Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([CH2:10][CH:11]([CH2:22][CH2:23][C:24]([O:26]CC1C=CC=CC=1)=[O:25])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([S:8]([CH2:10][CH:11]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:12]([OH:14])=[O:13])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CS(=O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC(CS(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a cooled solution (5° C.) of dibenzyl 2-[(benzylsulfinyl)methyl]pentanedioate (15.2 g, 33.9 mmol) in tetrahydrofuran (750 mL) was added 0.1 N NaOH (745 mL, 74.5 mmol NaOH) with stirring. The cloudy reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture had become homogenous. The solution was concentrated under reduced pressure to remove the tetrahydrofuran. The remaining aqueous solution was washed with ethyl acetate, then made acidic (pH 1) with concentrated HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate was removed under reduced pressure and the resulting waxy solid was purified by column chromatography to yield 6.9 g (76%) of white solid.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)=[CH:13][CH:14]=2)[C:9]([OH:25])=[C:8]([C:26]([O:28][CH3:29])=[O:27])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:25][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1nc(COC(C)=O)c2ccc(Oc3cc(F)cc(F)c3)cc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2ccc(Oc3cc(F)cc(F)c3)cc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 8c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (8c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:54]1([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:62]3[CH2:63][CH2:64][CH:59]([N:54]4[CH2:58][CH2:57][CH2:56][CH2:55]4)[CH2:60][CH2:61]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reaction time: 16 h
Yield: 90.1 %

Procedure:
7.20 g (17.5 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) were dissolved in 290 ml of DMF and treated with 6.846 g (17.5 mmol) of HATU. 7.30 ml=5.30 g (52.4 mmol) of Et3N were added and after 30 min, a solution of 2.72 g (17.5 mmol) of 4-pyrrolidin-1-yl-piperidine in 70 ml of DMF was added. After 16 hours, the reaction mixture was poured into crashed ice and extracted three times with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 8.65 g (90%) of the title compound as light brown foam. MS: 549.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[CH:6]=[C:7]2[C:11]=1[N:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:9]=[CH:8]2.[OH-].[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[CH:6]=[C:7]2[C:11]=1[N:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2cnn(C3CCCCO3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (102 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added 1 N aqueous lithium hydroxide (0.67 mL, 0.67 mmol). The reaction was stirred at room temperature overnight. LCMS showed the reaction to be incomplete. Additional lithium hydroxide (0.35 mL, 2 M, 0.7 mmol) was added and the reaction was heated to 40° C. for 1 hour. The reaction was then left stirring at room temperature for 70 hours. The tetrahydrofuran was removed in vacuo and the residue was acidified to pH=4 with 1 N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (84 mg, 91%) as a solid. (M+1-THP) 193.2; 1H NMR (400 MHz, CDCl3, δ): 8.18 (d, J=1.37 Hz, 1H), 8.12 (s, 1H), 7.46 (d, J=1.17 Hz, 1H), 6.26 (dd, J=10.15, 2.54 Hz, 1H), 4.07-4.12 (m, 1H), 4.06 (s, 3H), 3.65-3.81 (m, 1H), 2.54-2.72 (m, 1H), 2.10-2.22 (m, 1H), 2.01-2.10 (m, 1H), 1.71-1.85 (m, 2H), 1.57-1.67 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[S:10][N:9]=1.[ClH:26].C(OCC)(=O)C>CO>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[S:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3F)ns2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A mixture of tert-butyl 4-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (5.70 g, 15.6 mmol), 4 N hydrogen chloride/ethyl acetate (200 ml) and methanol (100 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give 4.31 g (86.5%) of the desired product as a solid.
Reaction SMILES: C[CH:2]1[CH2:6][O:5][C:4](=O)[C:3]1=[O:8].[C:9]([O-])(=O)C.C(O)(=O)C.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH3:9][C:6]1[O:5][CH2:4][C:3](=[O:8])[C:2]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1COC(=O)C1=O
Reactant: C1CCNC1
Reactant: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(N2CCCC2)C(=O)CO1
Temperature: 25 °C

Procedure:
From 4-Methyl-dihydro-furan-2,3-dione and pyrrolidium acetate in ethanol. A solution of 4-methyl-dihydro-furan-2,3-dione (100 mmol, prepared according to Fleck et al., Helv. Chim. Acta 1950, 33, 130), acetic acid (100 mmol) and pyrrolidine (100 mmol) in ethanol (225 mL) was refluxed for 2,5 h. After cooling down to room temperature, the solvent was removed in vacuo and the residue was taken up in water (200 mL). The solution was then extracted with diethyl ether (5×100 ml), the combined organic layers were dried over sodium sulphate and then freed from solvent in vacuo. The residual oil was dissolved in pentane/diethyl ether (3/2, v/v; 10 mL) and then applied onto a column (30×500 mm) filled with a slurry of aluminium oxide (basic activity III-IV, Merck, Darmstadt, Germany) in pentane. Chromatography was performed using pentane (300 mL; fraction A), pentane/diethyl ether (9/1, v/v; 400 mL; fraction B), pentane/diethyl ether (80/20, v/v; 400 mL; fraction C), pentane/diethyl ether (70/30, v/v; 400 mL; fraction D), pentane/diethyl ether (60/40, v/v; 400 mL; fraction E), pentane/diethyl ether (50/50, v/v; 400 mL; fraction F). Fraction F containing 2(5H)-MPF (2.25 g, 14% in yield) was collected and freed from solvent under vacuo affording the target compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH3:13])[C:7]2=[O:14].P(Cl)(Cl)([Cl:17])=O.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:17])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: Cn1c(=O)[nH]c2c(Br)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(Cl)nc2c(Br)cccc2c1=O
Yield: 84.3 %

Procedure:
A slurry of 8-bromo-3-methylquinazoline-2,4(1H,3H)-dione (722b, 1.14 g, 4.47 mmol), phosphoryl trichloride (4.09 mL, 44.7 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.11 mL, 17.88 mmol) was stirred at reflux for 19 h. The reaction mixture was concentrated, diluted with ice, basicified with 10 N NaOH to ˜pH 10, filtered, and washed with water to give brown solid. The solid was transferred to an Erlenmeyer flask and dissolved in DCM when a small aqueous layer formed; this was partitioned in a separatory funnel. The organic layer was partially concentrated, loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 8-bromo-2-chloro-3-methylquinazolin-4(3H)-one (722) (1.03 g, 3.77 mmol, 84% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.77 (s, 3H) 7.35 (t, J=7.92 Hz, 1H) 8.02 (dd, J=7.82, 1.37 Hz, 1H) 8.21 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 273.9/275.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1>C(Cl)Cl>[NH2:5][C:3](=[O:4])[CH2:2][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(N)=O)cc1OC
Temperature: 85 °C
Yield: 91.4 %

Procedure:
To a sealed tube was added 2-bromoacetamide (2.272 g, 16.47 mmol), DMF (50 mL), cesium carbonate (7.15 g, 21.96 mmol) and methyl 4-hydroxy-2-methoxybenzoate (1.00 g, 5.49 mmol). The tube was sealed and heated for 16 hours at 85° C. The reaction mixture was diluted with DCM, washed sequentially with 10 mL of 1M HCl, water, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed to give 1.2 grams of methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (78% yield) as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 3.71-3.76 (m, 3H), 3.80-3.84 (m, 3H), 4.45 (s, 2H), 6.56 (dd, J=8.66, 2.38 Hz, 1H), 6.65 (d, J=2.26 Hz, 1H), 6.77 (br. s., 1H), 6.92 (br. s., 1H), 7.75 (d, J=8.78 Hz, 1H). LCMS Rt=1.385 min., m/z 240.2 (M+H), 92% purity.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]1([CH:17]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOC(C)=O.C(#N)C>[Cl-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18](=[O:19])[CH:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)[CH2:22]2
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccsc1)N1CCCCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccsc1)N1CCCCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
2-Chloro-1-phenylethanone (107 mg, 0.69 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(piperidin-1-yl)-2-(thiophen-3-yl)acetate (210 mg, 0.63 mmol) in EtOAc (4.2 ml) and acetonitrile (2.1 ml) and. The mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=9/1) to collect the title compound (117 mg, 38.1% yield) as an off-white spongy solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:42]([C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH2:46])[CH3:43]>>[CH2:42]([C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH:46][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1)[CH3:43]
Reactant: CCc1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: CCc1ccccc1NC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 2-ethylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[CH2:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>O>[CH2:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=1)[CH2:13][CH3:14]
Reactant: C=C(Cl)c1ccc(CCC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C#Cc1ccc(CCC)cc1

Procedure:
Potassium t-butoxide (21-5 g) was added to stirred t-butanol and warmed to gentle reflux. The alkene product from step 2.3 (20 g) was added dropwise and then the mixture was heated under reflux for 3 hrs. Water (100 ml) was added and the product extracted into petroleum spirit (3×100 ml), washed with 10% HCl and water. The crude alkine product was 97% pure by gc. Yield 12 g.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:14]([O:13][C:11]([O:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6])=[O:12])[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: N#CC(=NO)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)ON=C(C#N)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a mixture of water (100 ml) and acetone (15 ml), sodium salt of 2-hydroxyimino-2-cyanoacetic acid amide (19.6 g) is added, and the obtained solution in which a part of the sodium salt is present in a suspended state is cooled at 0°C. Ethyl chloroformate (15 g) is dropwise added thereto, and the resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred at room temperature for 1 hour and then filtered to collect the precipitated crystals. To the filtrate, a small amount of acetonitrile is added, and the mixture is extracted with ether. The ether layer is washed with water, dried and concentrated to give crystals, which are put together with the above obtained crystals to obtain 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (22.5 g). A part of the product is recrystallized from ethyl acetate to give crystals melting at 194° to 196°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](Cl)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1.[N+](C)([O-])=O.C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:14]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:13])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COc1ccc(O)c2ccccc12
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(O)c2ccccc12
Yield: 71.8 %

Procedure:
A solution of 4-methoxy-1-naphthol 11 (435 mg, 2.5 mmol) in toluene (5 mL) and nitromethane (0.75 mL) was treated with scandium triflate (61.52 mg, 0.125 mmol) and acetyl chloride (0.195 mL, 2.75 mmol) and irradiated in the microwave reactor (Personal Chemistry, Inc) at a temperature of 170° C. for 5 minutes. The cooled reaction was diluted with methylene chloride and filtered through a small pad of silica gel. The filtrate was evaporated to dryness and purified via flash chromatography, eluting the pure C-acylated product 12 with CH2Cl2/hexanes (1:1). Pooled fractions were evaporated to afford 12 as a greenish yellow solid (0.388 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 2.69 (s, 3H, COCH3), 3.99 (s, 3H, OCH3), 6.84 (s, 1H, Ar-3-H), 7.80 (m, 2H, Ar—H), 8.10 (d, 1H, Ar—H), 8.21 (d, 1H, Ar—H), 13.76 (s, 1H, OH).
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:13]C(OCC[Si](C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[C:1]([O:5][C:6]([C@:8]1([NH2:13])[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@]1(NC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@@]1(N)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the product of Step 3 (3 g, 9 mmol) was added a 1.0 M TBAF solution in THF (9.3 mL, 9.3 mmol) and the mixture heated to reflux for 1.5 h, cooled to rt and then diluted with 500 ml of EtOAc. The solution was successively washed with water (2×100 mL), brine (2×100 mL), dried (MgSO4), concentrated in vacuo to provide the title intermediate.
Reaction SMILES: C([O:4][C@@H:5]([C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH3:14])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+].CO>O>[CH:9]1([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[C@@H:12]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:13][CH3:14])[CH2:11][CH2:10]1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (2S,3S)-3-(tert-butoxycarbonylamino)-1-(cyclopropylamino)-1-oxopentan-2-yl acetate (1.09 g, 3.47 mmol, Eq: 1.00) and NaOH 1N in H2O (5.2 ml, 5.2 mmol, Eq: 1.5) were combined with methanol (10 ml) to give a colorless solution. The reaction was stirred for 2 h at RT. The reaction mixture was poured into 25 mL H2O and extracted with ethyl acetate (2×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light brown solid (540 mg, 57.2%, MS (m/e)=273.4 [M+H+]).
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])[N:9]1[N:15]=[N:16][C:17]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[C:8]1[NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:30]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]2[N:15]=[N:16][C:17]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[C:8]2[N:7]=1
Reactant: COc1cc2c(=O)[nH]c3c(S(=O)(=O)c4ccccc4)nnn3c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: COc1cc2c(Cl)nc3c(S(=O)(=O)c4ccccc4)nnn3c2cc1OC
Temperature: 120 °C
Yield: 59 %

Procedure:
A mixture of 7,8-dimethoxy-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5-a]quinazolin-5(4H)-one (262 mg, 0.68 mmol) and tetrabutylammonium chloride (189 mg, 0.68 mmol) in POCl3 (10 mL) was heated at 120° C. for 30 min and then cooled to room temperature. After removal of POCl3 in vacuo, the residue was purified by column chromatography on silica gel eluting with 30% ethyl acetate in hexane to yield 5-chloro-7,8-dimethoxy-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5-a]quinazoline (162 mg, 59%). 1H NMR (CDCl3, 600 MHz) δ 8.28-8.26 (m, 2H), 8.04 (s, 1H), 7.61 (s, 1H), 7.60-7.58 (m, 1H); 7.56-7.54 (m, 2H), 4.18 (s, 3H), 4.10 (s, 3H); MS (ES+) m/z 405.0 (M+H)+
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]3[C:17]([CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:24]=O.[ClH:26]>>[ClH:26].[ClH:26].[C:1]12([CH2:11][CH2:12][N:13]3[C:17]4[CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH:20][CH2:24][C:16]=4[N:15]=[CH:14]3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=O
Reactant: N[C@@H](Cc1cncn1CCC12CC3CC(CC(C3)C1)C2)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.8 g 3-(2-(1-adamantyl)ethyl)histidine.2HCl in 100 mL 1N HCl is treated with 5 mL 36% formaldehyde, stirring 30 min at 25° C. followed by 90 min at reflux. Evaporation gives 1-(2-(1-adamantyl)ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid dihydrochloride as a white solid. NMR (D2O) 8.90 (s, 1H, 2-Im).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:31]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4([C:27]5[CH:26]=[N:25][N:24]([CH3:28])[C:23]=5[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[O:16]4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:29][CH3:30])[CH2:33][CH2:32]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1C1CC1
Temperature: 120 °C

Procedure:
To a microwave vial was added (4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (70 mg, 0.15 mmol), cyclopropylboronic acid (26 mg, 0.30 mmol), Fibre cat (49 mg, 0.0075 mmol), DMF (0.7 mL), and K2CO3 (150 μL of 3.0 M, 0.45 mmol). The vial was purged with nitrogen and was heated at 120° C. for 2 hours. The reaction was filtered and purified by HPLC (20-99%) MeOH:H2O. ESI-MS m/z calc. 429.2, found 430.4 (M+1)+. Retention time: 2.95 minutes (4 min run).