Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH3:38])[C@@H:25]([CH2:36][CH3:37])[C:26]([NH:28][C@@H:29]([CH2:34][OH:35])[C:30]([O:32][CH3:33])=[O:31])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([NH:23][C@@H:24]([C@H:25]([C:26]1[O:35][CH2:34][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:28]=1)[CH2:36][CH3:37])[CH3:38])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC[C@@H](C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CC[C@@H](C1=N[C@H](C(=O)OC)CO1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Burgess reagent (1.35 g, 5.66 mmol) was added in one portion to a solution of (S)-methyl 2-((2R,3R)-3-((tert-butoxycarbonyl)amino)-2-ethylbutanamido)-3-hydroxypropanoate (1.71 g, 5.14 mmol) in anhydrous THF (79 ml) under a nitrogen atmosphere. The reaction was then allowed to stir at 60° C. for about 4 hr. TLC indicated complete consumption of starting material and a less polar spot (1:1 hexane:ethyl acetate; KMnO4 staining). After cooling to 0° C., saturated aqueous sodium bicarbonate solution (30 mL) was added and the mixture extracted with ethyl acetate (3×25 mL). The combined organics were then dried (MgSO4) and evaporated in vacuo to give (S)-methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)-4,5-dihydrooxazole-4-carboxylate (1.62 g, 5.14 mmol, 100% yield) as an oil which was used immediately in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH:30]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31]2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH:30]3[CH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][CH2:35]3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1(C)CCC(N(CCOc2ccc(Br)cc2)C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC1(C)CCC(N(CCOc2ccc(-c3cccc(C#N)c3)cc2)C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
A mixture of m-cyanophenyl boronic acid (0.086 g; 0.59 mmol), 1,1-dimethylethyl {2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.250 g; 0.59 mmol; Example V-8), PdCl2(dppf).CH2Cl2, 2M Na2CO3 (4 mL) and DME (4 mL) was sparged 5 min with N2 and then heated to 80° C. for 5 h. Upon cooling, the mixture was diluted with EtOAc, washed with water and the washing was back-extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4, adsorbed onto a minimal amount of silica gel and purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H), 0.94 (s, 3H, partially overlapping 0.92), 1.21-1.87 (m, 17H), 3.45-3.63 (m, 2H), 3.88 (br. s, 1H), 4.10 (br. s, 2H), 7.00 (m, 2H), 7.49 (m, 2H), 7.52 (d, J=7.8 Hz, 1H; partially overlapping 7.49), 7.58 (d, J=7.6 Hz, 1H), 7.77 (partially resolved ddd, Jortho=7.8 Hz, 1H), 7.82 (unresolved dd, 1H).
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=1.C1C(=O)N([Br:27])C(=O)C1>>[Br:27][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cncc2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc2cccc(Br)c12
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a mixture of conc. H2SO4 (16 mL) and methyl isoquinoline-4-carboxylate (Intermediate-15) (2.8 g, 15 mmol) at 0° C. was added, NBS (3.3 g, 18.7 mmol) slowly and the reaction mixture was allowed to come to RT and stirred overnight. After completion (TLC), it was quenched with ice, neutralized (NaHCO3) and extracted with EtOAc (50 mL×3). The organic phase was separated, dried (Na2SO4) and concentrated to give dark brown oil (3.6 g) as crude product that was purified by flash column chromatography (25% EtOAc in Hexanes) to furnish the desired compound (1.4 g, 35%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]#N)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O:21]C)[O:19]C.C([O-])([O-])=O.[K+].[K+]>>[OH:21][C:18]([CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:10]=1)[CH3:16])=[O:19]
Reactant: N#CCc1cccc(C(=O)c2ccccc2)c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 80 %

Procedure:
A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2CO3 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140° C. for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title product are obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzed to obtain ketoprofen by known methods.
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1O)#[N:2].[CH3:13]I.[C:15](=[O:18])([O-])[O-].[K+].[K+]>O>[CH3:13][O:12][C:8]1[CH:7]=[CH:6][C:4]([O:18][CH3:15])=[C:3]([C:1]#[N:2])[C:9]=1[C:10]#[N:11]
Reactant: CI
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(OC)c(C#N)c1C#N

Procedure:
A mixture of 17.1 g. of 2,3-dicyanohydroquinone, 143.5 g. of methyl iodide and 43.5 g. of potassium carbonate is stirred in dimethylformide for approximately 20 hours. The mixture is then treated with 1 liter of water and filtered. The precipitate is washed with water and methanol and dried to yield 3,6-dimethoxyphthalonitrile. The nitrile is then slurried in 150 ml. of sodium hydroxide and heated at 115° C. for approximately seven hours. The resulting solution is cooled, filtered and acidified with hydrochloric acid to precipitate 3,6-dimethoxyphthalic acid. The acid is refluxed in 150 ml. of acetic anhydride for 15 hours and then cooled to room temperature. The resulting crystals are filtered and washed with ether to yield 3,6-dimethoxyphthalic anhydride having a melting point of 265°-268° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)[C:19](O)=O)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:4]=2)[N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Nc1cccc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Reactant: NC(=NO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc2c1ccn2C(c1ccc(Cl)cc1)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N′-Hydroxybenzenecarboximidamide (49 mg, 0.36 mmol) was added to a stirred solution of compound 6a (90 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 1-hydroxybenzotriazole (44 mg, 0.29 mmol) and N,N,-diisopropylethylamine (50 μL, 0.29 mmol) in DMF (2.4 mL). The reaction was allowed to stir at rt for 2 h, at which time, the reaction was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to a crude oil that was dissolved in toluene (2.0 mL). The resulting mixture was heated to 100° C. for 1 h, at which time, the reaction was concentrated in vacuo, and the resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 63. m/z (ES) 479 (MH)+; IP=C rating.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[C:13](=[C:14]([CH2:18][NH:19][C:25](=[O:27])[CH3:26])[CH:15]=[CH:16][CH:17]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Temperature: 4 °C
Yield: 77.8 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added slowly to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The resulting mixture was cooled in an ice bath to 4° C. Acetyl chloride (0.73 g, 9 mmol) was added dropwise at a rate such that the temperature stayed between 4–7° C. After addition was complete, the mixture was stirred in the ice bath for an additional 30 minutes and then allowed to warm to room temperature and maintained for 2 hours. The reaction mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by chromatography (dichloromethane/ethyl acetate 6 to 4) to afford 1.65 g (80%) of the product as an oil: 1H NMR (CDCl3) δ 7.86 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz); 7.46 (t, J=7.7 Hz); 6.29 (b, 1H), 4.39 (d, J=6.1 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[OH:6])[CH2:4][O:3]1.[CH2:17]([O:19][CH:20]=[CH2:21])[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCN(CC)CC>C(Cl)Cl>[CH2:17]([O:19][CH:20]([O:6][CH:5]([C@@:2]1([CH3:1])[CH2:4][O:3]1)[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:21])[CH3:18]
Reactant: CC1([C@H](O)c2ccc(S(C)(=O)=O)cc2)CO1
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)OC(c1ccc(S(C)(=O)=O)cc1)[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step 4 (7.2 g) and ethylvinyl ether (50 mL) in 200 mL of CH2Cl2 cooled to 0° C. was added 50 mg of camphorsulfonic acid. The reaction mixture was stirred at r.t. for 20 min. and then treated with 1 mL of Et3N, concentrated to give the crude title compound (9 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2C=CC=C[C:17]=2[OH:22])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSCCO)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([CH2:16][CH2:17][OH:22])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Agent: COC(=O)c1c(CSCCO)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)CCO)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from methyl 3-bromo-6-(2-hydroxyethylthiomethyl)-2-methoxybenzoate (Intermediate 174).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[O:22])=[CH:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.O.[O-:29]Cl=O.[Na+]>C1COCC1.C(O)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([OH:29])=[O:22])=[CH:13]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cn(C(=O)COCc2ccccc2)c2ccccc12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cn(C(=O)COCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-benzyloxy-acetyl)-1H-indole-3-carbaldehyde (1.53 g, 5.22 mmol) in a mixture of THF (80 mL) and t-butanol (24 mL). A 2 M 2-methyl-2-butene solution in THF (104 mL, 209 mmol) was added, followed by a water (20 mL) solution of NaClO2 (80%, 5.9 g, 52.2 mmol) and NaH2PO4 (5 g, 41.7 mmol). The resulting yellow solution was stirred at RT for 2 h. The solvents were concentrated and the aqueous layer was filtered and the resulting precipitate was washed with Et2O to give the desired compound. LC/MS: 310.1 [M−H]−, 332.0 [M+Na]+, 308.0 [M−H]−, 617.0 [2M−H]−; tR (HPLC conditions a): 3.62 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]([OH:33])=O)[NH:28][C:29]=1[CH3:30].Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[N:50]=2)[C:45]([NH2:47])=[O:46])[CH2:38][CH2:37]1>CN(C=O)C>[Cl:51][C:49]1[CH:48]=[C:44]([CH:43]=[C:42]([N:39]2[CH2:40][CH2:41][CH:36]([NH:35][C:31]([C:27]3[NH:28][C:29]([CH3:30])=[C:25]([Cl:24])[CH:26]=3)=[O:33])[CH2:37][CH2:38]2)[N:50]=1)[C:45]([NH2:47])=[O:46]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Cl

Procedure:
Diisopropylethylamine (0.34 ml, 2.0 mmol), EDC (0.121 g, 0.63 mmol) and HOAT (0.086 g, 0.63 mmol) were added to a stirred solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 8, 0.1 g, 0.63 mmol) in DMF (2 ml) at room temperature. The resultant solution was stirred for 15 mins then a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.19 g, 0.75 mmol) in 3 ml of DMF was added. The reaction was concentrated after 2 hours and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were washed with 1 N HCl, water and brine, then dried over magnesium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (water/acetonitrile gradient, 20-95%) to give the title product as a white solid.
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:33])[C:15]([CH2:27][C:28]([O:30]CC)=[O:29])=[C:16]([CH3:26])[C:17]=2[NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:33])[C:15]([CH2:27][C:28]([OH:30])=[O:29])=[C:16]([CH3:26])[C:17]=2[NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCN1CCCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
N-(1Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2,2-dimethylpropanamide (230 mg) was dissolved in ethanol (5 ml), and a solution of NaOH (100 mg) in water (2 ml) was added, which was followed by stirring at 50° C. for 1 hr. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (50 ml) and washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 1-2 with 2N sulfuric acid and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 130 mg of powdery title compound. TLC; Silica gel 60F254 Art. 5714 (Merck), CHCl3-MeOH (10:1), Rf value 0.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12]>C(Cl)Cl>[NH2:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 1-methylpiperazine (2.5 g, 24.96 mmol) in DCM (30 mL) at 0° C. was added a solution of Intermediate 69A (1.13 g, 5.63 mmol) in DCM (10 mL) slowly. The reaction was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography, (SiO2, 24 g, 0-10% MeOH/DCM) to give Intermediate 69B (0.77 g, 52%) as a yellow oil. HPLC: Rt=0.360 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=265 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([NH2:8])[NH:5][N:4]=1)[CH3:2].[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])=[CH:17][C:12]=2[N:11]=[N:10]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[NH:8][C:6]4[N:5]([N:4]=[C:3]([CH2:1][CH3:2])[N:7]=4)[C:20](=[O:21])[CH:19]=3)=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: CCc1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of 3-ethyl-1H-1,2,4-triazol-5-amine (150 mg, 0.89 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (500 mg, 2.15 mmol) and TsOH (8 mg, 0.04 mmol), and the reaction mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (20 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-ethyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (66.4 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[CH3:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Product: CNc1nc(Cl)nc2c1COC2c1ccc(F)cc1
Yield: 60.8 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (250 mg, 0.877 mmol) and methanamine hydrochloride (89 mg, 1.315 mmol) were combined and purified as per Preparation Ia to give 2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (149 mg, 0.533 mmol, 60.8% yield). LC-MS (M+H)+=280.0. 1H NMR (500 MHz, MeOD) δ ppm 7.31-7.44 (2H, m), 7.05-7.17 (2H, m), 5.80-5.95 (1H, m), 4.94-5.21 (2H, m), 2.93-3.07 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([NH:14][NH2:15])=[O:13])=[CH:5]2.[N:16]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])=[CH:5]2
Reactant: NNC(=O)c1cc2cc(F)ccc2cn1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2cc(F)ccc2cn1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of 6-fluoro-isoquinoline-3-carboxylic acid hydrazide in HCl (1 N, 50 mL) and water (1 L) was added a solution of NaNO2 (11.4 g, 170 mmol, 1.5 eq) in water (100 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 1 h. Another solution of NaNO2 (5.7 g, 85 mmol, 0.5 equiv.) in water (30 mL) was added and the reaction was stirred at 0-5° C. for 3 h until LC-MS indicated the completion of the reaction. The precipitate was filtered, washed with cold water, and dried under high vacuum to give 6-fluoro-isoquinoline-3-carbonyl azide as a light yellow solid (21.3 g, 89%). LRMS (M+H+) m/z 217.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[C:4]([Cl:13])[CH:3]=1.[Li+].[Cl-].[O:16]1CCO[CH2:18][CH2:17]1>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>[Cl:13][C:4]1[CH:3]=[C:2]([C:17](=[O:16])[CH3:18])[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: C1COCCO1
Reactant: Clc1cc(Br)ccc1-c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Product: CC(=O)c1ccc(-c2ncco2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-1,3-oxazole (2.88 g, 11.14 mmol) in 1,4-dioxane (70 mL) were added tributhyl(1-ethoxyvinyl)tin (4.5 mL, 13.37 mmol), LiCl (1.18 g, 27.85 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.28 g, 1.11 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 4 hours, and cooled down to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (30 mL) then 2N HCl (30 ml) was added at room temperature. After 2 hours, saturated NaHCO3 (100 mL) was added to the mixture. The mixture was extracted with ethyl acetate (300 mL) dried over MgSO4. Removal of the solvent, gave an oily residue, which was purified by flash chromatography eluting with ethyl acetate/hexane (1/4) to give title compound (1.891 g, 77% yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:22]=[C:21]([F:35])[CH2:20][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:24][CH2:25]2)=[CH:27][CH:28]=1)[CH3:34]
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(C=C(F)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Yield: 40.6 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (2.35 g), tetrahydrofuran (10 ml) and magnesium (0.21 g) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-ethoxyphenyl)cyclopropane (Example 18) (0.6 g). The residue after evaporation was purified by column chromatography (solvent: diethyl ether/hexane; 5:95) to afford 1-(4-ethoxy-phenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (0.34 g, 41%)
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]([CH3:19])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:5][C:6]([CH3:19])([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:3][CH:2]=[CH2:1])=[CH:16][CH:17]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCBr
Reactant: COC(=O)C(C)(C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CC(C)(C)C(=O)OC)cc1

Procedure:
Allyl bromide (0.66 ml) was added to a stirred suspension of methyl 2,2-dimethyl-3-(4-hydroxyphenyl)propionate (1.41 g) and potassium carbonate (1.08 g) in butan-2-one (12 ml). The reaction mixture was heated at reflux for 19 hours, cooled, and filtered. The filtrate was evaporated to give methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.59 g) as an oil; NMR(CDCl3): 1.17(6H,s), 2.78(2H,s), 3.65(3H,s), 4.50(2H,m), 5.33(2H,m), 6.02(1H,m), 6.70(2H,m) and 7.00(2H,m); m/z 248(M+).