Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[C:24]([F:35])[C:23]=2[F:36])=[CH:10][CH:9]=1>>[Cl:19][C:17]1[S:16][C:15]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[C:24]([F:35])[C:23]=2[F:36])=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[CH:18]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-chlorothiophen-2-yl)methoxy)-2,3-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ: 7.44 (s, 4H), 7.00 (s, 1H), 6.90-6.93 (m, 1H), 6.77-6.80 (m, 1H), 5.16 (s, 2H) 3.58 (t, J=6.3 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 1.78-1.83 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H16Cl2F2O2S, 393.1 (M-Cl). found 393.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:35][C:36](=[O:37])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=2)[CH:13]=[C:14]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCC(NC(=O)c2c[nH]c(C(=O)OCc3ccccc3)c2)CC1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2cc(C(=O)OCc3ccccc3)n(CC(=O)Nc3ccc(Cl)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.1 %

Procedure:
To a solution of 4-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (50 mg) in DMF (2 mL) was added Cs2CO3 (176 mg), followed by 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (34 mg). The mixture was stirred for 20 h at RT whereupon it was filtered. The filtrates were directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA). Pure 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (28.5 mg) was obtained as its trifluoroacetate salt. MS (ESI+): m/e=538 [M+H]+, chloro pattern.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10])=[O:5])C.[OH-].[Na+]>C(O)C>[F:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:9]([C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3])=[O:10]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Yield: 60.7 %

Procedure:
The crude trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid ethyl ester (0.55 g, 2 mmol) was suspended in ethanol and sodium hydroxide solution (4 ml, 1N, 4 mmol) was added. The resultant solution was stirred for 4 hr at 20° and 0.5 hr at reflux. The ethanol was removed in vacuo and the residue mixed with water. The mixture was extracted with ethyl acetate. The aqueous layer was separated and made acidic with 12 N HCl. The precipitate was collected and air dried to give trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid as an off-white solid (0.30 g), mp 276-277 dec. LC/MS mw=247; retention time 1.19 min. Mol wt calc1d for C13H10F NO2: 247.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:15])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CC(=O)CC.O>[CH3:15][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:9]=2)[N:6]=1
Reactant: Cc1cc(CO)n(-c2ccc(O)cc2)n1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cc(CO)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of 4-(5-hydroxymethyl-3-methylpyrazol-1-yl)phenol (326 mg, 1.60 mmol) in 2-butanone (8 mL) was added potassium carbonate (243 mg, 1.76 mmol) and 1-(3-chloropropyl)pyrrolidine (260 mg, 1.76 mmol). The reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated to give 315 mg of the desired product. LC-MS (C18H25N3O2 calculated 315) m/z 316 (M+H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:35])([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 93 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (440 mg, 0.90 mmol) in ethanol (8 mL), tetrahydrofuran (10 mL) and an aqueous sodium hydroxide solution (10%, 3 mL) was heated at 50° C. for 16 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (290 mg, 92%) which was used in the next step without further purification: LC/MS m/e calcd for C23H26N2O [M+H]+ 347.48, observed 347.2.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[H-].[Na+].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH3:18])[O:19][C:22](=[O:27])[CH:23]=1
Reactant: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 16.9 g (60.9 mmol) of 4-(4-tert-butyldimethylsilyloxyphenyl)-2-butanone (prepared in Example R), 7.32 g (183 mmol) of 60% NaH dispersion in mineral oil, 21.2 g (183 mmol) of methyl acetoacetate, 114 mL (1.64M, 183 mmol) of n-butyllithium and 360 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4) and the solvents were evaporated.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][N:19]=1>>[Br:24][C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1
Reactant: Nc1cc(Br)ccn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(Br)cc2n1
Yield: 33 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (2.0 g, 7.2 mmol) was converted, using 2-amino-4-bromopyridine instead of 2-amino-3-methylpyridine, to the title compound (824 mg, 33%) which was obtained as a light yellow foam. MS: m/e=354.1/355.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=1>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:12]2[C:17]([CH3:18])([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)C=C(Cl)C(C)(C)C1=O
Reactant: OCc1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)C=C(OCc2ccc(Br)s2)C(C)(C)C1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 5-bromothiophen-2-ylmethanol (6.76 g, 35 mmol) in tetrahydrofuran (100 ml) at 0° C. is added, carefully, sodium hydride, 60% dispersion in mineral oil, (1.2 g, 30 mmol over a period of 10 minutes. The reaction is allowed to warm to room temperature and stirred for a further hour. 5-Chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (5.02 mg, 25 mmol) is then added in one portion and the reaction mixture is allowed to stir at room temperature for 17 hours. The reaction is concentrated in vacuo and purified by flash chromatography on silica gel to give the desired compound as a white solid (4.45 g)
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](OCC)=[O:15])=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([NH2:29])[CH3:28]>CO>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](=[O:15])[NH:29][CH2:27][CH3:28])=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Solvent: CO
Product: CCNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Yield: 82.2 %

Procedure:
In methanol, 2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and a 70% aqueous solution of ethylamine were processed as in Example 43, whereby the title compound was obtained in a yield of 82.2%.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9]([NH:15]C(=O)C)[CH:10]=[CH:11][C:12]=2[CH3:14])[C:7](=[O:19])[CH:6]([NH:20][C:21](=[O:23])[CH3:22])[CH2:5]1)(=O)C.C(NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)C>>[C:21]([NH:20][CH:6]1[C:7](=[O:19])[C:8]2[C:13](=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH2:15])[NH:4][CH2:5]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CN2C(C)=O
Agent: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CNc2c(C)ccc(N)c2C1=O

Procedure:
The procedure of Example 1-(4) was followed by using 1.40 gm of the compound prepared in (3) above instead of 2,8-diacetylamino-1-tetralone. The reaction product was post-treated to obtain 0.79 gm of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[NH:12][N:13]=[CH:14][CH:15]=2)=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: Fc1ccc(CCBr)cc1
Reactant: CCOC(=O)c1sc(-c2ccn[nH]2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccn(CCc3ccc(F)cc3)n2)nc1C
Temperature: 90 °C
Yield: 41.4 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester (2.5 g, 10.54 mmol) in dimethyl sulfoxide (50 mL) was treated with 1-(2-bromo-ethyl)-4-fluoro-benzene (2.10 g, 10.54 mmol) and potassium carbonate (4.30 g, 31.64 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester as a white solid (1.57 g, 45% yield). MS (M+H)+=360; Rt=1.65 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C@@H:16]([NH2:18])[CH3:17].Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[N:28]1[C:20]([NH:18][C@H:16]([C:8]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:21]2[C:25]([NH:24][CH:23]=[N:22]2)=[N:26][CH:27]=1
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of (S)-1-(3-pyridin-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (0.134 g, 0.56 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.186 g, 0.78 mmol) and DIPEA (0.18 mL, 1.01 mmol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and treated with HCl/dioxane (4M, 1.0 mL, 4.00 mol) and stirred for 30 min. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give 293 as a white solid (0.160 g, 80%). LCMS (method K): Rt 2.28 min, [M+H]+ 358. 1H NMR (DMSO-d6): δ 13.20-12.70 (1H, bs), 8.59 (1H, s), 8.31 (1H, m), 8.13 (2H, m), 8.03 (2H, tm), 7.81-7.81 (1H, m), 7.47 (1H, s), 7.36 (1H, m), 5.99 (1H, m), 1.67 (3H, d, J=6.82 Hz)
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:17])=C([CH:9]=[C:10]([Br:16])[C:11]=1[S:12][CH2:13][CH:14]=[CH2:15])C#N)[CH:2]=[CH2:3].[OH-].[Na+].Cl.C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>CCO.O>[Br:16][C:10]1[C:11]([S:12][CH:13]=[CH:14][CH3:15])=[C:4]([CH:1]=[CH:2][CH3:3])[C:5]([Cl:17])=[C:26]([CH:9]=1)[C:24]([O:23][CH3:22])=[O:25]
Reactant: CCOC(C)=O
Reactant: C=CCSc1c(Br)cc(C#N)c(Cl)c1CC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=CSc1c(Br)cc(C(=O)OC)c(Cl)c1C=CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-allyl-4-(allylthio)-5-bromo-2-chlorobenzonitrile 94 (1.1 g, 3.35 mmol) in a mixture of EtOH (90 mL) and H2O (10 mL) was added NaOH (545 mg, 13.4 mmol). The reaction mixture was warmed up to 100° C., and stirred overnight. After reaction complete, the resulting solution was cooled down to room temperature. 1 N HCl solution was used for acidify reaction solution, and normal work-up with EtOAc was proceeded. Removal of volatile solvent was preceded by drying with MgSO4. Without further purification, crude acid was used for next step. The crude acid was dissolved in MeOH (50 mL), treated with SOCl2 (1 mL) provisionally. The reaction mixture was refluxed overnight and resulting solution was cooled down to room temperature and evaporated in vacuo. The residue was purified by silica gel chromatography to afford the desired product (710 mg, 63% overall yield) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:6]>C(OCC)(=O)C>[C:5]([C:7]1[CH:8]=[C:9]([N+:1]([O-:4])=[O:2])[C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:6]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C#N)ccc1O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To 25 ml of fuming nitric acid was added 2.50 g of methyl 5-cyano-2-hydroxybenzoate. This solution quickly turned dark orange, and the reaction was complete after stirring for 1 h. The solution was slowly transferred to 100 ml of ice-cold water. To the resultant suspension was added 100 ml of ethyl acetate and the biphasic mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate (2×60 ml), and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml) and filtered through a small plug of silica gel, eluting with more ethyl acetate (50 ml). The eluent was concentrated in vacuo to provide the title compound (2.71 g, 87%). Mass spectrum (ESI) 221.2 (M−1).
Reaction SMILES: C[Mg]Br.C(OC(=O)[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:28]([F:31])([F:30])[F:29])=[N:18][N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:13]=2[C:12]1=[O:32])C>O1CCCC1>[OH:26][C:23]([CH3:24])([CH3:22])[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:28]([F:31])([F:29])[F:30])=[N:18][N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:13]=2[C:12]1=[O:32]
Reactant: CCOC(=O)CCCN1CCc2c(C(F)(F)F)nn(-c3ccc(OC)cc3)c2C1=O
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCC(C)(C)O)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3M methylmagnesium bromide (0.682 g, 2.05 mmol) was added to 4-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-butyric acid ethyl ester (0.348 g, 0.818 mmol) dissolved in tetrahydrofuran (10 mL). The reaction was stirred at rt overnight. The reaction was quenched with 1N hydrochloric acid (50 mL), extracted with ethyl acetate (3×50 mL), washed with brine (1×50 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford 0.111 g (34%, based on recovered starting material): 1H NMR (CDCl3) δ 7.45 (d, j=9.2 Hz, 2H), 6.96 (d, j=8.7 Hz, 2H), 3.84 (s, 3H), 3.69 (t, j=6.8 Hz, 2H), 3.50(t, j=7.4 Hz, 2H), 3.00(t, j=6.8 Hz, 2H), 1.75–1.62 (m, 2H), 1.49–1.41 (m, 2H), 1.21 (s, 6H) ppm; Mass Spec (M+H)+ 412.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:15][O:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CO[C@@H]1CCN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-methoxypiperidin-3-ylcarbamate (1.37 g, 4.28 mmol) and 10% Pd/C (0.46 g, 0.43 mmol) in MeOH (20 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 18 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-methoxypiperidin-3-ylcarbamate (0.99 g, 100%) as a solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CC(C)=CCOc1ccc(C(=O)O)c(OCC=C(C)C)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)cc1OCC=C(C)C
Yield: 98 %

Procedure:
In a manner identical to Example 15, 2,4-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.96 g (98%) of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.Cl.[NH2:22][OH:23].C(N(CC)CC)C.O>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19](=[N:22][OH:23])[NH2:20])[CH:3]=1
Reactant: NO
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: NC(=NO)c1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (10.0 g, 31.1 mmol) was dissolved in 150 ml of dry dioxane, and then hydroxylamine hydrochloride (3.35 g, 46.8 mmol) and triethylamine (6.6 ml, 47.4 mmol) were added with stirring at room temperature. The mixture was stirred at room temperature for 74 hours and the reaction solution was poured into 300 ml of iced water. The solution was stirred for 30 minutes and the deposited crystal was filtered. The resulting crystal was washed with water and then dried under reduced pressure to obtain 8.30 g (23.4 mmol) of the title compound as a colorless crystal. The aqueous layer obtained by combining the above filtrate and wash was extracted three times with 150 ml of ethyl acetate. The extracted solution was washed three times with 500 ml of an aqueous saturated sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the resulting crystal was washed with 50 ml of chloroform-hexane (1:1) and then filtered to obtain 1.19 g (3.36 mmol) of the title compound as a pale brown crystal. Yield 86%.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[N:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>C1C=CC=CC=1>[N:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[O:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[C:2]([CH3:1])[C:11]3=[O:12])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCCN1CCCCC1
Reactant: Cc1cccc(-c2oc3c(C(=O)Cl)cccc3c(=O)c2C)c1
Agent: Cl
Solvent: c1ccccc1
Product: Cc1cccc(-c2oc3c(C(=O)NCCCN4CCCCC4)cccc3c(=O)c2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of 3,3'-dimethylflavone-8-carboxylic acid chloride (prepared from 1.00 g of 3,3'-dimethylflavone-8-carboxylic acid and 0.50 ml of thionyl chloride) in 30 ml of benzene were added 0.44 g of 3-piperidinopropylamine and the mixture was stirred for 2 hours at room temperature. To the mixture was added aqueous HCl soluction and the mixture was shaken. The water layer was separated and made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried, and evaporated, and to the residue was added isopropyl ether. The precipitate was filtered to give 0.80 g of reddish brown crystals, which were recrystallized from a mixture of acetone and water as colorless needles, m.p. 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][CH:14]([OH:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 4.5 h

Procedure:
3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14 mmol) was dissolved in a 1:1 mixture of methanol (35.0 mL) and CH2Cl2 (35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0 mmol) was added slowly, gas evolution was observed. After 4.5 h at rt under nitrogen, the reaction was concentrated in vacuo. The crude mix was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using HPFC Jones 50 gram silica gel column eluting with 50% EtOAc:Hex to 100% EtOAc, to yield the title compound as a light yellow solid; MS (ES+): m/z 349.81 (100) [MH+], 351.50 (30) [MH+++]; HPLC: tR=2.49 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.41-2.54 (m, 2H) 2.78-3.05 (m, 1H) 3.12-3.32 (m, 1H) 4.08-4.75 (m, 1H) 5.30 (s, 1H) 7.31 (d, J=5.05 Hz, 1H) 7.57 (d, J=4.80 Hz, 1H)