Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH2:36]([NH:38][CH2:39][CH2:40][CH3:41])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:38]([CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: CCCNCC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 59.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-ethyl-1-propylamine (0.242 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (253 mg, 1.19 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-ethyl-1-propylaminomethyl)indol-2-yl]isoindolinone (68.4 mg, yield 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[Br:17]Br.BrBr.C(O)(=O)C>C(O)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH2:15][Br:17])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(=O)c1ccccc1-c1ccc(C)cc1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Temperature: 30 °C
Yield: 943.7 %

Procedure:
A solution of 4'-methyl-2-acetyl-1,1'-biphenyl (2.06 g, 9.79 mmol) in 10 mL of glacial acetic acid was treated dropwise with a solution of bromine (1.722 g, 1.07 mmol) dissolved in 3.0 mL of glacial acetic acid. After initiating the reaction with the first few drops of the bromine/acetic acid reagent by heating the reaction mixture at 30° C., the remainder of the bromine solution was added dropwise at 25°-30° C. The reaction mixture was stirred at room temperature until the consumption of bromine was complete (approximately 2 hrs). The reaction mixture was diluted with 150 mL of hexane then washed with water (3×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to give 2.92 g of an oil that was used in the next step without purification. 1H NMR (crude product) (200 MHz,CDCl3): 2.38 (s,3H), 3.66 (s,2H), 7.21 (s,4 H), 7.3-7.6 (m,4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][C:46]=1[CH:52]1[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]1>ClCCl>[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:18](=[O:20])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:47][C:46]=1[CH:52]1[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]1
Reactant: CN1CCC(c2cc(N)ccc2Cl)CC1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CN1CCC(c2cc(NC(=O)Cc3ccc(-c4ccncc4)c4ccccc34)ccc2Cl)CC1
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of 4 -(pyridin-4-yl)napth-1-ylacetic acid (D2, 260 mg, 1.0 mmol) in dichloromethane was added 1-hydroxybenzotriazole hydrate (153 mg, 1.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg, 1.0 mnmol) and the mixture stirred for 0.5 h. To the mixture was added dropwise a solution of 4-chloro-3-(1-methylpiperidin-4-yl)aniline (D7, 200 mg, 0.90 mmol) in dichloromethane (3 ml) and stirring continued for 48 h. Purification of the crude by flash chromatography gave the title compound as a white solid (30 mg, 7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:17]=[CH:16][C:15]2[CH2:14][CH:13]3[CH:18]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]([CH2:11][CH2:12]3)[CH2:9][C:8]=2[CH:7]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:15]2[CH2:14][CH:13]3[CH:18]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:10]([CH2:11][CH2:12]3)[CH2:9][C:8]=2[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCc1ccc2c(c1)CC1CCC(C2)C1NC(=O)OC(C)(C)C
Yield: 94.3 %

Procedure:
3-(13-tert-Butoxycarbonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-acrylic acid methyl ester (300 mg, 0.809 mmol, prepared in Example 32 Step 3) and 20% palladium hydroxide on carbon (30 mg) in ethanol (30 ml) were stirred under 1 atm. of hydrogen at room temperature for 18 hours. The mixture was filtered through Celite and the filtrate concentrated to give a colourless oil 285 mg (94%). 1H NMR (CDCl3, 400 MHz) δ 7.00 (1H, d, J=8.2 Hz), 6.90 (2H, m), 4.97 (1H, m), 4.03 (1H, m), 3.67 (3H, s), 2.99 (2H, m), 2.89 (2H, m), 2.55–2.62 (4H, m), 2.48 (2H, m), 1.71 (2H, m), 1.47 (9H, s), 1.19 (2H, m).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N+:19]([C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:19]([C:22]1[N:23]=[CH:24][N:25]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:26]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc([N+](=O)[O-])c2)CC1
Temperature: 120 °C
Yield: 32.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243a (7.0 g, 25.1 mmol), DMF (120 mL), 4-nitro-1H-imidazole (2.80 g, 25.1 mmol), and K2CO3 (6.9 g, 50.2 mmol). The mixture was heated at 120° C. for overnight. After this time the reaction was cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 2:2:1 ethyl acetate/petroleum ether/dichloromethane to afford 243b (2.4 g, 32.4%) as a yellow solid. MS-ESI: [M+H]+ 297.3
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@H:3]([OH:36])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:7][CH:6]1[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].CCN(C(C)C)C(C)C.[CH3:48][NH2:49].C(N=C=NCCCN(C)C)C>CO>[CH3:48][NH:49][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([CH:6]2[CH2:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]2[CH2:4][C@@H:3]([OH:36])[C:2]([F:1])([F:38])[F:37])[CH:28]=1
Reactant: O=C(O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Reactant: CN
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydroquinoxalin-2-yl}benzoic acid (100 mg, 0.185 mmol) (from Scheme A12) was dissolved in MeOH (925 μl), Hunig's Base (97 μl, 0.555 mmol), methylamine (93 μl, 0.185 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (106 mg, 0.555 mmol) were added, and the mixture was stirred at 25° C. overnight. The product was purified on a reverse phase column, 10-90% MeCN/H2O gradient, 0.1% TFA modifier, yielding Example 19, N-methyl-3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoro-methoxy)benzyl]-1,2,3,4-tetrahydro quinoxalin-2-yl}benzamide. MS m/z=554.04.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+].O>CS(C)=O>[N:9]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8])=[N+:10]=[N-:11]
Reactant: O=Cc1sccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccsc1C=O
Temperature: 65 °C
Yield: 76.1 %

Procedure:
3-Bromothiophene-2-carbaldehyde (1) (2000 mg, 10.47 mmol) was treated with sodium azide (1994 mg, 30.7 mmol) in DMSO (27 ml). The reaction was heated to 65° C. for 48 h in a sealed 40 mL vial. The reaction mixture was then taken up into H2O (35 mL) and extracted with diethyl ether (3×20 mL). The organic product layer was washed with 25 ml of saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to give 3-azidothiophene-2-carbaldehyde (1.22 g, 76% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccncc3)cc2)CC1
Yield: 70 %

Procedure:
4-[3-Formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester is reacted with 4-pyridylboronic acid as described in Example 65 to afford 4-[3-formyl-1-[(4-pyridin-4-yl)-phenyl]-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (70% yield) as a yellow solid. ESI/MS 483 (M+1); NMR (CDCl3) 10.30 (1H, s); 8.76 (2H, d); 8.28 (1H, d, J=6 Hz); 7.89 (2H, d, J=9 Hz); 7.64 (5H, m); 7.20 (2H, m); 3.36 (8H, m); 1.58 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:45])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.17 mmol) in dichloromethane (20 mL), add methanol (5.85 mmol) and triphenylphosphine (3.51 mmol). To this solution, add diethyl azodicarboxylate (3.51 mmol) dropwise at room temperature. After stirring for 12 h, remove the solvent under vacuum and chromatograph the intermediate over silica gel eluting with ethyl acetate/hexane (2-35%) to afford (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as a colorless oil. To this intermediate in dichloromethane (5 mL), add TFA (2 mL). After stirring for 2 h, quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (10 mL). Separate the organic portion, dry over sodium sulfate, filter, and remove the solvent under vacuum. This provides the title compound as a crude oil that is further used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](OC)=[O:26])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:18]=[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[O:26])[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:29]
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Tetrahydro-2H-pyran-4-amine (900 microl, 8.69 mmols) was added to a solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmols, preparation 109) in toluene (36 ml). A 2M solution of Trimethyl aluminium in toluene (7 ml, 14.00 mmols) was added and it was stirred at 80° C. overnight. Water (50 ml) and a 0.5M solution of sodium tartrate (25 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (617 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorobenzyl-thio)-4-morpholino-pyrimido[5,4-d]-pyrimidine (m.p.: 135°-145° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:14])[C:7]=2[CH:15]=1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2occ(CC(C)N3CCN(c4cccc5cccnc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.60˜6.70 (m, 8H); 3.87 (s, 3H); 3.50˜2.50 (m, 11H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:9]2)[O:7][NH:30]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.888 g, 4.87 mmol) was dissolved in MeOH (18 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.195 g, 4.87 mmol) dissolved in water (1.800 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.299 mL, 4.87 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. A mixture of cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate and trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)-piperidine-1-carboxylate (1.027 g, 59%) was obtained as white solid after freeze drying. MS m/z 357 (M+H)+
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C>C1COCC1.CCOCC>[CH3:6][C:7]1[S:8][C:9]([B:16]([OH:17])[OH:15])=[CH:10][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(B(O)O)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2-methyl thiophene (3.0 g, 31 mmol) in THF (20 ml) at −78° C. The solution was kept at −78° C. for 10 min. then warmed to 0° C. for an additional 0.5 hr. The solution was then transferred by steel canula under nitrogen into a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether (15 ml) at −78° C. The resulting milky white solution was stirred at −78° C. for 20 min. then at room temperature for 2 hours. The reaction was quenched by the addition of 10% aqueous HCl (5.0 ml) and the solution was extracted into ether. The combined ether extracts were extracted with 10M NaOH (2×30 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted into ether (3×25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronic acid as a light brown solid. This was used in the next step with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.[NH4+:18].[OH-]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:18])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Fluoro-2-nitro-benzoic acid (17.9 g, 96.8 mmol) was heated in thionyl chloride (35 mL, 5 mol eq.) for two hours at 85° C. (oil bath temperature). The reaction mixture was evaporated, taken up and evaporated twice with dry toluene. The resulting acid chloride was dissolved in dry dioxane (180 mL) and added to an ice-water bath cooled solution of 33% NH4OH (23.5 mL, 2 mol eq.) in dioxane (180 mL). The reaction was allowed to warm up gradually to room temperature and then evaporated to dryness. The crystalline residue was triturated in water (50 mL), collected by filtration, washed with a small amount of water and dried in vacuo at 80° C. to constant weight (17.56 g, 98.5%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:20]1([N:6]2[CH2:5][CH2:4][N:3]([C@@H:7]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]3)[C:2]2=[O:1])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(C3CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (10.0 g, 31.17 mmol), cyclopropylboronic acid (6.39 g, 74.35 mmol) and pyridine (8.82 g, 111.5 mmol) in anhydrous DMF (100 mL) was added Cu(OAc)2 (6.75 g, 37.17 mmol). The resulting mixture was stirred at 40° C. under O2 atmosphere (balloon) for 48 hours. After quenched with NH3.H2O (10 mL), the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine, dried, concentrated, and subjected to silica flash column chromatography using 0 to 70% EtOAc in PE to isolate (R)-tert-butyl 3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391) (2.6 g, 23%) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:10]=[C:9]([NH:25][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CNC(=O)CC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 3,3-dicyclohexylpropionyl chloride (6.1 g, 0.063 mol) in 70 ml of chloroform was treated portionwise at 7°-12° C. with a solution of 8.3 g (0.063 mol) of glycine tert-butyl ester and 8.9 ml (0.064 mol) of triethylamine in 30 ml of chloroform. After the addition, the solution was stirred at room temperature for 2 hours, kept overnight, refluxed for 0.5 hours, cooled, washed with water (5×25 ml), dried (magnesium sulfate), and the solvent removed on a rotary evaporator, to give a light yellow viscous oil. The latter, which crystallized partly on standing, was dissolved in 50 ml of boiling hexane, cooled, seeded, and rubbed; a crystalline solid gradually separated. After crystallizing at room temperature and cooling overnight, the voluminous colorless solid was filtered, washed with cold hexane and air-dried (13.3 g, melting point 72°-74° C. s, 69° C.).