Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:16])=O>>[Cl:16][CH2:2][CH:3]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCC1CCCCCCCCCC1
Reactant: O=S(Cl)Cl
Product: ClCC1CCCCCCCCCC1

Procedure:
The starting material 3-cycloundecylpropan-1-ol is obtained as follows: hydroxymethylcycloundecane is reacted with thionyl chloride to give chloromethylcycloundecane, which is reacted with malonic acid diethyl ester in the presence of sodium ethylate to give (cycloundecylmethyl)-malonic acid diethyl ester, which, after saponifying the ester group and decarboxylating the corresponding malonic acid, gives 3-cycloundecylpropionic acid. 3-Cycloundecylpropionic acid is reduced with lithium aluminum hydride in tetrahydrofuran to give 3-cycloundecylpropanol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (207 mg, 0.83 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (279 mg, 0.83 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (469 mg, 1.00 mmol) in chloroform (8 mL). DIEA (730 μL, 4.18 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (209 mg, 0.36 mmol, 43%): LC-MS (ES) m/z=517 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[S:26]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O:29][CH3:30])(=[O:28])=[O:27]>>[S:26]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O-:29])(=[O:28])=[O:27].[CH3:30][P+:9]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Product: COc1ccc([P+](C)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 73 %

Procedure:
A mixture of 5.37 g (15.2 mmol) of tris (4-methoxyphenyl)phosphine and 2.95 G (15.8 mmol) of methyl tosylate was allowed to react for 1 hr at 135° C. A total of 5.96 g (11.1 mmol, 73.0%) of the product was obtained, which was further purified by recrystallization from 97:3 toluene-ethanol.
Reaction SMILES: O.[OH-].[Li+].C[CH:5]([CH2:9][CH2:10][S:11][C:12]1[N:13]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]2[CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]([OH:8])=[O:7]>O1CCCC1.O>[CH3:22][N:18]1[C:19](=[O:21])[C:20]2=[C:12]([S:11][CH2:10][CH2:9][CH2:5][C:6]([OH:8])=[O:7])[N:13]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[N:14]=[C:15]2[N:16]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:17]1=[O:23]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCC(C)C(=O)O)n(Cc3cccc4ccccc34)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)nc21
Yield: 53.5 %

Procedure:
Lithium hydroxide monohydrate (80 mg) was added to a solution of methyl 4-[(4,5,6,7-tetrahydro-5-methyl-7-{2-methylpropyl}-2-{1-naphthalenylmethyl}-4,6-dioxo-2H-pyrazolo[3,4-d]pyrimidin-3-yl)thio]butanoic acid (250 mg) in tetrahydrofuran (20 ml) and water was then added to give a homogeneous solution. After 18 hours the reaction mixture was partitioned between ether and 2 M sodium hydroxide. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate which was then dried over magnesium sulfate. The organic phase was concentrated in vacuo and recrystallised from cyclohexane:ethyl acetate to give the title compound (130 mg).
Reaction SMILES: C=C.[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][N+:32]([O-:34])=O)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[C:37]1(N=C=O)C=CC=C[CH:38]=1>C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:31]3[CH2:38][CH2:37][O:34][N:32]=3)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Agent: C=C
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)CC(C2=NOCC2)c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
Ethylene was bubbled into a mixture of 40.3 (235 mg, 0.5 mmol, see Example 40) in benzene (2 mL) for 20 minutes. Phenyl isocyanate (0.22 mL, 2 mmol) and TEA (3 drops) were then added. The mixture was stirred at room temperature for 2 days. The solid was removed by filtration and washed by benzene. The filtrate was concentrated and purified by flash chromatography to give 42.1 (200 mg). MS ESI (pos.) m/e: 476 (M+H). 1HNMR (CDCl3) δ 7.37 (d, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 6.92 (m, 6H), 5.05 (dd, 2H), 4.98 (s, 2H), 4.25 (m, 2H), 4.10 (t, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.24 (dd, 1H), 2.79 (m, 3H).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reaction time: 1 h

Procedure:
To a mixture of 2.00 g (4.63 mmol) (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 126, Step B) in water (0.125 g, 6.94 mmol) and DCM (50 mL) was added Dess-Martin periodinane (2.94 g, 6.94 mmol) at ambient temperature. After being stirred for 1 h (no SM detected by TLC), the reaction was quenched by addition of 10 mL of 0.5 M Na2S2O3, extracted with DCM, and washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (80 g SiO2, 5 to 20% EtOAc/hexanes) provided the title compound as a white foam.
Reaction SMILES: C([O:5][C:6]([C@:8]12[CH2:15][CH:14]([F:16])[CH2:13][C@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:16][CH:14]1[CH2:15][C@@:8]2([C:6]([OH:7])=[O:5])[C@H:12]([C:11](=[O:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:9]2)[CH2:13]1
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)OC(C)(C)C)CC(F)C[C@H]2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,5R)-7-Fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (705 mg, 2.03 mmol) was dissolved in methylene chloride (4 mL). Trifluoroacetic acid (4 mL) was added under ice-cooling, and then the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure again to give 595 mg (quantitative) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CCCCC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL) was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4), filtered and reduced to give a brown orange solid residue. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a white solid (3.02 g).
Reaction SMILES: CO[C:3]([CH2:5][CH:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:7]CC(OC)=O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:30]CC>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][CH:6]([CH2:5][CH2:3][OH:4])[CH2:7][OH:30]
Reactant: CCOCC
Reactant: COC(=O)CCC(CC(=O)OC)OCc1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCC(CO)OCc1ccccc1F
Temperature: 0 °C
Yield: 35.5 %

Procedure:
27 g (0.1 mol) of 2-(2-fluorobenzyloxy)-butane-1,4-dicarboxylic acid dimethyl ester were added dropwise, at 10° C., to a dispersion of 4.5 g of lithium aluminium hydride in 100 ml of absolute ether. After completion of the addition, the mixture was heated for 1 hour under reflux, and was cooled and hydrolysed with 35 ml of ice-water. After decanting the ether phase, the residue was repeatedly digested with ethanol. The combined organic phases were freed from the solvent and the residue was taken up in chloroform and chromatographed on a short silica gel column. The eluate was freed from the solvent and the residue was distilled. 7.5 g (35.5% of theory) of 2-(2-fluorobenzyloxy)-butane-1,4-diol of boiling point 155° C./0.5 mm Hg were obtained.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27]1(=[O:31])O[CH2:29][CH2:28]1.[C:32]1(C)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:32][CH2:29][CH2:28][C:27]5=[O:31])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: O=C1CCO1
Reactant: Cc1ccccc1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 45 %

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), propiolactone (30 mg) and toluene (10 ml) was heated under reflux for 2 hr. Then the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (150 mg) as an oil. This oil was then crystallized from ethyl acetate by using oxalic acid (32 mg) to give the oxalate (100 mg) of the title compound as a pale yellow amorphous substance (yield: 45%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:22][CH2:19][C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 182.2 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (5.0 g), benzyl bromide (14.8 g), potassium carbonate (13 g) and N,N-dimethylformamide (120 ml) was stirred for two hours at 60° C. To the reaction mixture was added cold water (200 ml), which was subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with a 5% aqueous solution of potassium hydrogencarbonate, which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 3,4-dibenzyloxybenzaldehyde (10.5 g) as colorless crystals. m.p.: 87-88° C.
Reaction SMILES: B(Br)(Br)Br.[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([O:24]C)[C:21]([O:26]C)=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].CO>ClCCl>[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:26])=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(CBr)c2cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(c1sc2cc(O)c(O)cc2c1CBr)N1CCOCC1
Reaction time: 1 h

Procedure:
A solution of 1 N boron tribromide in dichloromethane (3.4 ml) was added to a solution of (3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone) (0.46 g) in dichloromethane (10 ml) at −20° C. Stirring was continued at 0° C. for one hour. Methanol was added and the mixture was evaporated to dryness. To the residue 5% Na2SO3 solution (5 ml) was added, the mixture acidified and the precipitate filtered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=O)[N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2].C(OC(C1C=C([Cl:34])N2N=CC=C2N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:11]=1[Cl:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(-c3cccc(Cl)c3)cnn2c1=O
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Product: CCOC(=O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1Cl

Procedure:
This compound was synthesized from 7-oxo-3-(3-chlorophenyl)-4,7-dihydro-pyrazolo-[1,5-a]-pyrimidine-6-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing 7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester. mp: 140-141° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:15]([CH:18]=1)[C:16]#[N:17])#[CH:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(C#Cc2ccnc(Cl)n2)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of copper(I) iodide (117 mg, 0.613 mmol), dichloropalladium-triphenylphosphane (1:2) (215 mg, 0.306 mmol), 2,4-dichloropyrimidine (913 mg, 6.13 mmol), and 5-ethynyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (880 mg, 3.06 mmol) in a mixed solvents of TEA (18 mL, 129 mmol) and tetrahydrofuran (12 mL), was added triphenylphosphine (161 mg, 0.613 mmol) under Argon. The reaction mixture was stirred for 12 h at 60° C., filtered, washed with EA, concentrated. Purification via ISCO system (EtOAc=1:20 to 1:5) afforded the title compound as a brown solid. LC-MS (ESI): m/z 400 [M+H]+; 3.86 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][CH2:10][C:11](Cl)=[O:12]>[OH-].[Na+].ClCCl>[Cl:9][CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCl)c1
Reaction time: 18 h
Yield: 76.1 %

Procedure:
3-Methylaniline (1 g, 9.3 mmol) in 2N aqueous sodium hydroxide (30 mL) was treated with chloroacetyl chloride (0.82 mL, 10.27 mmol) dropwise at room temperature as a solution in dichloromethane. After 18 hours, the reaction mixture was quenched with water and the layers separated. The organic phase was washed with an aqueous solution of 1N HCl and dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to provide 1.3 g (76%) of the title compound as a white solid. 1H NMR (300 MHz, CDCI3) δ 2.35 (s, 3H), 4.20 (s, 2H), 7.00 (s, 1H), 7.22 (m, 1H), 7.35-7.45 (m, 2H), 8.15 (br s, 1H); MS (DCI/NH3) m/e 201 (M+NH4)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C(Cl)Cl.C(N(C(C)C)CC)(C)C.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][CH2:11][NH:12][C:13]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NCCCl
Reactant: Nc1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NCCN1c1cccc(I)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 3-iodoaniline (1 g) in CH2Cl2 (5 ml) and diisopropylethylamine (2 ml) was treated with 2-chloroethylisocyanate (0.4 ml) and the mixture was stirred at 20° C. for 3 d. The mixture was diluted with EtOAc and washed with 2M HCl, dried and evaporated to dryness. The residue was dissolved in DMF (5 ml), treated with sodium hydride (60% oil dispersion, 182 mg), and the mixture was stirred for 20 h under nitrogen. The mixture was diluted with EtOAc, washed with 2M HCl, brine, dried and evaporated to dryness. The residue was crystallised from hot EtOAc/MeOH. Trituration in Et2O of the residue obtained by evaporation of the mother liquor gave the title compound (240 mg). LCMS RT=3.03 min.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.9 mg, 40.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.35–7.10 (m, 7H), 7.02 (t, 1H, J=8.0 Hz), 6.90 (d, 1H, J=7.6 Hz), 6.84–6.75 (m, 2H), 6.65 (m, 1H), 5.09 (apparent dd, 1H, J=4.99, 8.1 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.30–1.70 (m, 8H), 1.18 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.I[CH3:17]>CN(C=O)C>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a stirred suspension of 60% NaH oil dispersion (87 mg, 2.2 mmol) in DMF (4 mL) was added methyl 1H-indazole-5-carboxylate (264 mg, 1.50 mmol). The mixture was stirred at room temperature for 1 hour before the dropwise addition of iodomethane (0.11 mL, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and the residue was purified by Biotage chromatography (40S column, 15% acetone/heptane) to afford methyl 1-methyl-1H-indazole-5-carboxylate (107 mg, 38%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](N)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].[BrH:22]>O>[Br:22][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:9]=[CH:10]2
Reactant: Br
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.00 g (4.34 mmol) 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine is dissolved in 9.76 mL 48% hydrobromic acid and 9.76 mL water and the solution is cooled to 0° C. 2.5 M sodium nitrite solution (300 mg in 1.74 mL water) is slowly added dropwise. The reaction is stirred for 10 min at 0° C. and then a solution of 935 mg (6.51 mmol) CuBr in 3.42 mL 48% hydrobromic acid is added dropwise. The reaction is heated to 60° C. and stirred for one hour at this temperature. The mixture is diluted with water and the aqueous phase is extracted with EtOAc. The organic phase is discarded and the aqueous phase is made alkaline with saturated NaHCO3 solution. The aqueous phase is extracted with EtOAc and the organic phase is washed with water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.