Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[CH3:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1
Reactant: Oc1ccc(O)cc1
Reactant: CN(CCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
A mixture of compound 9a (500 mg, 2.7 mmol), K2CO3 (740 mg, 5.4 mmol), and KI (445 mg, 2.7 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (589 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mLs water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 9 (170 mg, 0.66 mmol, 24% yield) as a white solid. HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.14886, found: 258.14888. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.27 (m, 2H), 6.94-6.70 (m, 7H), 5.94 (broad s, 1H), 4.00 (t, J=5.9 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.09 (p, J=6.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:38](F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CCC2
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[NH2:26][CH2:25][CH2:24][NH:27][C:21]([CH:9]1[CH:10]2[C:11]3([CH:19]=[CH:18][CH:17]=[CH:16][C:12]3=[N:13][CH2:14][CH2:15]2)[S:20][CH2:8]1)=[O:23]
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Reactant: NCCN
Product: NCCNC(=O)C1CSC23C=CC=CC2=NCCC13
Yield: 54 %

Procedure:
By following the same procedure as above using 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxylic acid and ethylenediamine as the starting materials, 0.19 g (yield of 54%) of N-(2-aminoethyl)-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboamide.di-hydrochloride was obtained (see Table 9-1, Table 10-1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[Li]CCCC.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C:19]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)Cl
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
To a solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (Aldrich Chemicals, 1.77 g, 10 mmol) in THF (100 mL) at −78° C. was added nBuLi (6.6 mL, 1.6 M in Hexane, 10.6 mmol) dropwise. After 10 minutes, hexanoyl chloride (1.68 mL, 12 mmol) was added. After 30 minutes the solution was allowed to warm to rt, at which time the reaction was quenched with saturated ammonium chloride solution. After 10 minutes, 1 M NaOH was added, and the mixture extracted 3 times with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (0% to 20% EtOAc/Hexane gradient) afforded pure product (1.98 g, 72%). 1H NMR (500 MHz, CDCl3) δ ppm 0.96-0.81 (m, 6H) 1.40-1.26 (m, 4H) 1.74-1.59 (m, 2H) 3.04-2.81 (m, 2H) 4.75 (dt, J=13.8, 6.7 Hz, 1H) 5.64 (d, J=7.32 Hz, 1H) 7.44-7.23 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:34][CH:33]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])[CH:27]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 16 h
Yield: 82.8 %

Procedure:
tert-Butyl bromoacetate (87.3 μl, 0.596 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide (150 mg, 0.40 mmol) and cesium carbonate (388 mg, 1.19 mmol) in anhydrous dimethyl formamide (10 ml) and then stirred at ambient for 16 hours. The reaction was diluted with ethyl acetate (10 ml), washed with water (3×20 ml) and the organic extracts were concentrated in vacuo to obtain crude product. The residue was purified by flash chromatography eluting with 10% methanol/dichloromethane to yield a yellow oil (163 mg, 56% yield). HPLC retention time 6.47 min Mass spectrum (ES+) m/z 509 (M+H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)c(Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,4-dichlorobenzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.42 g, 1.4 mmol, yield: 52%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: CCCCCCCCO
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1cccc(Cl)[n+]1[O-]

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.658 g (99%) (0.0050 moles) of 1-octanol was reacted with 0.200 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 4.5 hours to give 2-chloro-6-octyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-octyoxypyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (48%). It was recrystallized from ethanol and hexanes: mp 119°-120° C.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=O)(C)(C)C.C(O[K])(C)(C)C.[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(N(C)C)=O>[NH2:8][C:9]1([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Reactant: ClCc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A suspension of 7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (10.0 g, 41.6 mmol) in dimethylacetamide (100 mL) was cooled with ice, and t-butoxy potassium (4.67 g, 1.0 eq.) and benzyl chloride (5.27 mL, 1.1 eq.) were added thereto. The reaction mixture was returned to room temperature, followed by stirring for 2 hours. Thereafter, water was added to the mixture, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield 5-benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane as a crude product. The crude product was dissolved in toluene (100 mL), and methanesulfonic acid (2.97 mL) was added to the solution, followed by stirring under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the cooled mixture for extraction, and the formed organic layer was removed. Aqueous sodium hydroxide solution (5N) was added to the remaining aqueous layer so as to alkalify the layer, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield the title product as a pale brown solid (8.63 g, yield: 90.1%).
Reaction SMILES: N[C:2]1([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[CH2:6][S:5][CH:4]=[N:3]1.[OH-].[Na+].C[N:26]1C=CN=C1.CO>O1CCCC1>[NH2:26][C:4]1[S:5][CH:6]=[C:2]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C1(N)CSC=N1
Reactant: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 261.6 %

Procedure:
Ethyl 2-(4-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1 N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: NCc1cc2cc(F)c(F)cc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2cc1F

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6,7-difluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6,7-difluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=551 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.46 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.83-7.94 (m, 3H), 7.49-7.55 (m, 2H), 7.41-7.48 (m, 1H), 7.35-7.41 (m, 1H), 4.89-4.85 (m, 2H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:26][CH:25]=1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light yellow solid (85 mg, 63%), MS (ISP) m/z=402.3 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH2:9][NH2:10]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:9][NH2:10])[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NNc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-6-fluoropyridine (2-1) (1.0 g, 5.68 mmol) in THF (10 mL) was added hydrazine (0.91 g, 0.89 mL, 28.4 mmol). After stirring for 1 h room temperature, the mixture was heated at 65° C. for 1 h. The mixture was cooled, diluted with EtOAc (200 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (2-2) was used in the subsequent step without further purification. 1H NMR (300 MHz, CHCl3-d): δ 7.32 (app t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 0.6 Hz, 1H), 6.67 (dd, J=7.8, 0.6 Hz, 1H), 5.93 (s, 1H), 3.80 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:23]=[C:22]([Cl:32])[C:18]=1[C:19](O)=[O:20]>>[Cl:16][C:17]1[CH:25]=[C:24]([CH:23]=[C:22]([Cl:32])[C:18]=1[C:19]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1)=[O:20])[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:31]
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Reactant: CC(C)NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: CC(C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)-N-(propan-2-yl)benzamide (Compound No. 106) was prepared using N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropane carboxamide and 2,6-dichloro-4-[(propan-2-yl)carbamoyl]benzoic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:22]=1.Cl>ClCCl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][C:3]2[CH:12]=[CH:11][C:6]3[CH2:7][O:8][B:9]([OH:10])[C:5]=3[CH:4]=2)=[O:26])=[C:23]([C:30]([F:31])([F:32])[F:33])[CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc2c(c1)B(O)OC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)B(O)OC2)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A 500 ml round bottom flask was charged with a mixture of 6-amino-1-hydroxy-2,1-benzoxaborolane hydrochloride (5 g, 26.9 mmol, 1 eq), triethylamine (11.2 ml, 80.7 mmol, 3 eq) and dichloromethane (200 ml). 4-Fluoro-2-(trifluoromethyl)benzoyl chloride (4.3 ml, 28.2 mmol, 1.05 eq) was then added, and the reaction mixture was allowed to stir at room temperature overnight. 1M HCl (100 ml) was added to the mixture and the reaction was stirred for an additional hour. The resulting precipitate was then collected, and the off-white powder was dried under vacuum. LCMS (m/e) 340 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.96 (s, 2 H) 7.39 (d, J=8.4 Hz, 1 H) 7.61-7.73 (m, 2 H) 7.75-7.87 (m, 2 H) 8.13 (dd, J=1.8, 0.4 Hz, 1 H) 9.25 (s, 1 H) 10.59 (s, 1 H) Amount Obtained: 5.2 g, 57% yield.
Reaction SMILES: [NH2:1][C:2](=[O:15])[CH:3]([CH3:14])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11](O)=[O:12].Cl.C(N=C=NCCCN(C)C)C.FC1C=C(C2C3OCCNCC=3SC=2)C=CC=1.CN(C=O)C>O>[Br:10][C:9]1[C:5]2[O:4][CH:3]([CH3:14])[C:2](=[O:15])[NH:1][C:11](=[O:12])[C:6]=2[S:7][CH:8]=1
Reactant: CC(Oc1c(Br)csc1C(=O)O)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Fc1cccc(-c2csc3c2OCCNC3)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC1Oc2c(Br)csc2C(=O)NC1=O
Yield: 77.2 %

Procedure:
A solution of 3-(2-amino-1-methyl-2-oxoethoxy)-4-bromothiophene-2-carboxylic acid (400 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (521 mg), 1-hydroxybenzotriazole 1 hydrate (417 mg) and DMF (4 mL) was stirred at room temperature for 1.5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (290 mg, 77%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10](F)[CH:9]=1.O>C1COCC1>[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:9]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Reactant: OCC(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Potassium tert.-butylate (0.97 g, 8.7 mmol) was added to 2,2,2-trifluoroethanol (0.63 mL, 8.8 mmol) in 20 mL THF at ambient temperature and stirred for 10 min. Then the mixture was cooled to 5° C. and ethyl 4-amino-2-fluoro-5-nitro-benzoate (1.80 g, 7.9 mmol) in 20 mL THF was added and stirred for 1 h at 5° C. Then the mixture was poured into water, extracted with ethyl acetate, the combined organic layers dried over MgSO4 and evaporated to dryness.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 13.1, 36 g, 101 mmol), Pd(PPh3)4 (11.7 g, 10.1 mmol), and Zn(CN)2 (17.9 g, 152.4 mmol) in DMF (400 mL) under nitrogen was stirred overnight at 80° C. The mixture was cooled to ambient temperature, then the reaction was quenched by the addition of 600 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through Celite® and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with potassium carbonate (aq., sat., 200 mL), followed by brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:5) as the eluent to yield 23 g (75%) of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[CH:33]1([O:38][C:39]2[CH:40]=[C:41]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH2:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH:33]1([O:38][C:39]2[CH:40]=[C:41]([CH:47]3[CH2:48][CH2:49][N:50]([C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:51][CH2:52]3)[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(C2CCN(C(=O)/C=C/c3ccccc3)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of trans-cinnamic acid (1.20 mmol, 0.178 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC; 1.20 mmol, 0.230 g) and hydroxybenzotriazole (HOBT; 1.20 mmol, 0.162 g) was dissolved in dry CH2Cl2 (20 mL) and stirred at room temperature for 1.5 hours. To this solution was added 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (1.00 mmol, 0.275 g) in dry CH2Cl2 (10 mL) dropwise over 10 minutes and the resulting solution was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (70 mL) and 1N NaOH (70 mL). The aqueous phase was extracted with EtOAc (1×70 mL), the combined organics washed with H2O (1×70 mL), dried (Na2SO4) and concentrated in vacuo to yield a colorless oil. Purification by flash chromatography (SiO2 : 5% EtOAc/CH2Cl2) afforded the title compound as a white solid, mp=93°-95° C. (0.385 g, 95%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)CCN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CCNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 87.4 %

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (10 g), β-alanine methyl ester monohydrochloride (5.99 g), acetic acid (4 mL) and sodium triacetoxyborohydride (10.9 g) in dichloroethane (400 mL) was stirred overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (12.0 g, 87%) as a colorless oil.