Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH2:13])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]2=[C:16]([C:23](O)=[O:24])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:23]([C:16]3[CH:15]=[N:14][N:18]4[CH:19]=[CH:20][CH:21]=[N:22][C:17]=34)=[O:24])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1-c1cccc(Cl)c1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]nc1-c1cccc(Cl)c1)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 20.3 %

Procedure:
A mixture of 3-(3-chlorophenyl)-1H-pyrazol-4-amine (95.3 mg, 0.492 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90.6 mg, 0.555 mmol, 1.13 eq), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (247.3 mg, 0.6504 mmol, 1.32 eq), N,N-diisopropylethylamine (0.20 mL, 1.1 mmol, 2.3 eq), and 4-dimethylaminopyridine (24.1 mg, 0.197 mmol, 0.40 eq) in 5.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 33.8 mg (20%) of N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=339.0; 1H NMR (400 MHz, DMSO-d6) δ: 13.05 (s, 1H), 9.99 (s, 1H), 9.38 (d, 1H), 8.84 (d, 1H), 8.70 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.58 (t, 1H), 7.50 (d, 1H), 7.34 (d of d, 1H).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][O:11][CH2:12][C:13]1C=CC=CC=1F.O[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN1CCCC1=O>[C:25]1(=[O:26])[NH:21][C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]12.[CH3:9][CH2:10][O:11][CH2:12][CH3:13]
Reactant: Fc1ccccc1COCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOCC
Product: O=C1NC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.4 %

Procedure:
At 20° to 25° C. and over a period of 1 hour, 108 ml of triethylamine was dripped into a mixture of 165 g (0.71 mol) of 1-bromo-2-(2-fluorobenzyloxy)-ethane, 116 g (0.7 mol) of N-hydroxyphthalimide and 710 ml of N-methyl-2-pyrrolidone. After the mixture had been kept for 5 hours at 60° C., the cold mixture was poured into 2000 ml of ice water, the precipitate was suction filtered, washed with water and isopropanol and dried under reduced pressure over phosphorus pentoxide. There was obtained 185 g (82%) of phthalimide ether, m.p. 62°-64° C. 1H-NMR (250 MHZ, d6 -DMSO): δ=3.85 (m,2H), 4.35 (m,2H), 4.54 (s,2H), 7.10-7.40 (m,4H), 7.88 (s,4H).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.ClCCl.C(N([CH2:39][CH3:40])CC)C>O>[O:12]=[C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]1[O:1][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:1][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][C:3]=2[C:40]2[CH:39]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1c(-c2ccccc2)oc2ccccc2c1=O)c1ccc(C(=O)Oc2c(-c3ccccc3)oc3ccccc3c2=O)cc1
Temperature: 25 °C

Procedure:
To the three-necked round bottom flask attached with reflux condenser, calcium chloride guard tube and nitrogen inlet, 3-hydroxy-2-phenyl-4H-chromen-4-one (0.59 g), terephthaloyl chloride (0.59 g) and dichloromethane (50 ml) were charged. Then triethyl amine (0.29 g) was charged and the reaction mixture was stirred at room temperature and monitored by thin layer chromatography (TLC). On completion of the reaction 10 ml water was added to the reaction mixture and the organic layer was separated. The organic layer was dried and evaporated under reduced pressure to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([CH2:16][CH2:17][CH2:18]Cl)[CH2:7][CH2:6]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([CH2:16][CH2:17][CH2:18][N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)N(CCCCl)CC2
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc(CCN(CCCN2CCc3cc(OC)c(OC)cc3C2=O)Cc2ccccc2)cc1OC

Procedure:
1-[6,7-Dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl]-3-[N-benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane was prepared analogous to Example 1 (b) by reacting 1-(6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl)-3-chloropropane with N-(3,4-dimethoxy-phenylethyl)-N-benzyl-amine in chlorobenzene in the presence of potassium carbonate. Yield: 2.2 gm (69.8% of theory); Rf -value (chloroform/methanol = 19:1): 0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:22][CH:21]=1)=O>O.C(O)C.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccccc2F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(Cl)cc2c1C(=O)O
Yield: 67.2 %

Procedure:
To a stirred suspension of 4.54 g of 5-chloroisatin in 40 ml of water was added a solution of 5.62 g of sodium hydroxide in 20 ml of water. To the resulting solution at 85°-90° C. was added dropwise over 2 hours, a warm solution of 9.3 g of 2-amino-1-(2'-fluoro[1,1'-biphenyl]-4-yl)ethanone, hydrochloride in 70 ml of water, 70 ml of ethanol and 30 ml of tetrahydrofuran. This mixture was stirred at reflux for 2 hours then the ethanol was distilled off. The reaction was cooled in an ice bath, the solid collected and washed with water. This solid was stirred in 800 ml of water for 2 hours and then filtered. The filtrate was acidified to pH 4-5 with acetic acid. The resulting solid was collected, washed with water and dried, giving 6.6 g of the desired product as a yellow solid, mp 247°-249° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1.O>C(Cl)Cl>[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH:21][C:8]([C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[CH3:7])=[O:10])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1
Reactant: Cc1nc(Cl)sc1C(=O)O
Reactant: CC1CC(C)(C)c2cccc(N)c21
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Cl)sc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
252 mg (1.42 mmol) of 2-chloro-4-methylthiazole-5-carboxylic acid and 442 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidomethiodide were dissolved in 10 ml of methylene chloride and stirred at room temperature for 1 hour. Then, to the solution was added 249 mg (1.42 mmol) of 1,1,3-trimethyl-4-aminoindan and reaction was effected for 6 hours under reflux. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was concentrated and thereafter was purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 204 mg of N-(1,1,3-trimethyl-4-indanyl)-2-chloro-4-methylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=O)C.P([O-])([O-])([O-])=O>>[OH:7][CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH2:4]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The activity is determined by the following method. Namely, 0.3 ml of a 10% solution of N-acetyl-D-glucosamine is added as a substrate to 0.1 ml of a 200 mM phosphate buffer solution (pH 7.8). Next, 0.1 ml of an enzyme solution is further added thereto followed by incubation at 48° C. for 30 minutes. Then the D-glucosamine thus formed is determined by the indole/hydrochloric acid colorimetry. The amount of the enzyme by which 1 μmol of D-glucosamine is formed in a minute is referred to as 1 U (unit).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:18][OH:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:12]2[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CC=CCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CCC2)cc1
Reaction time: 64 h

Procedure:
A solution of 10.48 g (55 mmol) of p-toluenesulphonyl chloride in 10 ml of pyridine is slowly added dropwise to a solution, cooled to -10°, of 5.6 g (50 mmol) of (S)-3-cyclohexene-1-methanol in 20 ml of pyridine. The solution is stirred at -10° for 64 hours, thereafter evaporated in a high vacuum and the residue is taken up in ether. The ether solution is washed in succession with 1N hydrochloric acid, water and saturated sodium bicarbonate solution and subsequently evaporated under reduced pressure. [(S)-3-Cyclohexen-1-yl]methyl p-toluenesulphonate is thereby obtained as a colourless oil; MS: 173 (M)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[C:10]([CH3:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[C:10]([CH3:21])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C)cn(CC3CCCCC3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CC2CCCCC2)c2cc(C(=O)O)ccc12
Temperature: 70 °C

Procedure:
A mixture of methyl 1-cyclohexylmethyl-3-methyl-1 H-indole-6-carboxylate and lithium hydroxide (8.0 g) in aqueous methanol (300 ml, 1:2, v/v) was heated at 70° C. for 4 hours. The reaction mixture was cooled to room temperature, then acidified by addition of dilute hydrochloric acid and then extracted three times with ethyl acetate (150 ml). The combined extracts were dried over sodium sulphate then evaporated to give the title compound as a white solid (7.3 g). M+271.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])#[N:2].[ClH:16].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CN(C)C(=O)Oc1cc(F)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1cc(F)ccc1CN
Yield: 38 %

Procedure:
To a solution of intermediate 132, dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20 mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated in a Parr Shaker at 55 psi of hydrogen for 20 hrs. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give an oil which was partitioned between ethyl acetate (10 mL) and water (10 mL). After separation, the aqueous phase was washed with additional ethyl acetate (5 mL). The combined extracts were concentrated in vacuo to dryness. The residual oil was triturated with ether to provide 145 mg (Yield 38%) of the title compound, as a tan powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.06 (3H, s, NMe), 3.21 (3H, s, NMe), 4.11 (2H, s, NCH2), 7.13 (2H, m, Ar-Hs), 7.60 (1H, m, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 36.03, 36.25 37.58, 110.79, 110.99, 113.26, 113.43, 122.32, 132.18, 132.25, 151.55, 154.72, 162.69, 164.67. HRMS (ESI) calcd for C10H13N2O2F (M+H) 213.1039, found 213.1039.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18][CH2:19][CH3:20]>CC(C)=O>[IH:18].[CH2:19]([S:16][C:15](=[NH:17])[NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH3:20]
Reactant: CCI
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)=O
Product: CCSC(=N)Nc1ccc(Oc2ccccc2)cc1
Product: I
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-phenoxyphenyl)-2-thiourea (2.00 g, 8.19 mmol) in acetone (20 ml) was added iodoethane (7.61 g, 48.7 mmol). The mixture was heated to reflux for three hours, cooled to room temperature and concentrated at reduced pressure. The resulting viscous oil was crystallized from acetone-pentane to afford S-ethyl-N-(4-phenoxyphenyl)isothiourea hydroiodide as a beige solid. Mp=140-143° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][OH:26])[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[Cl-].F[C:29]1[CH:34]=[CH:33][NH+:32]=[CH:31][CH:30]=1>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][O:26][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: OCC[C@@H]1C[C@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1cc[nH+]cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cnc(N2CCC([C@@H]3C[C@H]3CCOc3ccncc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (100%, 20 mg, 0.85 mmol) was weighed into a vial, DMF (anhydrous, 2.1 mL) was added, followed by addition of rac-trans 2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (60 mg, 0.21 mmol) and the mixture stirred at room temperature for 5 min. The 4-fluoropyridinium chloride was then added and stirred at room temperature for 10 min. The mixture was heated to 50° C. for 1.5 hours, cooled to room temperature, and diluted with ethyl acetate (5 mL), quenched with saturated aq.NH4Cl (5 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (30% ethyl acetate/hexane) to yield the titled compound as a white solid. LC-MS (M+1): 359.54. Compounds Reported in Table 3 are Prepared by a General Procedure Analogous to that Described in Example 6, Steps 1 and 2, Described Above
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: COC(=O)CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 50 °C
Yield: 70 %

Procedure:
Methyl 3-bromopropionate (553 μL, 5.07 mmol) was added to a stirred solution of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.00 g, 3.38 mmol; prepared as described in Preparation 1) and DIPEA (1.76 mL, 10.1 mmol) in ACN (34 mL) at 50° C. and the reaction mixture was heated at 50° C. overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in DCM (30 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (5-10% MeOH/DCM) to give 905 mg of the title intermediate (70% yield).
Reaction SMILES: [C:1]1([NH:7][S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[OH:42][C@@H:34]([CH2:33][O:32][C:29]1[CH:30]=[CH:31][C:25]2[S:24][C:23]([CH3:22])=[N:27][C:26]=2[CH:28]=1)[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH2:11][S:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH2:40][CH2:41]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: C=CS(=O)(=O)Nc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCS(=O)(=O)Nc4ccccc4)CC3)ccc2s1
Temperature: 85 °C

Procedure:
To a solution of phenyl(vinylsulfonyl)amine (141 mg, 0.77 mmol) and DIEA (0.47 mL, 4.9 mmol) in EtOH (7.5 mL) was added (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (470 mg, 1.5 mmol, crude). The solution was heated for 2 hours at 85° C. on a J-Kem™ block. Upon cooling, the reaction mixture was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11]([O:13]C)=[O:12])[CH2:7][CH:6]1C(OC)=O>CO.O.O1CCCC1>[O:4]=[C:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: COC(=O)C1CC(C(=O)OC)(c2ccccc2)CCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Yield: 99 %

Procedure:
Lithium hydroxide monohydrate (11.08 g, 264 mmol) was added to a suspension of dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate (Description 1, 25.5 g, 87.9 mmol) in methanol (250 mL), water (83 mL) and tetrahydrofuran (83 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled and the tetrahydrofuran and methanol were evaporated under reduced pressure. The pH was adjusted to 1 with hydrochloric acid (5M) and the mixture was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light yellow solid (19 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.50-7.29 (5H, m), 2.29-2.73 (2H, m), 2.62-2.55 (2H, m), 2.47-2.41 (2H, m), and 2.35-2.27 (2H, m).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:37]4[C:36]5[N:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:30]=[CH:29][C:28]=4[N:27]=[CH:26]3)[O:21][N:20]=2)=[CH:15][CH:14]=1.[OH-].[NH4+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:37]4[C:36]5[N:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N+:30]([O-:6])=[CH:29][C:28]=4[N:27]=[CH:26]3)[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(-c2cc(Cn3cnc4cnc5cccnc5c43)on2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1cc2ncn(Cc3cc(-c4ccc(F)cc4)no3)c2c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (2.4 g of 75% pure material) was added to a suspension of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridine (2.76 g, 7.99 mmol) in dichloromethane (100 mL). The reaction was stirred at room temperature for 30 minutes; an analysis by TLC then indicated the presence of starting material. Additional mCPBA (0.065 g of 75%) was added, and the reaction was stirred for another 30 minutes and found to be complete by TLC analysis. Concentrated ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (1.68 g, 8.79 mmol) were sequentially added. The mixture was stirred for 30 minutes. The volatiles were removed under reduced pressure, and 1 N aqueous sodium hydroxide and water were added to the resulting mixture, which was filtered to isolate a solid. The solid was washed with diethyl ether. Additional solid precipitated from the aqueous filtrate, and was isolated by filtration and combined with the first solid to provide 2.48 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine, which was dissolved in a mixture of methanol (80 mL) and dichloromethane (80 mL). The resulting mixture was heated to 50° C., and concentrated ammonium hydroxide (20 mL) and benzenesulfonyl chloride (1.2 mL, 7.6 mmol) were added. The reaction was heated under a nitrogen atmosphere for one hour, and additional benzenesulfonyl chloride (0.5 mL) was added. The solvents were removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2% to 10% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.612 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white solid, mp 265.0-266.0° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.O=[V].Cl.Cl.Cl>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccccc1
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl chloride (1.9 mg, 0.01 mmol) in 3 mL of anhydrous CH2Cl2 was placed. To the above solution, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH2Cl2 (2 mL) was slowly added to the above brownish solution, and the reaction mixture was stirred for 7.5 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 154.2 mg of 2-phenethyl acetate (94%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 2 of the following Table 1.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:15][C:16]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1.[NH2:24][CH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2>>[NH:30]1[C:31]2[C:27](=[C:26]([CH2:25][NH:24][C:2]3[C:3]4[CH:4]=[CH:5][C:6]([NH:23][C:22]5[C:16]6[O:15][C:14]([CH3:13])=[CH:18][C:17]=6[CH:19]=[CH:20][CH:21]=5)=[N:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NCc1cccc2[nH]ccc12
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(NCc5cccc6[nH]ccc56)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=419.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 4-aminomethylindole.