Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:18][CH2:19]Cl)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1.[C:21]([O-:24])([O-])=O.[K+].[K+].[C:27]1([CH:34]=[CH:33][C:31]([OH:32])=[CH:30][CH:29]=1)[OH:28]>CN(C=O)C>[OH:28][C:27]1[CH:34]=[CH:33][C:31]([O:32][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][O:28][C:27]2[CH:34]=[CH:33][C:21]([OH:24])=[CH:30][CH:29]=2)[C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=2)=[CH:30][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(N(CCOc2ccc(O)cc2)CCOc2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
A mixture of compound 27a (470 mg, 1.48 mmol), K2CO3 (440 mg, 3 mmol), and KI (50 mg, 0.3 mmol) in DMF (50 mL) was bubbled with argon for 10 min. Hydroquinone (660 mg, 6 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the compound 27 (150 mg, 0.32 mmol, 22% yield) as a brown oil. 1H NMR (CDCl3, 400 MHz) δ 7.05 (d, J=8.4 Hz, 2H), 6.67-6.81 (m, 9H), 5.58 (bs, 2H), 4.09 (t, J=6.4 Hz, 4H), 3.80 (t, J=6.0 Hz, 7H), 3.69 (s, 3H), 2.56 (t, J=7.2 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 1.89-1.96 (m, 2H); HRMS (ESI, positive) m/z calcd. for C27H32NO6 [M+H]+: 466.2230, found: 466.2204.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:15]2=[O:27])[CH:8]=1>O1CCCC1>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([O:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:28])=[O:5])[C:15]2=[O:27])=[CH:24][CH:23]=1)#[N:26]
Reactant: COC(=O)c1cccc(O[C@@H]2CCN(c3ccc(C#N)cc3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CC[C@@H](Oc3cccc(C(=O)O)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Add water (2 mL) followed by lithium hydroxide (0.62 g, 14.9 mmol) to a solution of 3-[(R)-1-(4-cyano-phenyl)-2-oxo-pyrrolidin-3-yloxy]-benzoic acid methyl ester (1.00 g, 2.98 mmol) of in tetrahydrofuran (4 mL). Stir the mixture overnight at room temperature then concentrate under reduced pressure to remove volatile organics. Wash the concentrated aqueous mixture with EtOAc and then acidify to pH 4 using a 0.5 M solution of citric acid. Extract the mixture with EtOAc and concentrate under reduced pressure to provide 0.74 g of 3-[(R)-1-(4-cyano-phenyl)-2-oxo-pyrrolidin-3-yloxy]-benzoic acid as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([O:7]C)=O.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CC(O)(C)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=3)[C:5]2=[O:7])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2Cc3cccc([N+](=O)[O-])c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-bromomethyl-6-nitro-benzoate (0.73 mmol, 1 eq.) and t-BuOH (3 mL) in a sealed reaction vial was added 4-t-butylaniline (0.73 mmol, 1 eq) and DIEA (0.38 mL, 3 eq). The reaction was stirred at RT for 30 min then heated at 170° C. for 10 min in a microwave. A yellow solid was filtered and washed with t-BuOH and H2O then dried under high-vacuum to afford 2-(4-tert-butyl-phenyl)-7-nitro-2,3-dihydro-isoindol-1-one. MS m/e 311 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[NH2:17])=O)C.C[O-].[Na+].[CH:21]([NH2:23])=O>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]2=[N:8][C:7]3[C:6]([C:4](=[O:3])[NH:23][CH2:21][N:17]=3)=[C:14]2[CH:13]=1
Reactant: CCOC(=O)c1c(N)[nH]c2ccc(OC)cc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
A solution of 2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.15 g (9.2 mmol), sodium methoxide (0.5 g (9.3 mmol), and formamide (200 mL), is heated under N2 at 220° C. for 1.5 h. The solution is cooled to room temperature, stored for 2.5 days, and filtered. The solvent is evaporated by Kugelrohr distillation at 95° C./0.8 mm. The residual solids are washed with H2O, then heated in 35 mL of boiling N,N-dimethylformamide. The hot suspension is filtered hot over a pad of flash silica gel. The cooled filtrate is concentrated in vacuo to a solid that is sonicated in about 30 mL of MeOH. The solids are filtered, washed with MeOH, and dried to leave 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (1.71 g, 72%) that is about 83% pure. 1H NMR (DMSO) δ12.16 (1H, br s, exchanges with D2O), 12.04 (1H, br s, exchanges with D2O), 8.08 (1H, d, J=3.4 Hz, exchanges to s with D2O), 7.46 (1H, d, J=1.9 Hz), 7.37 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=8.8, 2.5 Hz), 3.81 (3 H, s).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].Cl>ClCCl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:19](=[O:20])[CH2:18][Cl:17])=[CH:3]1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 250 ml round bottom flask containing the bicyclo[3.2.1]octane-2,4-dione (10 g, 72 mmol) is added dry dichloromethane (100 ml) and pyridine (6.28 g, 87 mmol). To the stirred mixture is added dropwise over a period of 15 minutes the chloroacetyl chloride (9.82 g, 72 mmol) diluted in dichloromethane (100 ml). The reaction mixture is therefore stirred for 2 hours at room temperature. The reaction mixture is therefore poured into 100 ml of aqueous 2N HCl and extracted with ethyl acetate (2×100 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an orange oil. The crude product is distilled under reduced pressure to give chloro-acetic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester (13.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[N:21]=[C:20]([CH3:22])[NH:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[N:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1nc(NC(=O)c2c(O)cc(C)n(C)c2=O)n[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88.6 %

Procedure:
211 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 90 mg of 3-amino-5-methyl-1,2,4-triazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 7 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 214 mg of 1,6-dimethyl-4-hydroxy-N-(5-methyl-1,2,4-triazol-3-yl)-2-ox o-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 24) represented by the formula:
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22]([CH3:25])(=[O:24])=[O:23])=[O:11])[C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:29]O.C([O-])(=O)C.[Na+]>ClCCl.C(O)C>[CH:7]1([C:5]2[O:6][N:29]=[C:3]([S:2][CH3:1])[C:4]=2[C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:9][CH2:8]1
Reactant: CSC(SC)=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a solution of 12.5 g (28.4 mmol) 2-(bis-methylsulfanylmethylene)-1 -cyclopropyl-3-(2-methanesulfonyl-4-trifluoromethylphenyl)propane-1,3-dione in 80 ml dichloromethane, 140 ml each of ethanol, 2.82 g (39.8 mmol) hydroxylamine hydrochloride and 3.4 g (41.2 mmol) anhydrous sodium acetate is successively added. The reaction mixture is then agitated for 48 hours at a temperature of 20° C. Then 50 ml dichloromethane, 50 ml ethanol, 1.4 g hydroxylamine hydrochloride and 1.7 g anhydrous sodium acetate are added, and the mixture is agitated for a further 3 days at 20° C. The reaction mixture is subsequently heated to a temperature of 30° C., and 2.8 g hydroxylamine hydrochloride and 3.4 g sodium acetate are added. After 18 hours' agitation at a temperature of 30° C., the solvents are distilled off and the residue taken up in 300 ml ethyl acetate. The organic phase is washed twice with water and once with concentrated aqueous sodium chloride solution. After the organic phase has been dried over sodium sulfate, it is treated with activated charcoal, filtered and evaporated to dryness. After recrystallization from a little diisopropylether, 10.7 g 5-cyclopropyl-3-methylsulfanyl-4-(2-methanesulfonyl-4-trifluoromethylbenzoyl)isoxazole is obtained in the form of crystalline solid matter with a melting point of 145-146° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].C[Si](I)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
4-Acetoxy-3,5-di-tert-butylanisole (0.50 g) was dissolved in dichloromethane (2 ml). After cooling with ice, trimethylsilyl iodide (0.31 ml) was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 days; thereafter, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The mixture was subjected to extraction with diethyl ether and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butylphenol [0.38 g (yield, 80%)] as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C=NC1CCCCC1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)NC3CCCCC3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (350 mg) and cyclohexyl isocyanate (0.32 ml) in dry THF (15 ml) containing triethylamine (0.62 ml) was stirred at room temp for 48 h. The mixture was then evaporated and the residue partitioned between water and DCM. The dried extracts were evaporated giving the crude title compound as a white solid (616 mg, >100%, contaminated with dicyclohexyl-urea)
Reaction SMILES: [CH:1]1([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(OCC)C>[Cl:18][CH:8]([C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of ethyl 3-cyclohexyl-3-oxopropanoate (1.0 g, 5.0 mmol) in diethyl ether (15 mL) was added sulfuryl chloride (750 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (150 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (870 mg, 60%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1
Reactant: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2c(c1)CC(CN1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (170 mg, 0.70 mmol), NaBH3CN (84 mg, 1.3 mmol) and HOAc (80 mg, 1.3 mmol) in 50 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (235 mg, 1.3 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.46˜7.51 (m, 4H), 7.34 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.48 (d, J=7.0 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.21 (s, 2H), 2.69˜3.09 (m, 11H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][Br:15])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccnc(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(CBr)ccn2)cc1
Yield: 88.7 %

Procedure:
A mixture of 2-(p-fluorophenyl)-4-methyl-pyridine (0.5 g, 2.67 mmol), N-bromosuccinimide (0.48 g, 2.69 mmol), and a catalytic amount of benzoylperoxide in CCl4 (50 ml) was stirred at reflux temperature and irradiated by means of an ordinary 250-W UV lamp for 4 hrs. Afterwards, the reaction mixture was cooled and subsequently triturated with Et2O/petroleum benzine. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 2-(p-fluorophenyl)-4-bromomethyl-pyridine (0.63 g, 88%, unstable) as a dark yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12>CN(C=O)C>[NH:22]1[C:18]2=[N:19][CH:20]=[CH:21][C:16]([O:12][C:6]3[CH:7]=[C:8]4[C:3](=[CH:4][CH:5]=3)[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9]4)=[C:17]2[CH:24]=[N:23]1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: Nc1cccc2cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Aminonaphthalen-2-ol (356 mg, 2.24 mmol) was dissolved in DMF (2.5 mL) then cooled to 0° C. Sodium hydride (94 mg) was added slowly and the stirring was continued for 15 min at 0° C. 4-Iodo-1H-pyrazolo[3,4-b]pyridine (274 mg, 1.12 mmol) was then added slowly and the reaction was heated at 100° C. for 16 h, followed by 4.5 h at 120° C. The mixture was partitioned between water and EtOAc then washed with water, 1N aqueous NaOH, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine as a brown solid. MS (ESI, pos. ion) m/z: 277.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:16]([CH3:18])[CH3:17])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:21]([NH2:25])(=[O:24])[C:22]#[CH:23]>[Cu]I.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.CN(C=O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:16]([CH3:18])[CH3:17])=[N:7][C:8]3[C:9]([C:23]#[C:22][C:21]([NH2:25])=[O:24])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(C)c1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Reactant: C#CC(N)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
9-bromo-4-iodo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (140 mg, 0.32 mmol), propynoic acid amide (26 mg, 0.38 mmol), copper (I) iodide (9.0 mg, 0.047 mmol), and Pd(Ph3P)4 (37 mg, 0.032 mmol) were added to a vial, followed by DMF (1.5 ml) and TEA (0.13 ml, 0.95 mmol). The resulting suspension was purged with argon (subsurface bubbling) for 10 min, and then stirred for 15 hr at room temperature. The reaction mixture was diluted with DMF and purified directly by reverse phase preparative HPLC using an acetonitrile/water (with 0.05% TFA as a modifier) gradient to afford 3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl)prop-2-ynamide. 1H NMR (500 MHz, DMSO-D6) δ 12.33 (br s, 1H), 10.21 (d, 1H), 8.46 (d, 1H), 8.04 (s, 1H), 7.93 (dd, 1H), 7.91 (br s, 1H), 7.58 (s, 1H), 4.07 (septet, 1H), 1.40 (d, 61-1). LRMS (ESI) calc'd for (C18H14BrN3O2) [M+H]+, 384.0; found 384.0.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCOS(C)(=O)=O

Procedure:
To a solution of 5-hexen-1-ol (5.0 mmol) and triethylamine (5.5 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (5.5 mmol) dropwise at −5° C. The mixture was continuously stirred until the reaction was complete (˜2 h). Dichloromethane (50 mL) was added to the mixture followed by washing with 10% sodium bicarbonate solution (2×15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and concentrated to give 5-hexenyl methanesulfonate, which was used next without further purification. The methanesulfonyl ester (4.0 mmol) and sodium azide (10 mmol) were dissolved in 8:1 DMF—H2O (16 mL) and stirred overnight at 50° C. The mixture was allowed to cool to room temperature, diluted in 50 mL of water, and extracted with diethyl ether (3×30 mL). The ethereal layers were combined, washed with brine (2×15 mL), dried over sodium sulfate, and concentrated in vacuo to give 5-hexenyl azide. The azide (5.0 mmol) was dissolved in diethyl ether (50 mL) and lithium aluminum hydride (5.0 mmol) was added in three portions under argon in a water bath. The grayish suspension was vigorously stirred for ˜40 min and then quenched by the addition of water (5 mL). Sodium hydroxide solution was added to dissolve the solid and the resulting solution was extracted with diethyl ether (5×30 mL). The organic phase was dried over sodium sulfate and concentrated to give amine 13 (57% yield from the alcohol). 1H NMR (250 MHz, D2O): δ 6.11–5.95 (m, 1H), 5.26–5.14 (m, 2H), 3.14 (t, J=7.3 Hz, 2H), 2.25 (m, 2H), 1.87–1.75 (m, 2H), 1.67–1.58 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=4)=[CH:21][C:20]=3[Cl:35])[C:14]2=[O:36])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:62][C:63]([F:71])([F:70])[CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([Si:5]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:20]([Cl:35])=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:67]5[CH2:68][CH2:69][CH:64]([C:63]([F:71])([F:70])[F:62])[CH2:65][CH2:66]5)=[O:34])=[CH:28][CH:27]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:36])[CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.2 %

Procedure:
Treat a solution of 4′-{3-[4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-1-ylmethyl}-3′,5′-dichloro-biphenyl-4-carboxylic acid (0.35 g, 0.5 mmol) in CH2Cl2 (20 mL) with 1,1′-carbonyldiimidazole (0.162 g, 1.0 mmol) and stir for 45 minutes at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.142 g, 0.75 mmol) and diisopropylethylamine (0.097 g, 0.75 mmol), and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 50% ethyl acetate in hexanes to afford 0.21 g (50%) of the title compound. MS (m/z): 835 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11]Br.C([O-])([O-])=[O:14].[Ca+2].CCOC(C)=O>O1CCOCC1.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:14]
Reactant: COc1cc(C)c(Br)c(CBr)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c(Br)c(CO)c1
Temperature: 110 °C
Yield: 12 %

Procedure:
A solution of 2-bromo-1-bromomethyl-5-methoxy-3-methyl-benzene ((Example 192: step b) 10.8 g, 36.7 mmol) in dioxane:water (1:1, 200 mL) was treated with CaCO3 and heated to reflux (110° C.) 18 h. The reaction mixture was cooled to room temperature and filtered by gravity to remove solid salts. The dioxane was removed in vacuo. Dilute HCl (10 mL) was added, and the mixture was extracted with CH2Cl2 (2×150 mL). The combined organic layers were dried over MgSO4. The solvents were removed in vacuo to afford a pale orange oil, which slowly solidified upon standing. Silica gel chromatography (25% EtOAc in hexanes) yielded the product (2-bromo-5-methoxy-3-methyl-phenyl)-methanol (1.03 g, 12%) as a yellow oil. 1H NMR (CDCl3): δ 6.905 (d, 1H, J=3.2 Hz), 6.746 (d, 1H, J=3.2 Hz), 4.720 (d, 2H, J=3.6 Hz), 3.798 (s, 3H), 2.390 (s, 3H).