl)-8-aminooctanoic acid and 6000 mL water and stirred. To this slurry was added a solution of 265 g of sodium hydroxide dissolved in 2000 mL water. The mixture was heated to about 80° C. causing most of the solids to dissolve. The undissolved material was allowed to settle to the bottom of the flask and the supernate decanted. The resulting mixture was transferred to the pot flask of a large laboratory rotary evaporator. The rotary evaporator was operated with a bath temperature of about 60° C. and a pressure of about 70 mmHg. Water was removed from the disodium salt mixture until a solid mass was obtained in the rotary evaporator pot flask. The vacuum was released and pot flask removed from the rotary evaporator. The solids were scraped from the pot flask into trays. These trays were then placed in a vacuum oven and the solids dried at about 60° C. and full vacuum for about 48 hours. The dried solids were run through a laboratory mill until all the solids passed through a 35 mesh screen. The milled and served disodium N-(5-chlorosalicyloyl)-8-aminooctanate was put into trays and placed back into the drying oven. Drying was continued at full vacuum to yield 2161.7 g of the desired product as a dry powder.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:24])([CH2:13][CH2:14][N:15]([CH2:20][CH2:21][O:22][CH3:23])[CH2:16][CH2:17][O:18][CH3:19])[CH3:12])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][N:15]([CH2:16][CH2:17][O:18][CH3:19])[CH2:14][CH2:13][C:11]([CH3:24])([NH2:10])[CH3:12]
Reactant: COCCN(CCOC)CCC(C)(C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CCOC)CCC(C)(C)N
Temperature: 85 °C
Yield: 100 %

Procedure:
A glass microwave reaction vessel was charged with benzyl(4-(bis(2-methoxyethyl)amino)-2-methylbutan-2-yl)carbamate (500 mg, 1.42 mmol) in TFA/DCM (1:1, 4 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 85° C. for 7 h. The solvent was removed and the residue was filtered through a plug of Si-carbonate (0.59 mmol/g) and washed with DCM (300 mL, 5% MeOH in DCM (200 mL) and the filtrate was concentrated to give N1,N1-bis(2-methoxyethyl)-3-methylbutane-1,3-diamine (310 mg, 1.42 mmol, 100% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.47 (4H, t, J=6.1 Hz), 3.34 (6H, s), 2.71 (4H, t, J=6.1 Hz), 2.60-2.67 (2H, m), 1.50-1.59 (2H, m), 1.10 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][CH:5]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:6](=[O:34])[N:7]1[CH:12]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH:11]2[CH2:33][CH:8]1[CH2:9][CH2:10]2.[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[NH:55][C:56]([C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[C:64](Br)[CH:65]=3)[CH:60]=2)=[CH:57][N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[NH:55][C:56]([C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[C:64]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:12]6[CH:11]7[CH2:33][CH:8]([CH2:9][CH2:10]7)[N:7]6[C:6](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:41])[CH:35]6[CH2:36][CH2:37][O:38][CH2:39][CH2:40]6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH:65]=3)[CH:60]=2)=[CH:57][N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
To a solution of [2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]hept-2-yl)-ethyl]-carbamic acid methyl ester (0.24 g, 0.42 mmol) in DME (2.5 mL) was added 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.43 mmol), Tetrakis(triphenylphosphine)Palladium (0.03 g, 0.02 mmol) and aqueous potassium phosphate (2 M, 0.65 mL, 1.3 mmol). The solution was degassed with argon for 15 min and heated to 80° C. for 18 h with stirring. The solution was cooled and concentrated. The crude oil was purified by column chromatography (SiO2, 30-100% EtOAc (10% MeOH) in Hexanes to 50% MeOH in EtOAc) to provide 2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-azabicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.26 g, 76%). LCMS-ESI+: calc'd for C46H53N7O6: 799.41 (M+); Found: 800.4 (M+H+).