Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]([O:34]CC)=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:37])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]([OH:34])=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:37])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccc(N3C(=O)c4[nH]nc(C(C)(C)C)c4C3c3ccccc3OC)cc2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(C(=O)O)no2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a mixture of 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.26 g, 2.5 mmol), methanol (4 mL), THF (4 mL) and water (3 mL), 2N aqueous sodium hydroxide (1.5 mL, 3 mmol) was added and the mixture was stirred at 50° C. for 1 hr. Water (40 mL) and 1N hydrochloric acid (2 mL) were added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was suspended in ether, and the precipitate was collected to give 3-t-butyl-5-[4-(3-carboxy-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.84 g, 71%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([Cl:13])=[C:6]([C:9]([O:11]C)=O)[NH:7][CH:8]=1)=[O:3].[OH-].[Li+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][CH2:50][C:51]1[C:52]([F:68])=[C:53]([O:58][C:59]2[CH:60]=[C:61]([CH:64]=[C:65]([Cl:67])[CH:66]=2)[C:62]#[N:63])[C:54]([Cl:57])=[CH:55][CH:56]=1>C1COCC1.O.CN(C=O)C>[Cl:13][C:5]1[C:4]([C:2]([NH2:1])=[O:3])=[CH:8][NH:7][C:6]=1[C:9]([NH:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([O:58][C:59]2[CH:60]=[C:61]([C:62]#[N:63])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[C:52]=1[F:68])=[O:11]
Reactant: COC(=O)c1[nH]cc(C(N)=O)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cc(C(N)=O)c3Cl)c2F)c1
Temperature: 35 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a solution of methyl 4-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate (0.04 g, 0.197 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.047 g, 1.974 mmol). The reaction mixture was stirred overnight at 35° C. The solvent was evaporated and the resulting solid placed under high vacuum. To the intermediate mixture was added DMF (1 mL), DIPEA (0.052 ml, 0.296 mmol), HATU (0.090 g, 0.237 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.197 mmol). The solution was stirred for 1 h at RT. Purification was accomplished by HPLC. The desired fractions were neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to afford 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-pyrrole-2,4-dicarboxamide (0.020 g, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.18 (br. s., 1H) 8.15 (t, 1H) 7.83 (d, 1H) 7.46-7.56 (m, 4H) 7.37 (t, 1H) 7.30 (br. s., 1H) 7.05 (br. s., 1H) 4.57 (d, 2H). MS: m/z 481.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([O:8][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(Cl)cnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-(5-Chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (39 mg) was suspended in N,N-dimethylformamide (7 ml). Cyclopentyl bromide (0.3 ml) and potassium carbonate (300 mg) were added to the suspension, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (29 mg, yield 62%).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:11][N:7]1[CH2:8][CH:9]([OH:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6]1
Reactant: OC1CNCc2sccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1Cc2sccc2C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
4,5,6,7-Tetrahydrothieno[2,3-c]pyridin-4-ol (6.21 g) prepared in Reference Example 5 and 8.29 g of sodium carbonate were suspended in 50 mL of DMF, 6.25 g of methyl iodide was added thereto by dropping thereinto and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured over 200 mL of water and subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 5.63 g of the objective compound.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.O.[NH2:10][NH2:11]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[NH:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CC2)n[nH]1
Yield: 80 %

Procedure:
5 g (0.046 mol) of 3-cyclopropyl-3-oxo-propanenitrile were dissolved in 200 ml of ethanol and 2.26 ml (0.046 mol) of hydrazine hydrate were added. The solution was maintained at reflux for 5 hours and then the solvent evaporated under vacuum. The residue was re-dissolved with methylene chloride and washed several times with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to give 4.53 g (80% yield) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:40][CH2:39][C:12]3[N:13]=[C:14]([C:19]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:20]=4[C:21]([CH3:38])=[CH:22][N:23]5[S:28]([C:31]4[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[N:15]=[C:16]([O:17]C)[C:11]=3[CH2:10]2)[N:6]([CH3:41])[N:5]=1)([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:40][CH2:39][C:12]3[N:13]=[C:14]([C:19]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:20]=4[C:21]([CH3:38])=[CH:22][N:23]5[S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=4)(=[O:30])=[O:29])[N:15]=[C:16]([OH:17])[C:11]=3[CH2:10]2)[N:6]([CH3:41])[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(O)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 85 °C

Procedure:
To a solution of 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.8 g, 3.15 mmol), prepared as described in Example 16, in ethanol (10 mL) in a 150 mL sealed tube, was added concentrated hydrochloride (10 mL). After the tube was sealed, the reaction was stirred and heated to 85° C. for 18 h. The reaction mixture wascooled to 0° C. and poured into ice water. Solid NaHCO3 was added to neutralize the reaction mixture, then the mixture was extracted with DCM twice and the combined organic layers were dried over Na2SO4. The resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to provide 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol. MS (ESI+) m/z 557.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: Ic1ccc(-c2nnc(CN3CCOCC3)o2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCOCC3)o2)cc1

Procedure:
Example 14 was prepared from 4-[5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-morpholine (Intermediate 10) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH2:40][N:41]([CH3:43])[CH3:42])[C:5]([NH:7][C@H:8]([B:25]1[O:29]C2CC(C)(C)CCC2(C)[O:26]1)[CH2:9][C:10]1[C:11](OC)=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:6].B(Cl)(Cl)Cl>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH2:40][N:41]([CH3:42])[CH3:43])[C:5]([NH:7][C@H:8]1[CH2:9][C:10]2[CH:22]=[CH:21][CH:20]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=2[O:29][B:25]1[OH:26])=[O:6]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(N)c2)B2OC3CC(C)(C)CCC3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: CN(C)Cc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1N

Procedure:
Prepared from tert-butyl 3-((2R)-2-(3-amino-4-((dimethylamino)methyl)benzamido)-2-(3a,6,6-trimethylhexahydrobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 384 (MH)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18])[CH2:9][CH2:10][CH3:11].C(CN)O>O.C(O)C>[CH2:8]([N:12]1[C:16](=[O:17])[C:15](=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[NH:14][C:13]1=[O:18])[CH2:9][CH2:10][CH3:11]
Reactant: O=Cc1cccs1
Reactant: CCCCN1C(=O)CNC1=O
Solvent: NCCO
Solvent: CCO
Solvent: O
Product: CCCCN1C(=O)NC(=Cc2cccs2)C1=O
Yield: 51.1 %

Procedure:
A mixture of thiophene-2-carboxaldehyde (5.6 g; 0.05 mole), 3-n-butylhydantoin (7.8 g; 0.05 mole) and ethanolamine (4.6 g; 0.075 mole) in water/ethanol (50 ml/30 ml) was stirred and boiled under reflux for 4 hours. The mixture was cooled in the refrigerator and the resultant brownish yellow crystals filtered off, washed with water, sucked dry and recrystallised from ethyl acetate (with carbon treatment) to give the title compound (6.4 g; 51%) having m.p. 140° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd].O>[N:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CC(N2CCCCC2)CN1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1

Procedure:
A solution of 10.0 g of [4S]-1-[phenylmethoxy)carbonyl]-4-(1-piperidinyl)-L-proline, methyl ester in 100 ml of methanol is treated with a suspension of 2 g of 5% palladium on charcoal in 10 ml of water and placed under 3 atmospheres of hydrogen. After an equivalent quantity of hydrogen is consumed, the suspension is filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCOCC1.N1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(CC=C)C=O.Cl>C1(C)C=CC=CC=1.O.C(#N)C>[CH3:19][CH:18]([CH2:17][CH:16]=[CH2:15])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4]
Reactant: c1ccncc1
Reactant: O=C(O)CC(=O)O
Agent: C=CCC(C)C=O
Agent: Cl
Solvent: C1COCCN1
Solvent: O
Solvent: CC#N
Product: C=CCC(C)/C=C/C(=O)O
Temperature: 75 °C
Reaction time: 21 h
Yield: 51.3 %

Procedure:
Malonic acid (99.90 g, 0.96 mol), acetonitrile (285 mL), morpholine (26 mL, 0.30 mol), and pyridine (97 mL, 1.20 mol) were added in this order to the solution of 2-methylpent-4-enal in toluene obtained by the method described above under a nitrogen atmosphere, and the mixture was warmed to 70 to 80° C. and stirred for approximately 21 hours. The reaction mixture was cooled to room temperature. To the reaction mixture, water (380 mL) was added, and concentrated hydrochloric acid (130 mL) was added to separate an organic layer. The aqueous layer was subjected to extraction with toluene (140 mL), and the extract was combined with the organic layer, followed by extractions into aqueous layers with a 2 M aqueous NaOH solution (358 mL) and a 1.3 M aqueous NaOH solution (134 mL) in this order. The aqueous layers were combined and then adjusted to be acidic by the addition of concentrated hydrochloric acid (80 mL), followed by two extractions with toluene (190 mL and 95 mL). The organic layers were combined and then washed with water (95 mL). The organic layer was concentrated under reduced pressure to obtain the title compound (69.05 g, brown oil substance).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9][NH2:10].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25]Cl.C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1ccc(F)cc1OCCN
Reactant: Fc1ccc2[nH]cc(CCCl)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(F)cc1OCCNCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylamine (0.51 g, 2.8 mmol), 2-(5-fluoro-1H-indol-3-yl)ethylchloride (0.44 g, 1.8 mmol) and triethylamine (0.29 g, 3 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 0.27 g (43%) of product as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]=2)[CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
To a solution of 2.2 g (4.0 mmol) 3,3-bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenol in 100 mL methylene chloride was added 7 g of activated manganese dioxide. After stirring the resultant mixture for 20 hours, the insolubles were removed by filtration and the filtrate concentrated in vacuo to give a quantitative yield of the title compound, m.p.=208° C. (dec).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C(O)C.O.[OH-].[Na+].O>[CH3:12][N:3]1[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]1[S:1][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([C:19](=[O:20])[C:18]2[CH:29]=[CH:30][C:15]([C:14]([F:13])([F:31])[F:32])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and 1N-sodium hydroxide/water (5.1 mg) in ethanol (10 ml) was added 4-(4-trifluoromethylbenzoyl)benzyl bromide (1.73 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate-hexane to provide the title compound as colorless solid (1.11 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl.C(N(CC)CC)C>[S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:11])=[O:10]
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
2-(2-methoxyethoxy)ethanol 3.06 g (25.6 mmol) and TsCl 6.25 g (32.78 mmol) were dissolved in freshly distilled CH2Cl2, triethylamine (7.1 mL) was added then stirred under argon overnight. Saturated sodium bicarbonate solution (40 mL) and ethyl acetate (100 ml) were added. The organic layer was washed with 1N potassium bisulfate (80 mL), then saturated sodium bicarbonate solution (80 mL), dried over Na2SO4, then dried on rotavap to produce an oil. The product was purified on silica gel flash column with CHCl3:EtOAc=5:1. Product (8) 6.77 g (97% yield) was obtained as a colorless oil. Solvents such as CH3CN and THF may be used instead of CH2Cl2 in the synthesis of compound 8.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CON(C)[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]>CCOCC>[CH:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CON(C)C(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
LiAlH4 (110 mg, 2.89 mmol) was added in portions to a 0° C. solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (525 mg, 1.93 mmol) in ether (9 mL). The reaction mixture was then stirred at rt for 30 min. The reaction mixture was cooled to 0° C. and carefully quenched by dropwise addition of aqueous 5% KHSO4 (10 mL). The mixture was then extracted with ether (2×15 mL). The organic extracts were combined, washed with 10% aqueous citric acid, 5% aqueous NaHCO3 and saturated aqueous NaCl. The ether was then dried over MgSO4, filtered and concentrated to give (R)-tert-butyl 2-formylpiperidine-1-carboxylate (392 mg, 1.84 mmol, 95% yield) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (1H, s), 4.71-4.44 (1H, m), 4.12-3.79 (1H, m), 3.05-2.78 (1H, m), 2.17 (1H, d, J=11.5 Hz), 1.73-1.55 (4H, m), 1.46 (9H, s), 1.34-1.18 (1H, m).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:29]([F:32])([F:31])[F:30])=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[C:8]=1[C:9](OC)=[O:10])(=O)[CH3:2].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][NH:38][NH2:39]>CCO>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][N:38]1[C:9](=[O:10])[C:8]2[N:7]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:15][CH2:14]3)[N:6]=[C:5]([C:29]([F:31])([F:32])[F:30])[C:4]=2[C:1]([CH3:2])=[N:39]1
Reactant: COc1ccccc1CNN
Reactant: COC(=O)c1c(C(C)=O)c(C(F)(F)F)nn1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCO
Product: COc1ccccc1Cn1nc(C)c2c(C(F)(F)F)nn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a stirred solution of 112 (361 mg, 0.796 mmol) in EtOH (3.2 mL) was added (2-Methoxy-benzyl)-hydrazine (242 mg, 1.592 mmol) and the resulting solution was allowed to stir for 1 h at room temperature, and for 2 h at 75° C. The solvent was evaporated, saturated NaHCO3 was added and the mixture extracted with EtOAc. After the usual work-up the residue was purified via Biotage (10% to 60% EtOAc/Hexane; 12M column) to afford 113 (81 mg. 18.3% yield) as white solid. LRMS (ESI): calc. 555.6; found 556.3 (MH)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N+:12]2([O-:47])[CH2:13][CH2:14][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=3)([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:41])([F:39])[F:40])=[CH:35][CH:36]=3)[OH:19])[CH2:16][CH2:17]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(C[N+]2([O-])CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a stirred solution of 0.5 gram (0.0008 mole) of N-[4-(2-propen-1-yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (Compound 42, prepared in Example 5) in 10 mL of chloroform was added 0.3 gram (0.0008 mole) of 50% 3-chloroperoxybenzoic acid. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 2 hours. After this time the reaction mixture was washed, first, with an aqueous solution saturated with sodium bicarbonate, and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of ethyl acetate and hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure to a residue. The residue was concentrated further under high vacuum, yielding about 0.2 gram of N-[4-(2-propen-1-yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.