Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(SC)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCn1ncc2c(Cl)c3cc(SC)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-(methylthio) anthranilic acid (4.5 g) and POCl3 (20 mL) was refluxed overnight. The reaction mixture was poured into water, then ice was added. The mixture was extracted with CH2Cl2 and then the CH2Cl2 layer was evaporated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate/hexane to afford 2.4 g of 1-ethyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-b]quinoline, m.p. 120°-121° C.
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])[CH3:5].Cl[CH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]2[CH:29]=1>CN(C)C=O>[C:4]([NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17][CH2:19][C:20]3[N:21]=[C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]4[CH:29]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])[CH3:5]
Reactant: CC(=O)Nc1nc2ccc(O)cc2o1
Reactant: Cc1ccn2cc(CCl)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(OCc3cn4ccc(C)cc4n3)cc2o1
Temperature: 50 °C
Reaction time: 17 h
Yield: 10.1 %

Procedure:
Methanolic sodium methoxide (28 wt. %, 1.25 g) was added to a solution of 2-acetamido-6-hydroxybenzoxazole (1.25 g) and 2-chloromethyl-7-methylimidazo[1,2-a]pyridine (1.41 g) in N,N-dimethylformamide (25 ml). After the mixture was stirred at 50° C. for 17 hours, the solvent was evaporated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (62.5 g) by eluting with chloroform-methanol (50:1, V/V), and the product obtained was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-acetamido-6-[(7-methylimidazo[1,2-a]pyridin-2-yl)methoxy]benzoxazole (0.22 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.000 g, 3.12 mmol) in methanol (5 ml) at rt was added 4M HCl in dioxane (15 ml). After stirring for 20 h the solution was concentrated to give the deprotected amine as the hydrochloride salt (0.785 g, 98%). LC-MS (LCT2) m/z 221 [M+H+], Rt 12.84 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[N:31]([CH3:35])[CH3:30])=[C:10]2[C:6]=1[CH2:7][N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:9]2=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(N)c3C2=O)ccc1OC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Temperature: 100 °C
Yield: 70 %

Procedure:
To (1S)-7-amino-4-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (800 mg, 1.82 mmol) was added dimethylcarbamyl chloride (3 ml). The mixture was heated at 100° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-3-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea as a white solid (600 mg, 70% yield): mp, 205-207° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 2.94 (s, 3H, CH3), 3.11 (s, 6H, N(CH3)2), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.88 (s, 3H, CH3), 4.05-4.22 (m, 4H, CHHSO2+CHHN+OCH2CH3), 4.40 (d, J=10 Hz, 1H, CHHN), 5.73-5.79 (m, 1H, NCH), 6.86-6.96 (m, 3H, Ar), 7.36 (d, J=9 Hz, 1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 9.77 (s, 1H, NHCO); 13C NMR (CDCl3) δ 14.68, 36.27, 41.51, 46.96, 51.47, 55.73, 55.97, 64.64, 111.64, 111.67, 112.28, 118.20, 118.54, 119.31, 120.08, 129.13, 133.24, 138.58, 138.77, 148.94, 149.88, 155.01, 169.72. Anal Calcd for C23H28ClN3O6S: C, 54.32; H, 5.65; N, 8.12. Found: C, 54.16; H, 5.42; N, 7.82.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(O)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Yield: 53.2 %

Procedure:
2-({4-[2-(4-Hydroxyphenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (600 mg) obtained in Example 50-2 and 4-chlorobenzylbromide (312 mg) were dissolved in acetone (10 mL), potassium carbonate (210 mg) was added, and the mixture was refluxed for 6 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (420 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[NH:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H-].[Na+].[Br:25][CH2:26][CH2:27]Br>CN(C=O)C.O>[Br:25][CH2:26][CH2:27][N:18]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:15]=2[CH:16]=[C:17]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOc1cccc(-c2nccc3[nH]c(C(=O)OC)cc23)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCBr)c1
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(3-ethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (230 mg, 0.776 mmole) in DMF (7 mL) was added NaH (60% dispersion in mineral oil, 40 mg, 1.000 mmole) at RT. After gas evolution had ceased 1,2-dibromoethane (1 mL, 11.60 mmole) was added rapidly. After stirring overnight the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine then dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (135 mg, 43%) as a clear gum. 1H NMR (400 MHz, CDCl3): δ8.51 (d, J=6.0 Hz, 1 H); 7.60 (d, J=1.0 Hz, 1 H); 7.49-7.45 (m, 2 H); 7.40 (m, J=7.9 Hz, 1 H); 7.31 (dd, J=6.0, 1.0 Hz, 1 H); 6.99 (ddd, J=8.2, 2.6, 1.1 Hz, 1 H); 4.92 (t, J=6.83 Hz, 2 H); 4.12 (q, J=7.0 Hz, 2 H); 3.91 (s, 3 H); 3.71 (t, J=7.12 Hz, 2 H); 1.43 (t, J=7.12 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[NH:21][CH2:20][CH2:19]2.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:21]1[CH:22]2[CH2:25][CH2:26][N:18]([CH2:24][CH2:23]2)[CH2:19][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Reactant: C1CN2CCC(CC2)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(N2CCN3CCC2CC3)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
2-Chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (333 mg, 1.32 mmol), 1,4-diazabicyclo[3.2.2]nonane (57%, 195 mg, 0.88 mmol), tri(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (58 mg, 0.093 mmol), sodium tert-butoxide (208 mg, 2.17 mmol) and toluene (1.55 mL) were added to a flame dried round bottom flask purged with nitrogen. The mixture was placed in an oil bath at 80° C. for 18 h and then cooled to RT. The mixture was filtered through a pad of celite and washed with chloroform and methanol. The filtrate was concentrated and the residue was purified by chromatography (Biotage, 12M) eluting with 8% methanol in chloroform with 20 drops of NH4OH per liter of eluent to afford 104 mg (34%) of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester: MS (Cl) m/z 343.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[CH:6]=[CH:7][NH:8]2.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc(OC)c2c(=O)cc[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,7-dimethoxy-1H-quinolin-4-one (300 mg, 1.4 mmol) in POCl3 (5 mL) was heated to reflux for 15 h. The reaction mixture was cooled to rt and poured into ice-water. The mixture was then basified to pH 7 with NaHCO3 and stirred overnight. The solid was filtered and washed with water and dried to give 4-chloro-5,7-dimethoxyquinoline. LCMS m/z=224 (M+1); 1H NMR (CDCl3) δ: 8.56 (d, 1H, J=4.4 Hz), 7.23 (d, 1H, J=4.4 Hz), 7.05 (s, 1H), 6.58 (s, 1H), 3.93 (s, 6H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH2:14]([C@H:17]1[CH2:18][CH2:19][C@H:20]([CH:23]=[CH:24][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:21][CH2:22]1)[CH2:15][CH3:16]
Reactant: C1CCNCC1
Reactant: CCC[C@H]1CC[C@H](CC=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCC[C@H]1CC[C@H](C=CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.078 mol of anhydrous sodium sulfate and 0.086 mol of piperidine were mixed and treated dropwise at -5° C. under nitrogen with 0.039 mol of trans-4-propylcyclohexylacetaldehyde. The reaction mixture was stirred at room temperature for 24 hours. Subsequently the precipitate was filtered off and washed with hexane. Distillation of the combined filtrates under a vacuum gave 1-[2-(trans-4-propylcyclohexyl)vinyl]piperidine of b.p. 118°-120° C./1 Torr in 75% yield.
Reaction SMILES: Cl.[NH2:2][OH:3].CO.[OH-].[K+].C[O:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=2)[N:24]=1)=[O:18].[OH-].[K+].Cl>O>[NH2:31][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:2][OH:3])=[O:9])[S:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc(N)c2)cs1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2csc(NC(=O)CCCCCCC(=O)NO)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.958 g, 13.8 mmol) in MeOH-KOH (0.772 g, 13.8 mmol) was added at 40° C. for 10 minutes. The reaction mixture was cooled to 0° C. and filtered. Compound 20 (0.250 g, 0.69 mmol) was added to the filtrate followed by KOH (50 mg, 0.89 mmol) at room temperature. After 2 hours, water (20 ml) was added, followed by 1 N HCl until pH reached 6.5. The reaction mixture was extracted with EtOAc, and organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed by rotary evaporation. The crude solid was purified by preparative HPLC to give compound 23 (0.110 g, 43.9%). 1H NMR (300 MHz, CD3OD) δ 7.98 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.55 (1H, t, J=7.8 Hz), 7.51 (1H, s), 7.29 (1H, dd, J=7.8, 1.2 Hz), 2.51 (2H, t, J=7.2 Hz), 2.11 (2H, t, J=7.2 Hz), 1.74 (2H, t, J=7.0 Hz), 1.65 (2H, t, J=7.0 Hz), 1.50-1.35 (4H, m). 13C NMR (100 MHz, CD3OD) δ 172.1, 158.0, 147.4, 136.3, 129.7, 125.1, 120.8, 119.2, 108.5, 34.6, 28.0, 27.9, 24.7, 24.3.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]#[N:17])[CH:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]#[N:17])[CH:10]=1
Reactant: COc1ccc(COc2cc(C#N)nc(C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(O)cc(C#N)n1
Reaction time: 0.17 h

Procedure:
The 6-[(4-methoxybenzyl)oxy]-2-methylpyrimidine-4-carbonitrile from step 2 of this example (2.8 g, 11 mmol) was dissolved in DCM (9.1 mL) and TFA (1.8 mL) was added via syringe drop-wise. The reaction was allowed to proceed 10 min. at room temperature and was concentrated to near dryness, without heating, under vacuum. The residue was dissolved in DCM (10 mL), and saturated NaHCO3 solution (aq, 5 mL) was added to adjust pH to ˜7. Acetic acid (1 mL) was then added to the solution to adjust pH to ˜4 and the mixture was concentrated to dryness i. vac. The residue was purified by chromatography on silica gel using gradient elution: starting at 30% ethyl acetate/hexane, then switching to 5% methanol/DCM to yield the titled compound as a white solid. LC-MS (M+1): 136.16.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]([CH3:17])=[N:10]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]([C:14]([C:13]2[N:9]([CH3:8])[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:15])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C(=O)N(CC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
Triethylamine (1.8 ml, 12.8 mmol) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (0.5 g, 3.2 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 3.2 mmol), and diethyl ether (30 ml). The reaction is stirred for 5 minutes at room temperature. The reaction is poured into 5% citric acid and extracted with ethyl acetate. The ethyl acetate is washed with sodium bicarbonate and brine and dried over sodium sulfate. The sodium sulfate is filtered off and the crude product is concentrated on a rotary evaporator to yield (1.15 g, 96% crude) of 4-{[(1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=379 (M++1); 1H NMR (CD3OD) (broad peaks due to rotamers) δ=6.29-6.17 (1H, br m), 4.23-4.10 (2H, br m), 3.98-3.90 (1H, br m), 3.78 (3H, br s), 3.25 (2H, d), 2.89-2.57 (2H, br m), 2.25 (3H, s), 2.20-2.04 (1H, br m), 1.86-1.70 (3H, br m), 1.46 (9H, s), 1.00-0.74 (6H, br m).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension containing 27.0 g of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid, 19.5 ml of oxalyl chloride, 270 ml of methylene chloride, and a few drops of N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. Separately, a few drops of carbon tetrachloride was added to a suspension of 3.08 g of magnesium in 6.4 ml of absolute ethanol, and then a solution of 19.2 ml of diethyl malonate in 12 ml of absolute ethanol was added dropwise to the suspension under heating at 50° C., and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then, toluene was added to dissolve the residue and the solution was again concentrated. To a solution of the residue in 30 ml of toluene, a solution of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride in 30 ml of toluene was added dropwise with stirring under ice cooling, and then stirring was continued for 2 hours at room temperature. The reaction mixture was added with 100 ml of 5% sulfuric acid, and was then extracted with diethyl ether. The extract was washed with brine, and then dried and concentrated to give 47.3 of brown oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=O)[CH3:2].Cl.[NH2:11]O>O>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:11])[CH3:2]
Reactant: CCn1cccc1C=O
Reactant: NO
Agent: Cl
Solvent: O
Product: CCn1cccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
1-Ethylpyrrole-2-carbaldehyde (cf. J. Chem. Soc. (C), 2563, 1970) (7.4 g, 60 mmole), hydroxylamine hydrochloride (4.8 g, 69 mmole) sodium acetate trihydrate (9.4 g, 69 mmole) and water (30 ml) are mixed, and the mixture is stirred at room temperature for 20 minutes and then allowed to stand in a cooled place overnight. The precipitated oxime compound is taken by filtration and dried. The oxime compound is refluxed in acetic anhydride (25 ml) for 20 minutes and then allowed to cool until room temperature. The reaction mixture is added to ice water, and the mixture is stirred for 2 hours and neutralized with sodium carbonate and extracted with ether twice. The ether layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is distilled under reduced pressure to give 1-ethylpyrrole-2-carbonitrile (5.25 g, yield: 73%).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1cccn1C
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccn3C)nc(=O)c1-2
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Sodium spheres (1.0 g, 43.5 mmol) were dissolved in ethanol (50 mL) at reflux and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.2 g, 10 mmol), followed by methyl 1-methylpyrrole-2-acetate (3.06 g, 20 mmol) in ethanol (30 mL) were added. The reaction mixture was refluxed under argon overnight, cooled to room temperature and evaporated to dryness. The residue was dissolved in water, the solution was cooled and the resulting solid was collected by filtration to afford recovered starting material. The filtrate was chilled, a solid formed which was collected by filtration, slurried with water and acidified with 2N HCl. The mixture was cooled and the product was collected by filtration and dried at 110° C. in vacuo to afford 1.2 g of 1-cyclopentyl-3-ethyl-6-(1-methyl-2-pyrrolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 214.5°-216.5° C. Additional product (0.6 g) was also obtained by acidifying the filtrate with acetic acid, collecting the product by filtration and recrystallizing it from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:25][OH:26])[N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.B.[O:28]1CCCC1>O1CCCC1>[OH:26][CH2:25][C@H:11]1[N:12]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:13][C@H:14]([OH:28])[C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10]1
Reactant: C1CCOC1
Reactant: COc1ccc(C2=CCN(S(=O)(=O)c3ccc(C)cc3)[C@H](CO)C2)cc1
Agent: B
Product: COc1ccc([C@H]2C[C@@H](CO)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 108.1 g of [(S)-4-(4-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-2-yl]-methanol in 1000 ml of tetrahydrofuran are added 504 ml of a solution of borane-tetrahydrofuran (1M) at room temperature. The reaction mixture is heated to 40° C. for 2-6 hours, cooled to room temperature, and quenched by the addition of 150 ml of 2N sodium hydroxide solution and 150 ml of 30% hydrogen peroxide solution. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a white solid. Rf=0.19 (EtOAc-heptane 1:1); Rt=3.67.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1CBr
Yield: 82.4 %

Procedure:
A mixture of 1-benzyl-5-bromo-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.28 g, 0.83 mmol), N-bromosuccinimide (0.163 g, 0.92 mmol), and benzoyl peroxide (20 mg, 0.083 mmol) in CCl4 (10 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-20% EtOAc/hexanes) to give 284 mg of the title compound as an amorphous solid. MS: (+) m/z 415.87 (M+1).