Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[N:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[N:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:19]4)[N:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-methylpyridin-3-yloxy)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine from Example 18A (44 mg, 0.14 mmol) in 2 mL of methylene chloride was added triethylamine (0.024 mL, 0.17 mmol) and isopropyl chloroformate (0.14 mL of a 1M solution in toluene, 0.14 mmol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with ethyl acetate, washed with sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to an oil. The residue was purified by silica gel chromatography (12 g ISCO cartridge, 0-100% ethyl acetate/hexane, 15 min gradient) to afford isopropyl 4-(4-(2-methylpyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate free base (10 mg). Took up in 2 mL ether, added 2N hydrochloric acid (0.07 mL, 0.14 mmol), concentrated to a solid, triturated with hexane and dried in vacuo to afford 8 mg (14%) of Example 18 as an off-white solid. 1H NMR (500 MHz, CD3OD) δ ppm 1.28 (d, J=6.05 Hz, 6H) 2.00-2.06 (m, 2H) 2.16-2.25 (m, 2H) 2.64 (s, 3H) 3.05-3.16 (m, 2H) 4.26-4.33 (m, 2H) 4.90-4.94 (m, 1H) 5.06-5.13 (m, 1H) 7.94 (dd, J=8.25, 5.50 Hz, 1H) 8.36 (s, 1H) 8.47-8.50 (m, 2H) 8.69 (d, J=4.40 Hz, 1H). LRMS (ESI): 397.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:7]1[S:11][C:10]([S:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:18][C:19](=[O:23])[O:20]3)=[CH:15][CH:14]=2)=[N:9][CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:3]([C:7]1[S:11][C:10]([S:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:18][C:19](=[O:23])[O:20]3)=[CH:15][CH:14]=2)=[N:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7-{[5-(1-ethyl-1-hydroxypropyl)-1,3-thiazol-2-yl]thio}-4-(4-fluorophenyl)-2H-chromen-2-one (26 mg, 0.06 mmol) in 1 mL of CH2Cl2 at 0° C. was added triethylsilane (100 μL) and TFA (100 μL). The mixture was stirred for 1 h at 0° C. then warmed to room temperature with more triethylsilane (250 μL). The solvent was removed in vacuo and chromatographed on silica gel (hexane:EtOAc; 90:10 to 80:20) to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[C:10]1([C@@H:9]2[N:7]3[C:6](=[O:8])[CH2:5][CH2:4][C@H:3]3[CH2:2][O:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12

Procedure:
A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)O)[CH:30]=[CH:31][CH:32]=1.C(N(CC)CC)C>C1COCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
1-Methylpiperidine-4-carboxylic acid hydrochloride (250 mg, 1.39 mmol), EDC (400 mg, 2.09 mmol), and HOBT (320 mg, 2.09 mmol) were dissolved in dry THF (10 ml). Bis(3-fluorophenyl)methanol (337 mg, 1.53 mmol) was dissolved in dry THF (4 ml) and then added to the reaction mixture. Triethylamine (6790, 4.87 mmol) was finally added, and the resulting reaction was stirred at room temperature overnight. The reaction was evaporated, and the residue was taken up with EtOAc and washed with water and sat.NaHCO3. The organic phase was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to afford bis(3-fluorophenyl)methyl 1-methylpiperidine-4-carboxylate (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10][C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1.[Se](=O)=[O:21].OO.O>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1)=[O:21]
Reactant: Fc1cccc(Cl)c1CSc1nc2cnccc2[nH]1
Reactant: O=[Se]=O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=S(Cc1c(F)cccc1Cl)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[(2-Chloro-6-fluorophenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine (2.6 g, 0.0089 mol) was dissolved in 140 mL of methanol containing 20 mL of ethyl acetate. An oxidizing solution was prepared by heating 0.99 g (0.0089 mol) of selenium dioxide in 40 mL of methanol and adding 1.01 g (0.0089 mol) of 30% hydrogen peroxide and 0.65 mL of water. The oxidizing solution was added dropwise with stirring to the sulfide solution. The reaction mixture was stirred overnight at room temperature. Approximately 1/2 the solvent was removed in a rotary evaporator and the reaction mixture was chilled in ice. The resulting precipitate was collected and amounted to 1.08 g. An analytical sample, m.p. 180°-183° C., was obtained by recrystallization from ethanol.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([N:48]1[CH:52]=[C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 93.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (136 mg, 0.455 mmol) using sodium carbonate (81 mg, 0.759 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in Toluene/ethanol/water (10/2/1 ml) to afford 200 mg of titled compound after purification by column (Silica gel 6/120) using 50% EtOAc/hexane as eluent. MS: m/z=703.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[OH:22][CH:4]1[C:3]2[C:7](=[C:8]([I:31])[CH:9]=[C:10]([F:11])[C:2]=2[Cl:1])[C:6](=[O:12])[N:5]1[C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21]
Reactant: II
Reactant: CC(C)(c1ccccc1)N1C(=O)c2ccc(F)c(Cl)c2C1O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(F)c(Cl)c2C1O
Yield: 49.7 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-3-hydroxy-5-fluoro-2-(1-methyl-1-phenylethyl)isoindolinone (1.20 g, 3.75 mmol) was dissolved in THF (48 mL), and the solution was treated with TMEDA (2.30 mL, 15.0 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 15.0 mL, 15.0 mmol) and iodine (1.430 g, 5.63 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain 3-hydroxy-4-chloro-5-fluoro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (830 mg, yield 50%).
Reaction SMILES: O[N:2]=[C:3]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:12][C:4]1[C:3]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:2][O:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1cccs1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2cccs2)c1C
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Ethyl 4-(hydroxyimino)-3-methyl-2-oxo-4-(thiophen-2-yl)butanoate (7.7 g, 30.2 mmol) and concentrated sulfuric acid (8 mL) were added to 120 mL of absolute ethanol and the mixture was refluxed for 20 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give 3.9 g of the title compound. MS: (+) m/z 238.38 (M+1).
Reaction SMILES: [K].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].[CH2:17](C(C)=O)C.CI>O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:17])=[O:7]
Reactant: CCC(C)=O
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: [K]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N

Procedure:
12.9 g of the potassium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid are heated for 20 hours under reflux in a mixture of 30 ml of water, 60 ml of methyl ethyl ketone and 11.4 g of methyl iodide. The aqueous phase is separated and the organic phase is concentrated by evaporation. Recrystallisation of the crude product (which contains only a small amount of impurities according to analysis by thin-layer chromatography) from ethanol affords 7.5 g of pure methyl 3,4,5,6-tetrachloro-2-cyanobenzoate with a melting point of 83°-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[OH:13][CH2:14][C@@H:10]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:9][CH2:8][C:3]1([O:2][CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(CC[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC1(CC[C@@H](CO)NC(=O)OC(C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
The above (S)-tert-butyl 4-(2-(1-methoxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate (1170 mg, 3.5 mmol, 1.0 equiv) was dissolved in 40 mL of methanol. Camphorsulphonic acid (417 mg, 1.8 mmol, 0.5 equiv) was added and the mixture stirred for 4 h at ambient temperature. The mixture was quenched by addition of ca. 1 mL of NEt3 and the reaction evaporated. The residue was taken up in EtOAc, washed with brine, then dried over MgSO4, filtered through a pad of silica gel, and evaporated. This afforded 1.03 g (3.5 mmol, 100% yield) of the desired (S)-tert-butyl 1-hydroxy-4-(1-methoxycyclopentyl)butan-2-ylcarbamate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:23])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: CI
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in 100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](C)[C:5](C)=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[NH:14][N:15]=[C:16]2[C:21]=1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.NC1C=C(C)C(C)=CC=1N.[Na+].[Cl-]>CN(C=O)C.C([O-])(O)=O.[Na+].ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[NH:14][N:15]=[C:16]2[C:21]=1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[O:12]
Reactant: Cc1cc(N)c(NC(=O)c2[nH]nc3c2CCN(C(=O)OC(C)(C)C)C3)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(N)c(N)cc1C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n[nH]c2C(=O)Nc2ccccc2N)C1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(2-amino-4,5-dimethylphenylcarbamoyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridine-6-carboxylate can be prepared in the following way: 8.5 g of HBTU and also 2.9 g of diisopropylethylamine are added, at ambient temperature, to a solution of 3 g of (tert-butyl 2,4,5,7-tetrahydropyrazolo-[3,4-c]pyridine-6-carboxylate)-3-carboxylic acid in 50 ml of anhydrous DMF. After twenty minutes' stirring at ambient temperature, 3.06 g of 4,5-diamino-o-xylene are added. After stirring at ambient temperature for 60 hours, the reaction medium is diluted in 3 l of an aqueous NaHCO3 solution at pH greater than 7, containing 20 g of NaCl. The aqueous phase is extracted three times with 1 l of ethyl acetate, and the combined organic phases are then dried over magnesium sulphate and concentrated under reduced pressure. The crude residue obtained is taken up in 150 ml of dichloromethane and the insoluble material is removed by filtration through sintered glass. The filtrate is then concentrated under reduced pressure and purified by chromatography on silica (20–45 μm Amicon) with a gradient of from 50 to 100% of ethyl acetate in cyclohexane. The fractions containing the desired product are combined and concentrated under reduced pressure. 4.37 g of tert-butyl 3-(2-aminophenylcarbamoyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridine-6-carboxylate are thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-3-methyl-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.24 g, 0.808 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.219 g, 1.010 mmol). The title compound was collected as a white solid (0.35 g, 92%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3H) 1.41 (d, J=6.57 Hz, 6H) 1.49-1.60 (m, 2H) 2.12 (s, 3H) 2.39 (s, 3H) 2.53 (s, 1H) 4.33 (d, J=5.05 Hz, 2H) 4.88-5.00 (m, 1H) 5.89 (s, 1H) 7.12 (d, J=1.52 Hz, 1H) 8.02 (d, J=1.77 Hz, 1H) 8.48 (t, J=4.93 Hz, 1H) 11.50 (s, 1H); LCMS (ES+): 459.1 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:37][CH:36]([CH3:43])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.65 g) in tetrahydrofuran (6 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 2.3 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.044 g) was added at 0° C. After stirring at 0° C. for 1 hr, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 95%).
Reaction SMILES: [CH:1]([N:4]1[CH2:15][CH2:14][C:7]2([O:12][CH2:11][C:10](=O)[NH:9][CH2:8]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[F-].[Na+].O>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][C:7]2([O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC2(CC1)CNC(=O)CO2
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC2(CC1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in THF and LiAlH4 (5 equivalents) was added. The reaction was heated at reflux for 4 hours and then cooled to room temperature. NaF (20 equivalents) and water (5 equivalents) were added and the reaction was stirred vigorously for 1 hour. The resulting precipitate was filtered away and the filtrate was concentrated to provide the title compound as a colorless oil. GC/MS (m/z) 198, Rt=12.57 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:20])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:21]>[Pd].C(O)(=O)C.CO>[NH2:1][C:2]1[CH:11]=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:20])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:21]
Reactant: Cc1nnn(C)c1-c1c(Cl)c2c(c(N)c1I)CCNC2=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nnn(C)c1-c1cc(N)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 178.8 %

Procedure:
Two batches were prepared by the following method: a mixture of 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293f, 2.9 g, 6.9 mmol each batch) and palladium on carbon (2.9 g) in glacial acetic acid (29 mL) and methanol (290 mL) was stirred under a hydrogen balloon at room temperature overnight. The combined reaction mixtures were filtered through celite, and the filter pad washed with methanol (300 mL). The filtrate was concentrated and the residue purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) affording 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293g, 3.6 g, 65% combined yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 6.82 (s, 1H), 3.75 (s, 3H), 3.29-3.28 (m, 2H), 2.70-2.67 (m, 2H), 2.07 (s, 3H). MS: 292 [M+1].
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (15.3 g, 43.7 mmole) in DCM (150 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (175 mmole, 65 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (10.38 g, 95%) as a white foam: LC-MS (ES) m/e 251 (M+H)+.