Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]([C:36]#[N:37])[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]2[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=1)[C:15](=[NH:2])[NH:16][C:36]2=[NH:37]
Reactant: CC(C)CCOc1c(C#N)c(C#N)c(OCCC(C)C)c(Sc2ccccc2N)c1Sc1ccc(C(C)(C)C)cc1
Reactant: N
Agent: [Na]
Solvent: CCCO
Product: CC(C)CCOc1c(Sc2ccc(C(C)(C)C)cc2)c(Sc2ccccc2N)c(OCCC(C)C)c2c1C(=N)NC2=N
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of sodium metal (0.6 g) in n-propyl alcohol (200 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 27.0 g of 4-(2-aminophenylthio)-5-(4-tert-butylphenylthio)-3,6-diisopentoxyphthalonitrile was added and the mixture was stirred at 50~60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 20.9 g (yield 75.2%) of 5-(2-aminophenylthio)-6-(4-tert-butylphenylthio)-1,3-diimino-4,7-diisopentoxyisoindoline of the following chemical formula. ##STR12##
Reaction SMILES: O[CH2:2][CH2:3][C@H:4](O)[C:5]([CH3:9])([CH3:8])[C:6]#[N:7].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:26][O:27][C:28]([O:31][CH3:32])([CH3:30])[CH3:29]>>[CH3:26][O:27][C:28]([O:31][CH3:32])([CH3:30])[CH3:29].[CH3:8][C:5]([CH3:9])([CH2:4][CH2:3][CH3:2])[C:6]#[N:7]
Reactant: CC(C)(C#N)[C@@H](O)CCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: COC(C)(C)OC
Product: CCCC(C)(C)C#N

Procedure:
6.73 g (47 mmol) of 5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the title compound of Example 1d is dissolved in 27 ml of acetone dimethylketal, and 546 mg of camphor-10-sulfonic acid is added. It is heated for 15 hours to 50° C. It is evaporated to the dry state in a vacuum. The residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The organic phase is dried on sodium sulfate and evaporated to the dry state in a vacuum. The oil that is obtained crystallizes while standing.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:27]=[CH:26][C:18]4[C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][O:21][C:17]=4[C:16]=3[CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:31][O:32][C:33](=[O:36])[CH2:34][N:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:27]=[CH:26][C:18]4[C:19]([C:22]([F:24])([F:23])[F:25])=[N:20][O:21][C:17]=4[C:16]=3[CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)CBr
Reactant: CCCc1c(OCCCOc2cccc3[nH]ccc23)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1c(OCCCOc2cccc3c2ccn3CC(=O)OC)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 6-[3-(1H-indol-4-yloxy)-propoxy]-7-propyl-3-trifluoromethyl-benzo[d]isoxazole (0.100 g, 0.24 mmol), methyl-2-bromoacetate (0.109 g, 0.72 mmol), potassium carbonate (0.050 g, 0.36 mmol), potassium iodide (0.008 g, 0.05 mmol), and acetonitrile (15 mL) was stirred and refluxed for 12 hours. The mixture was cooled to room temperature and filtered to remove suspended salts. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was collected, washed with water (2×20 mL) and brine (2×20 mL), and then dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatograph over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford {4-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-propoxy]-indol-1-yl}-acetic acid methyl ester (0.089 g, yield: 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:42])([C:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:41])[C:19](=[O:40])[N:20](COCC[Si](C)(C)C)[N:21]=2)=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:42])([C:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:30])([F:29])[F:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:41])[C:19](=[O:40])[NH:20][N:21]=2)=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(c1cc2c(cc1C(F)(F)F)OCC1=NN(COCC[Si](C)(C)C)C(=O)C(C)N12)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=C(c1cc2c(cc1C(F)(F)F)OCC1=NNC(=O)C(C)N12)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A mixture of 3-methyl-3-{1-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-vinyl}-azetidine-1-carboxylic acid tert-butyl ester (1.214 g, 1.662 mmol) and tetrabutylammonium fluoride (1M in THF, 22.9 mL, 22.9 mmol) was stirred at 80° C. overnight. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-10% EtOAc in petroleum ether) to give 3-methyl-3-[1-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-vinyl]-azetidine-1-carboxylic acid tert-butyl ester (0.330 g, 45%). 1H NMR (CDCl3, 400 MHz): δ 8.25 (s, 1H), 7.35 (s, 1H), 6.66 (s, 1H), 5.46 (s, 1H), 5.15 (s, 1H), 4.7 (m, 2H), 4.6 (m, 1H), 3.95 (m, 1H), 3.86 (m, 1H), 3.65 (m, 2H), 1.55 (m, 3H), 1.50 (m, 3H), 1.40 (s, 9H). LC/MS (Table 1, Method 25) Rt=0.923 min; MS m/z: 503 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and isobutyryl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.13 (d, J=6.82 Hz, 6H) 1.27-1.37 (m, J=7.42, 7.42, 7.42, 7.42, 7.20 Hz, 2H) 2.20 (t, J=7.20 Hz, 2H) 2.65 (dt, J=13.58, 6.73 Hz, 1H) 6.73 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.34 Hz, 2H) 7.83-7.93 (m, 4H) 8.13 (d, J=8.08 Hz, 1H) 10.22 (s, 1H); ESI-MS: m/z calc'd for C25H26N4O2S 446.56. found 447.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10](I)[C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nn(C3CCCCO3)c3nc(Cl)ccc23)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), and cesium carbonate (540 mg, 1.6 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 80° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M+H)+=318.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-(4-fluoro-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=377.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][C@H:16]1[CH2:18][O:17]1.C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:15][C@@H:16]([OH:17])[CH3:18])[CH:10]=2)[O:3]1
Reactant: C[C@H]1CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 92.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.5 mmol)(Aldrich Cat. No. 525057), (S)-(−)-methyloxirane (130 μL, 1.9 mmol) and triethylamine (0.45 mL, 3.2 mmol) in acetonitrile (1.0 mL) in a reaction vial was stirred at 50° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.35 g). LCMS (M+H)+=253.0.
Reaction SMILES: [CH3:1]I.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[SH:12]>C1COCC1>[CH3:1][S:12][C:4]1[O:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: Sc1nc2ccccc2o1
Reactant: CI
Solvent: C1CCOC1
Product: CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
Methyl iodide (20 mL, 320 mmol) was added to a solution of benzooxazole-2-thiol (25.0 g, 165 mmol) taken in dry THF (250 mL) and the reaction mixture was stirred at room temperature for 80 hours, after which it was concentrated to give 2-methylsulfanyl-benzooxazole.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:1][C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: O=c1[nH]c(S)nc2ccccc12
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4c(=O)[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 24 is prepared from 2-mercapto-4(3H)-quinazolinone and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2]([O:4]CC)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.[O-]CC.[Na+].[Na]>O.C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:2](=[O:4])[C:1]([OH:8])=[O:7])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl oxalate (29.2 g, 0.2 mol) and 4-bromo-2-nitrotoluene (21.6 g, 0.1 mol, Lancaster) were poured into a cooled sodium ethoxide solution, prepared from sodium (4.6 g, 0.2 mol) and absolute ethanol (90 mL). The mixture was stirred overnight at room temperature and then refluxed for 10 minutes at the end of the reaction. Water (30 mL) was added and the reaction refluxed for 2.5 h. The reaction mixture was cooled and concentrated to remove excess ethanol. The precipitate was collected by filtration, washed with ether and dried. The crude sodium salt was dissolved in water and acidified with conc. HCl. The solid precipitated and was collected by filtration. The crude product was recrystallized from hexane and ethyl acetate to give 12.5 g (43%) as a feathery putty-colored solid; 1H-NMR (CDCl3): δ8.40 (d, 1H, J=1.9 Hz). 7,84 (dd, 1H, J=8.0, 2.0 Hz), 7.30 (d, 1H, J=2 Hz) 4.65 (s, 2H).
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>C(O)C>[OH:19]/[N:18]=[C:2](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCCC(=O)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC/C(=N\O)c1ccccc1
Yield: 88.4 %

Procedure:
A mixture of ethyl 5-oxo-5-phenylpentanoate (8.00 g), hydroxylamine hydrochloride (3.03 g), sodium acetate (4.47 g) and ethanol (70 ml) was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl E-5-hydroxyimino-5-phenylpentanoate (7.55 g, yield 88%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from hexane gave colorless crystals. m.p. 28-30° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:15][OH:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To propane-1-sulfonic acid (4-fluoro-3-hydroxymethyl-phenyl)-amide (671, 0.483 g, 0.00195 mol) in tetrahydrofuran (10.0 mL), cooled with ice/water, was added Dess-Martin periodinane (1.00 g, 0.00236 mol). The reaction was stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (672, 360 mg, 75%). MS (ESI) [M−H+]−=244.1.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([CH3:28])=[C:15]2[CH2:29][C:30]([NH2:32])=[O:31].[OH-].[Na+].Cl>C1COCC1.C(O)C>[NH2:32][C:30](=[O:31])[CH2:29][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:33])=[O:2])[CH:13]=2)[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH3:28]
Reactant: COC(=O)c1ccccc1COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(N)=O)c2cc(OCc3ccccc3C(=O)O)ccc2n1Cc1ccccc1
Reaction time: 17.5 h
Yield: 58.3 %

Procedure:
A mixture of 195 mg (0.44 mmol) of 2-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid methyl ester and 2 mL of 2N NaOH in 10 mL of THF and 35 mL of ethanol was stirred for 17.5 hours, the mixture made acidic with 5N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was crystallized from methylene chloride to give 110 mg (59% yield) of 2-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid, mp, 173°-176° C.
Reaction SMILES: Cl[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(#N)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(C(Cl)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C(c2ccccc2)n2ccnc2)cc1
Reaction time: 24 h
Yield: 53 %

Procedure:
To a stirred solution of 88.7 parts of 1-[chlorophenylmethyl]-4-nitrobenzene in 790 parts of acetonitrile were added 121.8 parts of 1H-imidazole. After stirring for 24 hours at reflux temperature, the reaction mixture was evaporated. The residue was taken up in methylbenzene. This solution was washed with K2CO3 (aq.), dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 53 parts (53%) of 1-[(4-nitrophenyl)phenylmethyl]-1H-imidazole (interm. 42).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:32])([C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:21]>>[CH3:21][C:20]([OH:32])([C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]1[S:26][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:28][CH:29]=1)[CH3:19]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(O)C(C)(C)CCc1cccs1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(C)(C)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2,3,3-trimethyl-5-thiophen-2-yl-pentan-2-ol from Step A.
Reaction SMILES: [Ce+4].[NH4+].[CH3:3][O:4][C@@H:5]1[C@@H:10]2[CH2:11][C@@H:7]([C:8](=[O:21])[N:9]2CC2C=CC(OC)=CC=2)[CH2:6]1>O.CC#N>[CH3:3][O:4][C@@H:5]1[C@@H:10]2[CH2:11][C@@H:7]([C:8](=[O:21])[NH:9]2)[CH2:6]1
Reactant: COc1ccc(CN2C(=O)[C@H]3C[C@H](OC)[C@@H]2C3)cc1
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CO[C@H]1C[C@H]2C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ammonium cerium(IV) (3.3 g, 6.06 mmol) in water (10 mL) was added to (1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (527 mg, 2.02 mmol) in CH3CN (40 mL). The reaction mixture was stirred at ambient temperature for 2 h and extracted by EtOAc (60 mL). The organic extract was washed with water and brine, dried over Na2SO4, and evaporated to give the crude (1S,4R,6S)-6-methoxy-2-azabicyclo[2.2.1]heptan-3-one. MS (ESI+): m/z 142 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH:28]([CH3:30])[NH:27][CH2:26][CH2:25]3)=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:20]([C:19]5[C:15]([CH3:14])=[N:16][O:17][C:18]=5[CH3:31])[CH:21]=[CH:22][CH:23]=4)[CH:28]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1noc(C)c1-c1cccc2c1C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1noc(C)c1-c1cccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20](=O)[CH3:21])[C:7]1=[O:23])[CH3:2].[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[C:7]1=[O:23])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCC(C)=O)C[C@H]1Cc1ccccc1
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1Cc1ccccc1

Procedure:
A mixture of 12-5 (230 mg, 0.6940 mmol), 1-4, (2-amino-3-formylpyridine, 110 mg, 0.9022 mmol) and proline (80 mg, 0.6940 mmol) in absolute ethanol (10 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/MeOH) to give 12-6 as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: O=Cc1cnc2ccccc2c1
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4cnc5ccccc5c4)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoline-3-carbaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 11.0 (brs, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.29 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.90-7.88 (m, 1H), 7.70-7.66 (m, 1H), 7.56-7.51 (m, 1H), 5.01-4.92 (m, 1H), 4.03-3.83 (m, 2H), 3.40 (t, J=8.7 Hz, 1H), 3.07 (d, J=9.5 Hz, 1H), 2.89-2.86 (m, 1H), 2.68-2.67 (m, 1H), 2.48-2.47 (m, 1H), 2.08-2.02 (m, 1H), 1.48 (dd, J=6.6, 16.59 Hz, 6H), 1.20 (J=7.1 Hz, 3H). MS: (M+H m/z 403.1).
Reaction SMILES: [CH:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]3[CH:12]=[N:13][C:14]([CH2:24]Cl)=[C:15]([O:16]CC4C=CC=CC=4)[C:10]=3[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]3[CH:12]=[N:13][C:14]([CH2:24][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:15]([OH:16])[C:10]=3[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCc1ncc2c(c1OCc1ccccc1)COC2(c1ccccc1)C1CCCCC1
Reactant: C1CCNC1
Product: Oc1c(CN2CCCC2)ncc2c1COC2(c1ccccc1)C1CCCCC1
Yield: 67 %

Procedure:
The method of example 3 was repeated, but starting with 1,3-dihydro-3-cyclohexyl-3-phenyl-6-chloromethyl-7-benzoxy-furo-(3,4-c)-pyridine and with pyrrolidine instead of dimethylamine. Yield 67% of a yellow crystalline product melting at 204° C. (Tottoli), elemental analysis of which showed a good correspondence with the formula C24H30N2O4.