Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br:13][C:14]1[C:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.[H-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[Br:13][C:14]1[C:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])=[CH:16][C:17]2[C:18]([CH3:26])([CH3:27])[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[C:22]=2[CH:23]=1
Reactant: CC1(C)CCC(C)(C)c2cc(OCCCCCO)c(Br)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(OCCCCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The acetate obtained above is saponified and the resulting hydroxyl group is then protected according to the following procedure: tert-Butyldimethylsilyl chloride (2.64 g) is added to a mixture of 5-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)pentan-1-ol (4.3 g, 11.7 mmol) and 80% sodium hydride (422 mg) in THF (20 ml). The mixture is stirred at room temperature for 2 h. The solution is poured into a mixture of water and ethyl acetate. The organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31].O.[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a well stirred solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethylamino)pyridine (9.3 g, 75.8 mmol) in CH2Cl2 (200 mL) was added powdered 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) at 0° C. The reaction mixture was stirred for 12 h at room temperature and then water (50 mL) was added. The pH of the aqueous layer was adjusted to 10-11 by the addition of 6 N sodium hydroxide. The dichloromethane layer was separated and dried (Na2SO4). Solvent was evaporated in vacuo and the residue was purified by column chromatography (SiO2, dichloromethane/hexane, 20%-50%) to yield the product as a viscous oil (32.0 g, 98%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([I:3])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Cc2ccc(I)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was the product from step 3 (310 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (290 mg, 59%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.08 (m, 4H), 3.26-3.46 (m, 2H), 3.70-3.93 (m, 1H), 3.85 (s, 2H), 4.02-4.19 (m, 2H), 6.82-6.88 (m, 2H), 6.91 (d, J=7.6 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H):
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1.C(=O)(O)[O-].[Na+].O>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.O1CCOCC1>[CH3:19][C:17]1[N:18]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:15][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: O=[N+]([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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc([N+](=O)[O-])cc2)nc1C
Yield: 83 %

Procedure:
The same operation as in Example (91a) was performed using 4-nitrophenylboronic acid (1 g, 6 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1 g, 4 mmol), sodium bicarbonate (1.34 g, 16 mmol), tetrakis(triphenylphosphine)palladium (460 mg, 0.4 mmol), water (5 mL) and 1,4-dioxane (10 mL), to obtain 0.97 g of the title compound as a light yellow solid (83%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
reaction of androst-4-ene-3,17-dione with acetic anhydride to produce 3-acetoxyandrost-3,5-diene-17-one,
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(O[N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:28])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]1=C=O)C.[OH-].[Na+]>C(Cl)Cl>[CH3:28][N:18]([CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1)[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN(c1ncccc1[N+](=O)[O-])C1CCN(OC(C)(C)C)C(=C=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ncccc1[N+](=O)[O-])C1CCNCC1
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (13.0 ml) is added to a solution of 1-((1,1-dimethylethoxy)-carbonyl-4-(N-methyl-N-(3-nitro-2-pyridinyl)amino)piperidine (PREPARATION 49) in methylene chloride (100 ml) with cooling to -78°. The mixture is warmed to 20°-25° , stirred 17 hrs, cooled to 0° and basified to pH 12 with 5% sodium hydroxide. The phases are separated and the aqueous phase is extracted with methylene chloride (2×50 ml). The combined organic phases are dried over sodium sulfate and concentrated to give the title compound, mp 115.5°-117°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:37])[N:11]([CH:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:30]3([CH:34]([OH:36])[CH3:35])[CH2:33][CH2:32][CH2:31]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[C:34]([C:30]1([CH:28]([O:27][CH:24]2[CH2:25][CH2:26][CH:21]([N:11]3[C:10](=[O:37])[C:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:3][C:2]=4[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]4[N:18]=[CH:19][N:20]=[C:12]34)[CH2:22][CH2:23]2)[CH3:29])[CH2:33][CH2:32][CH2:31]1)(=[O:36])[CH3:35]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C(C)O)CCC3)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C(C)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A mixture of 3′-fluoro-4′-{[4-(4-{1-[1-(1-hydroxyethyl)cyclobutyl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (13 g), Dess-Martin periodinane (10 g) and acetonitrile (130 mL) was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution and 1 M aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (11 g, 88%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N+:11]([O-:16])([N+]([O-])=O)=[O:12]>>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:11]([O-:16])=[O:12]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Brc1coc2ccccc12
Product: O=[N+]([O-])c1oc2ccccc2c1Br
Reaction time: 0.08 h

Procedure:
To a stirred 80 g. sample of solid 3-bromobenzofuran is added a large excess of dinitrogen tetraoxide. The mixture liquifies within 5 minutes. After 2 hours, the mixture is triturated with ethanol and filtered to provide yellow crystals of 3-bromo-2-nitrobenzofuran. The product is identical to the product of Example 1 according to infrared spectral analysis.
Reaction SMILES: ClCCl.CS(C)=O.C(N(CC)CC)C.[C:15]([O:19][C:20](=[O:26])[N:21]([CH2:23][CH2:24][OH:25])[CH3:22])([CH3:18])([CH3:17])[CH3:16].S(=O)(=O)=O>O>[C:15]([O:19][C:20](=[O:26])[N:21]([CH3:22])[CH2:23][CH:24]=[O:25])([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Combine under a nitrogen atmosphere, dichloromethane (37.91 moles; 2.43 L), dimethyl sulfoxide (7.30 moles; 518.4 mL), triethylamine (1.85 moles; 257.7 mL), and (2-hydroxy-ethyl)-methyl-carbamic acid t-butyl ester (924.5 mmoles; 162.0 g). Add in steps sulfur trioxide:pyridine complex (1.849 moles; 300.3 g), maintaining the reaction temperature less than 20° C. Stir the reaction mixture at ambient temperature overnight. Add 1.0 L water, separate the organic layer, wash with 10% citric acid in water (800 mL), water and brine. Concentrate and pass through a silica plug, eluting with 20% ethyl acetate/hexanes. Add toluene (200 mL) and concentrate to provide the title intermediate (yield 62.45%, 100 g).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([I:24])=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])[CH:9]=1>CC1CCCO1.O.[OH-].[Na+]>[F:3][C:4]1[C:5]([I:24])=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Potassium hydroxide (669 mg, 7.7 mmol) was added to a solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (691 mg, 1.55 mmol) in 2-methyltetrahydrofuran:water (2:1 22.5 mL) and the solution was stirred at 70° C. for 2 h. The reaction was diluted with 1 N aq NaOH (50 mL). The organics were separated and the aqueous layer was washed with EtOAc (2×50 mL), and acidified to a pH of 3 using 3 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×60 mL), dried (MgSO4), filtered and concentrated to afford a yellow-white solid (290 mg, 44.8%). MS (LCMS) m/z 418.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3H) 2.08-2.20 (m, 1H) 2.36-2.48 (m, 1H) 3.13 (s, 3H) 3.79-4.02 (m, 2H) 7.03 (d, J=6.05 Hz, 1H) 7.96 (d, J=4.29 Hz, 1H) 13.82 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=2)[N:10]=[N:9]1.[ClH:26].C(OCC)(=O)C>>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=2)[N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3F)nn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1cc(C2=CCNCC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-[1-(2-fluorophenyl)-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (70 mg) prepared in Example 5 was dissolved in 2.0 ml of 4N hydrochloric acid/ethyl acetate solution followed by stirring at room temperature for 30 minutes. The solvent was evaporated in vacuo to give the title compound as a brown crude product.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[O:15]1[CH2:14][CH:13]1[CH2:11][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1
Reactant: BrCC1CO1
Reactant: O=c1[nH]nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CC2CO2)nc2ccccn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) and epibromohydrin (1.27 ml) in N,N-dimethylformamide (10 ml), sodium hydride (60% in oil) (326 mg) was added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained solid was washed with n-heptane to obtain the title compound (290 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[CH:42]=[N:43][N:44]([CH:48]2[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]2)[C:45]=1[CH2:46][OH:47].[F-].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:41]2[CH:42]=[N:43][N:44]([CH:48]3[CH2:49][CH2:50][NH:51][CH2:52][CH2:53]3)[C:45]=2[CH2:46][OH:47])=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc(Br)c2CO)CC1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2CO)cc1-c1nc2ccccc2o1
Temperature: 120 °C
Yield: 42.3 %

Procedure:
Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (250 mg), tert-butyl 4-(4-bromo-5-(hydroxymethyl)pyrazol-1-yl)piperidine-1-carboxylate (131 mg), bis(triphenylphosphine) palladium chloride (12.73 mg) and caesium fluoride (165 mg) were weighed out in a microwave vial and sealed. Methanol (3 ml) was added and argon was let to bubble in the resulting suspension for 5 minutes. The resulting mixture was heated in the microwave at 120° C. for 20 minutes. Insolubles were removed by filtration and the filtrate was concentrated. Hydrogen chloride (5N in isopropanol) (1.814 ml) was added and the mixture was heated at reflux for 2 hours. The resulting precipitate was collected by filtration, washed with isopropanol. The solid was taken up into methanolic ammonia (7N-2 mL) and dicalite speed plus. The crude product was purified by flash chromatography on silica gel eluting with 5 to 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-2-(4-piperidyl)pyrazol-3-yl]methanol (60 mg). NMR Spectrum: (DMSOd6) 1.80-1.89 (m, 2H), 1.93 (dd, 1H), 1.98 (dd, 1H), 2.25 (bs, 1H), 2.57-2.67 (m, 2H), 3.03-3.11 (m, 2H), 4.37-4.46 (m, 1H), 4.56 (d, 2H), 5.46 (t, 1H), 7.41-7.48 (m, 2H), 7.70 (bs, 2H), 7.71 (s, 1H), 7.79 (dd, 1H), 7.85 (dd, 1H), 8.35 (d, 1H), 8.36 (d, 1H). Mass spectrum: M+H+ 391;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[C@H:10]([F:16])[C@H:9]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].CP(C)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[C@H:10]([F:16])[C@H:9]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
A solution of (2R,3R,4R)-4-azido-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) (485 mg, 1.16 mmol), trimethylphosphine in THF (2.33 mL, 2.33 mmol) and water (0.04 mL, 2.33 mmol) in THF (20 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 95:5). MS (UPLC/MS): 390/392 [M+H]+, 434/436 [M+HCOO]−; tR (HPLC conditions f): 1.64 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].C([O:29][C:30]([C:32]1[S:33][C:34]([CH2:37]Cl)=[CH:35][CH:36]=1)=[O:31])(C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[C:30]([C:32]1[S:33][C:34]([CH2:37][C:20]([CH3:22])([CH3:21])[C:19]([OH:24])=[O:23])=[CH:35][CH:36]=1)([OH:29])=[O:31]
Reactant: CC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(CCl)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccc(C(=O)O)s1)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (478 μL, 3.40 mmol) was dissolved in tetrahydrofuran (2.0 mL), the mixture was stirred at −78° C. for 15 minutes, and 2.6N n-butyllithium/hexane solution (1.31 mL, 3.40 mmol) was added dropwise. After dropwise addition, the mixture was stirred at 0° C. for 30 minutes, and isobutyric acid (158 μL, 1.70 mmol) was added dropwise at −78° C. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 20 minutes, 5-chloromethylthiophene-2-carboxylic acid tert-butyl ester (360 mg, 1.55 mmol) dissolved in tetrahydrofuran (1.5 mL) was added at 0° C., and the mixture was stirred at room temperature overnight. Ethyl acetate and 1N aqueous hydrochloric acid solution were added to the reaction mixture, the mixture was partitioned, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the organic layers was combined and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:2]2[CH2:3][CH2:4][N:5]3[C:13]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[CH:7]=[C:6]3[C:1]2=[O:14])=[CH:22][C:23]([F:27])=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: O=C1NCCn2c1cc1c2CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 104j (3.8 g, 20 mmol), 104m (20 g, 60 mmol), XantPhos (1.2 g, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.8 g, 2 mmol), Cs2CO3 (16 g, 50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 16 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 104n as a white solid (5.2 g, 60%). MS: [M+H]+ 435. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (dd, J=3, 1H), 7.48 (dd, J=3, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:24])[CH2:4][C:5]2([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH2:17][O:18][CH3:19])[C:11]=3[Br:15])[C:6]=12.[CH3:25][Sn](C)(C)C.[Cl-].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.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>[Br:15][C:11]1[C:10]([O:16][CH2:17][O:18][CH3:19])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][C:5]1([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][C:3](=[O:24])[C:2]([CH3:25])=[C:6]12
Reactant: CCCCC12CCc3c(ccc(OCOC)c3Br)C1=C(Br)C(=O)C2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC12CCc3c(ccc(OCOC)c3Br)C1=C(C)C(=O)C2
Temperature: 100 °C

Procedure:
A mixture of 1,6-dibromo-3a-butyl-7-(methoxymethoxy)-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (71 mg, 0.15 mmol), dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.022 mmol), tetramethyltin (0.053 mL, 0.36 mmol), lithium chloride (13 mg, 0.30 mmol), and triphenylphosphine (8 mg, 0.03 mmol) in anhydrous N,N-dimethylformamide (DMF, 0.75 mL) was placed under a N2 atmosphere and heated in an oil bath at 100° C. for 2 days. After cooling, the mixture was concentrated under vacuum, the residue was taken up in CHCl3 and filtered through a pad of silica gel, and the filtrate was evaporated under vacuum to provide an oil. This material was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 2:1 hexane-EtOAc. The UV visible band at Rf 0.44-0.50 was eluted with EtOAc and the eluant evaporated under vacuum to provide 6-bromo-3a-butyl-7-(methoxymethoxy)-1-methyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one contaminated with approximately 10% of 3a-butyl-7-(methoxymethoxy)-1,6-dimethyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one.