Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(C)=C2C(=C(C)C=1C)OC(C)(C(O)=O)CC2.C(=O)([O-])[O-].[K+].[K+].C(Cl)C1C=CC=CC=1.[CH2:33]([O:40][C:41]1[C:42]([CH3:64])=[C:43]2[C:48](=[C:49]([CH3:52])[C:50]=1[CH3:51])[O:47][C:46]([CH3:63])([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:45][CH2:44]2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+]>O.CS(C)=O>[CH2:33]([O:40][C:41]1[C:42]([CH3:64])=[C:43]2[C:48](=[C:49]([CH3:52])[C:50]=1[CH3:51])[O:47][C:46]([CH3:63])([C:53]([OH:55])=[O:54])[CH2:45][CH2:44]2)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C(=O)OCc1ccccc1)O2
Agent: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C(=O)O)O2
Reaction time: 8 h

Procedure:
To a mixture of 0.5 g. of (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and 1.3 g. of anhydrous potassium carbonate in 3 ml. of dimethylsulfoxide was added 1.0 g. of benzyl chloride. This mixture was stirred at 23° overnight to give a solution containing (±)-benzyl 6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxylate. To this solution was added 3 ml. of 1N sodium hydroxide solution and 2 ml. of dimethylsulfoxide and the resulting 2-phase solution was stirred at 100° for 16 hours. The mixture was cooled, diluted wth H2O, washed with ether, acidified with 2N HCl, and extracted with ether. The ether solutions were washed with brine, dried over sodium sulfate and stripped of solvent. The residue was crystallized from ether-30°-60° petroleum ether to give (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxylic acid as a white solid, m.p. 154.5°-155° .
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22]Br)[CH2:18][CH2:17]1>CN(C=O)C.O>[N+:9]([C:3]1[C:4](=[O:8])[N:5]([CH2:22][C@H:19]2[CH2:20][CH2:21][C@@H:16]([O:15][CH3:14])[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: COC1CCC(CBr)CC1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@@H](Cn2ccc(C)c([N+](=O)[O-])c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-nitro-2-pyridone (0.93 g, 6.0 mmol) and sodium hydride (60% in oil, 0.25 g, 6.3 mmol) in DMF (20 mL) was stirred at rt for 1 hour. 4-Methoxycyclohexylmethylbromide (1.5 g, 7.2 mmol) in DMF (5 mL) was added. After 60 hours, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed, dried (MgSO4), and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/1 to 3/1) gave cis-3-nitro-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone which crystallized from ethyl acetate/hexane (0.16 g, 10%) and trans-3-nitro-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone which crystallized from ethyl acetate/hexane (0.18 g, 11%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:4])=[O:3]>CN(C=O)C.[Pd]>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (I65) (1.50 g, 3.76 mmol) was taken up in DMF (30 mL) then 10% Pd/C (750 mg) was added. The resulting suspension was stirred under H2 (1 atm) for 16 hours at room temperature. The crude reaction mixture was filtered through Celite, washing with MeOH. The filtrate was evaporated under reduced pressure to give a yellow liquid which was adsorbing onto silica. The silica adsorbed material was chromatographed on silica gel (0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I66) (1.38 g, 91%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=0.7 Hz, 1H), 7.30-7.12 (m, 4H), 3.72 (s, 2H), 3.68 (s, 3H), 3.41-3.35 (m, 2H), 3.35 (s, 3H), 3.20 (dd, J=9.6, 6.3 Hz, 2H). LCMS Method C: rt 5.92 min; m/z 425.1 (M+Na), 403.1 (M+1), 401.1 (M−1), 371.1 (M—OMe), 343.1 (M—COOMe).
Reaction SMILES: CON(C)[C:4](=[O:23])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[H-].[CH2:28]1COC[CH2:29]1>>[O:23]=[C:4]([CH2:28][CH3:29])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])(=[O:16])[O:17][CH2:18][CH3:19])[P:7]([O:9][CH2:10][CH3:11])(=[O:8])[O:12][CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: CCOP(=O)(OCC)C(CC(=O)N(C)OC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOP(=O)(OCC)C(CC(=O)CC)P(=O)(OCC)OCC
Temperature: -78 °C
Yield: 54 %

Procedure:
A solution of N-methoxy-N-methyl-3,3-bis(diethoxyphosphinyl)propionamide (1.00 g, 2.6 mmol) in THF (5 ml) was slowly added to a slurry of 80% sodium hydride (80 mg, 2.7 mmol) in THF (10 ml) at 0° C. Stirring was continued until all of the hydride was consumed (~20 minutes). The solution was cooled to -78° C. and ethylmagnesium bromide (1.0 ml of a 3.0M solution in diethyl ether, 3.0 mmol) was added. After the addition, the reaction mixture was warmed to 0° C. and stirred for one hour. The reaction was quenched by pouring slowly into a well-stirred ice-cold mixture of ethanol (40 ml) and concentrated HCl (5 ml). The solvents were removed in vacuo, the residue was taken up in brine (20 ml) and extracted with dichloromethane (4×20 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the resulting oil was purified by flash chromatography on silica gel eluting with 10% i-propanol in ethyl acetate to give the title compound (0.50 g, 54%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:24][C:17]1[C:18](=[O:19])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[C:14]([CH3:21])[NH:15][C:16]=1[CH3:20]
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(=O)c1Cl
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 3-(4-(4-chlorophenoxy)phenyl)-2,6-dimethylpyridin-4(1H)-one (0.8 g) in acetic acid (10 ml) was added N-chlorosuccinimide (0.39 g). The mixture was heated at 100° for 30 min, cooled to room temperature and the precipitate filtered and dried in vacuo to afford the title compound (0.33 g), m.p. 340°-343°, NMR δH (d6 -DMSO) 11.3 (1H, br.s), 7.42 (2H, m), 7.2 (2H, m), 6.95-7.12 (4H, m), 2.4 (3H, s), 2.1 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11].C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>CCCCCC.C(OCC)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:17]([OH:19])=[O:18])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: O=C=O
Reactant: Cc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The product of step (a) above (4.3 g) was mixed with diethyl ether (30 ml), the mixture cooled to -70° C., and maintained at this temperature whilst a solution of n-butyllithium in n-hexane (1.6 M, 16.4 ml) was slowly added. The mixture was stirred for a period of 1 hour during which time a fine white precipitate was formed. Dry carbon dioxide gas was then passed into the mixture for 30 minutes whilst the temperature was maintained within the range -70° to -40° C., and continued to be passed in thereafter whilst the mixture was allowed to warm to the ambient temperature. After acidifying with dilute hydrochloric acid (6 N, 40 ml) the organic phase was separated, washed with water and dried over anhydrous magnesium sulphate. After evaporation of the solvents under reduced pressure the residual solid was recrystallised from toluene to yield 2,3,5,6-tetrafluoro-4-toluic acid, m.p. 170° C. identified by infra red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C)cc(-c2ccsc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(-c2ccsc2)c1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
Methyl 3-methyl-5-(3-thienyl)benzoate (257 mg, 1.1 mmol) is treated with lithium hydroxide (186 mg, 4.4 mmol) in tetrahydrofuran/methanol/water (8 ml, 2:1:1) and the mixture is stirred for 2 hours at 20-25 degrees C. The mixture is acidified and concentrated to give the title compound, MS [M+H]+=217.0.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][NH:25][O:26][CH3:27].Cl>C1(C)C=CC=CC=1.O.C(OC)(C)(C)C>[CH3:27][O:26][N:25]([CH3:24])[C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg. MS (CI, CH4) m/e 208 (M++1, 100), 119.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:39]O)[CH:17]=[C:18]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:30]([CH3:33])=[N:31][N:32]=4)[C:24]=3[CH:23]=[C:22]2[C:34]2[O:35][CH:36]=[N:37][N:38]=2)[CH:19]=1.Cl.[NH:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1.S([O-])(=O)(=O)C>C(Cl)Cl.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:30]([CH3:33])=[N:31][N:32]=4)[C:24]=3[CH:23]=[C:22]2[C:34]2[O:35][CH:36]=[N:37][N:38]=2)[CH:19]=1)[CH2:39][N:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1
Reactant: OC1CNC1
Reactant: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CO)c3)n12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CN4CC(O)C4)c3)n12
Reaction time: 0.5 h

Procedure:
Triethylamine (49 μL, 0.35 mmol) and methanesulfonyl chloride (22 μL, 0.28 mmol, Aldrich) were added to a mixture of (3-chloro-5-{[1-methyl-7-(1,3,4-oxadiazol-2-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyridin-6-yl]methyl}phenyl)methanol (0.033 g, 0.084 mmol, from Step 4) in DCM (4.9 mL). After 30 minutes, additional triethylamine (49 μL, 0.35 mmol) and methanesulfonyl chloride (22 μL, 0.28 mmol) were added. After 30 additional minutes, the mixture was briefly heated to reflux and then cooled. The solvent was removed in vacuo. The crude mesylate was reconstituted in THF (1.9 mL) and Methanol (1.9 mL). Half of this solution was added to azetidin-3-ol hydrochloride (37 mg, 0.33 mmol, Aldrich) and triethylamine (46 μL, 0.33 mmol) in THF (0.2 mL). [The other half of the mesylate solution was used in Example 140]. After 20 minutes, additional azetidin-3-ol hydrochloride (125 mg, 1.12 mmol, Aldrich) and triethylamine (156 μL, 1.12 mmol) were added and the mixture was stirred overnight. Sequential preparative HPLC-MS runs were used to purify the product (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA, followed by Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 10%).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17]Cl.[CH3:20][O:21][C:22](=[O:35])[CH2:23][NH:24]S(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C[O-].[Na+]>CN(C=O)C.CO.O.C(O)(=O)C>[CH3:20][O:21][C:22]([C:23]1[N:24]=[CH:17][C:5]2[C:4]([C:3]=1[OH:19])=[CH:9][CH:8]=[C:7]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=2)=[O:35]
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1CCl
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O

Procedure:
A reactor was charged with a solution of 2-chloromethyl-4-phenoxybenzoic acid methyl ester (˜68 Kg) in DMF, and stirring was initiated. The reactor was then charged with p-toluenesulfonylglycine methyl ester (66 Kg), potassium carbonate (60 Kg), and sodium iodide (4 Kg). The mixture was heated to at least 50° C. until reaction completion. The mixture was cooled. Sodium methoxide in methanol was charged and the mixture was stirred until reaction completion. Acetic acid and water were added, and the mixture was stirred, filtered and washed with water. Solid was purified by acetone trituration and dried in an oven giving 1a (Yield from step b): 58%; HPLC: 99.4%). 1H NMR (200 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.74 (s, 1H), 8.32 (d, J=9.0 Hz, 1 H), 7.60 (dd, J=2.3 & 9.0 Hz, 1H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.96 (s, 3 H); MS-(+)-ion M+1=296.09
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6 g), 2-chloromethylpyridine hydrochloride (80 g) and cesium carbonate (320 g) in DMF (1 L) was stirred at 70° C. for 2 days. The mixture was cooled, poured into water (2 L) and extracted with EtOAC (×6). The organic layers were washed with brine, dried (MgSO4) and filtered to give a tan solid (A-1, 114 g) which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([Mg]Cl)[CH3:11].CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: CC[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a chilled (−78° C.) solution of 2-bromopyridine-4-carboxaldehyde (7.0 g, 38 mmol) in THF (200 mL) is added a 2 M solution of ethylmagnesium chloride in ether (23.5 mL, 47.0 mmol) over a 10 minute period. After 15 minutes, the mixture is gradually warmed to room temperature over 1 hour. The reaction is quenched by the slow addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material is purified by silica gel chromatography eluting with a gradient of 20-40% EtOAc in hexanes to afford 1-(2-bromopyridin-4-yl)-propan-1-ol.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[C:25]2[C:26]([N:29](C(OCC(Cl)(Cl)Cl)=O)[C:30](OCC(Cl)(Cl)Cl)=[O:31])=[N:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:18][O:19][C:20]1[C:25]2[C:26]([NH:29][C:30]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:31])=[N:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2onc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c12
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2onc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)c12
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (492 mg, 2.00 mmol), bis(2,2,2-trichloroethyl) (4-methoxy-1,2-benzisoxazol-3-yl)imidodicarbonate (515 mg, 1.00 mmol), diisopropylethylamine (0.350 ml, 2.00 mmol) and dimethyl sulfoxide (10 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to yield 325 mg (74.5%) of the desired product.
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]1([C:17]#[C:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:3]1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Sc1c[nH]c2ccccc12
Product: O=C(O)C=Cc1cccc(Sc2c[nH]c3ccccc23)c1

Procedure:
By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and phenylpropiolic acid gives 20.0 g of product after recrystallization from acetone-water, mp 165°-167° C.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C[O:36]B(OC)OC.C(O)(=O)C.OO.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[N:17]1[C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:13]([OH:36])[C:14]=2[CH:15]=[N:16]1
Reactant: Brc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reactant: COB(OC)OC
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: OO
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Oc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
Under a nitrogen atmosphere, a 1.57M-n-butyllithium/hexane solution (12.00 ml, 0.0189 mol) was added dropwise to a solution of the 4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (6.0 g, 0.0157 mol) obtained in Example 607 in tetrahydrofuran (120 ml) at −78° C. over a period of 15 minutes. After 30 minutes, a solution of trimethoxyborane (2.65 ml, 0.0236 mol) in tetrahydrofuran (30 ml) was added dropwise thereto over a period of 5 minutes and the resulting mixture was slowly heated. After 15 hours, acetic acid (1.98 ml, 0.0346 mol) was added thereto. After 15 minutes, a solution of 30%-aqueous hydrogen peroxide solution (4.46 ml, 0.0393 mol) in tetrahydrofuran (20 ml) was added dropwise thereto over a period of 10 minutes, and the resulting mixture was slowly heated to room temperature. After 8.5 hours, a 30%-aqueous hydrogen peroxide solution (4.72 mmol) was further added thereto. After 15 hours, a 10%-aqueous sodium hydrogensulfite solution and a saturated aqueous sodium hydrogencarbonate solution were added thereto, and the resulting mixture was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with hexane by repulping to obtain 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol (2.9892 g, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].Cl>C(Cl)Cl.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[C:29](=[O:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(c1ccc(O)cc1)c1ccc2cc(O)ccc2c1
Reaction time: 0.83 h
Yield: 10 %

Procedure:
A solution of 830 mg (3.30 mmol of 6-[(4-hydroxyphenyl)amino]-2-naphthalenol (prepared as described in Example 3) and 840 ul (6.60 mmol, 2 eq.) of dimethylaniline in 15 ml of dry CH2Cl2 and 5 ml of dry THF was stirred at 0° C., then 415 ul (5.80 mmol, Mallinckrodt) of acetyl chloride was added dropwise. After 50 minutes, 1N aqueous HCl was added and this was extracted with EtOAc. The organic layers were washed with 1N aqueous HCl, dried (MgSO4) and concentrated in vacuo. The aqueous layers were extracted with hot EtOAc and the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification of all the organic phases was accomplished via flash chromatography (1:2, 1:1 EtOAc/petroleum ether) and recrystallization (aqueous MeOH) afforded 97 mg (10%) of title compound as pale orange crystals: m.p. 255° C.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:11])[N:17]=2)[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: Cc1nccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(Cl)cc1Nc1ccnc(C)n1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (30 mL), 3-bromo-5-chloro-2-methoxypyridine (865 mg, 3.9 mmol), 2-methylpyrimidin-4-amine (327 mg, 3.0 mmol), Pd2(dba)3 (275 mg, 0.30 mmol), XantPhos (173.4 mg, 0.30 mmol), and cesium carbonate (1.96 g, 6.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 5:1 ethyl acetate/petroleum ether to afford 222a (555 mg, 74%) as a white solid. MS-ESI: [M+H]+ 251.0