Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(OCC)(=O)C.ClCCl>[CH2:14]([O:13][C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])[CH3:15]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ncccn1
Yield: 17.7 %

Procedure:
Heat a mixture of ethyl 3-aminoindole-2-carboxylate (204 mg, 1.0 mmol) and 2-chloropyrimidine (1.2 g, 10.5 mmol) at 100° C. for 16 h. Cool the reaction and add aqueous ammonium chloride and ethyl acetate. Filter off excess 2-chloropyrimidine, separate the organic layer, dry with MgSO4, filter and concentrate to afford a crude mixture. Flash chromatograph the mixture on silica gel eluting with 25% ethyl acetate/dichloromethane to afford 50 mg of the title compound: MS 283 (M+H), TLC (silica gel, 25% ethyl acetate/dichloromethane) Rf=0.44.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCC>[CH2:28]([C:29]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:3]2[NH:2][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH2:11][C@H:12]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH:13]1)[CH2:27][CH2:26][CH3:25]
Reactant: CCCCC(=O)CCCC
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cs1
Agent: Cl
Solvent: CCCCO
Product: CCCCC1(CCCC)N[C@@H](c2nc(-c3ccccc3)cs2)Cc2c1[nH]c1ccccc21
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)-1-ethanamine hydrochloride (210 mg, 0.59 mmol) in n-butanol (15 ml) was added 0.45 ml (2.5 mmol) of 5-nonanone. The mixture was heated under reflux for about two hours and then 5 ml of n-butanol was removed by Dean-Stark. Reflux was continued for about 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between 15 ml ethyl acetate and 15 ml 10% NaHCO3 solution. After decantation the organic layer was washed with water and dried over MgSO4. Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate 97:3). The pure fractions were collected and concentrated. The residue was dissolved in diethyl ether, and 1N HCl in ethyl acetate was added. The hydrochloride was collected by filtration and washed with diethyl ether to give 85 mg of the title product as an orange powder. Melting point: 134-136° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CCO>[CH2:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: C1CNCCN1
Solvent: CCO
Product: C#CCCCN1CCNCC1
Yield: 24 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (19.55 g) and piperazine (41.5 g) in EtOH (80 mL) was heated to reflux for 1 h, and evaporated. The residue was taken in NaOH 2M (70 mL) and extracted with Et2O (70 mL). Evaporation gave 1-(pent-4-ynyl)piperazine (4.4 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:17])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
4′-Trifluoromethyl-biphenyl-carboxylic acid (5.0 g) was dissolved in dimethylformamide (50 mL), and to this solution were added at room temperature 4-amino-1-benzylpiperidine (3.55 g), 1-hydroxybenzotriazole hydrate (3.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.58 g). The mixture was stirred at room temperature overnight, and the reaction solution was concentrated in vacuo to precipitate crystals. The crystals were washed successively with saturated aqueous sodium bicarbonate and water, and dried in vacuo to give the title compound (7.42 g).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([NH:26][NH2:27])[N:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:2](=[O:4])[NH:27][N:26]=[C:24]3[CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1cc(-c2ccc(Cl)cc2)ncn1
Solvent: C1CCOC1
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)ncn12
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of triphosgene (2.86 g, 9.66 mmol) in THF (10 mL) at room temperature under argon was added a suspension of 4-(4-chlorophenyl)-6-hydrazinylpyrimidine (825 mg, 3.22 mmol) in THF (10 mL). The reaction mixture was stirred overnight. Analysis by HPLC/MS indicated that no starting material remained. Solvent was removed under reduced pressure and water (50 mL) was added. After stirring for 30 min, the solid precipitate was collected and further washed with water (3×10 mL), then methanol (3×5 mL). The title compound (793 mg) was obtained as an off-white solid. HPLC/MS: retention time=2.74 min, [M+H]30 =247.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9](OCC)=O)[CH:6]=CC=CC=1.C(O[CH:17]1[CH2:21][CH2:20][CH:19]([O:22][CH2:23][CH3:24])[O:18]1)C>C(O)(=O)C>[N:7]1([CH:20]([C:21]2[CH:17]=[CH:17][CH:21]=[CH:20][CH:19]=2)[C:19]([O:22][CH2:23][CH3:24])=[O:18])[CH:1]=[CH:6][CH:9]=[CH:8]1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CCOC1CCC(OCC)O1
Solvent: CC(=O)O
Product: CCOC(=O)C(c1ccccc1)n1cccc1

Procedure:
52.8 g (0.24 mole) of ethyl phenylglycinate were dissolved in 136 ml of glacial acetic acid. Thereafter 39 g (0.24 mole) of 2,5-diethoxytetrahydrofuran were added over 10-15 minutes with stirring. The mixture was heated under reflux for one hour. After this time had elapsed, the mixture was allowed to cool and the major portion of the acetic acid was drawn off under reduced pressure. Finally, the residue was distilled under vacuum and the fraction distilling out at 115°-118° C. at 0.2 mm Hg was collected. The product obtained was first a colourless oil which crystallised on cooling, adopting a waxy aspect and weighing 46.5 g (70%). M.p. 51°-53° C. Centesimal composition: 73.31% C.; 6.08% N; 6.53% H. The IR spectrum in 0.5% KBr is illustrated in FIG. 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:20]#[N:21]>>[F:25][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=3[CH:15]=2)[CH:24]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CC1(C)Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1(C)Nc2ccc(-c3cc(F)cc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-2,2,4,4-tetramethyl-1,4-dihydro-2H-3,1-benzoxazine and 3-bromo-5-fluorobenzonitrile. A white solid: 1H-NMR (DMSO-d6) δ 8.03 (s, 1H), 7.87 (d, 1H, J=10.7 Hz), 7.65 (d, 1H, J=10.7 Hz), 7.57 (d, 1H, J=1.98 Hz) 7.45 (dd, 1H, J=8.33, 1.98 Hz), 6.65 (d, 1H, J=8.33 Hz), 6.42 (s, 1H), 1.52 (s, 6H), 1.34 (s, 6H); MS (ES) m/z 311 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl:15][O-].[Na+].C1C=CC(/C=C/CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1>>[Cl:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: [O-]Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2c(Cl)c1O

Procedure:
Example 2 was repeated in every detail except that part of the 2-hydroxy-3-naphthoic acid in the solution thereof was reacted with sodium hypochlorite before addition of the Rosin N solution. Example 3 contained 1% (0.0007 mole), Example 4 contained 2% (0.0014 mole) and Example 5 contained 4% (0.0028 mole) of 10% sodium hypochlorite solution to form, in each case, 1-chloro-2-hydroxy-3-naphthoic acid in situ. The ratio of amino sulfonic acid/coupling component in Examples 2-5 is 1/1.07 (0.0727/0.068 moles).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH2:17]([O:19][C:20](OCC)(OCC)OCC)[CH3:18]>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([O:19][CH2:17][CH3:18])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 80 °C

Procedure:
A mixture of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (652 mg, 1.98 mmol), (triethoxymethoxy)ethane (2.0 mL, 9.89 mmol) and acetic acid (0.09 mL) was heated at 80° C. for 40 minutes. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (5 mL) and washed with saturated aqueous sodium hydrogencarbonate (2×10 mL) and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as an orange solid 1H NMR (500 MHz, CDCl3) delta 1.55 (3H, t, J=7.09 Hz), 4.71 (2H, q, J=7.25 Hz), 5.21 (2H, br. s.), 7.13 (1H, d, J=5.67 Hz), 7.35-7.42 (2H, m), 8.36-8.40 (2H, m); LC-MS: m/z=+334.00/335.75 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:39][CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:37])O[C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:39][CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:37])[N:41]([OH:42])[C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)OC(C)(C)C)C4)C(=O)OC2=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)OC(C)(C)C)C4)C(=O)N(O)C2=O)c2ccccc21
Temperature: 100 °C
Yield: 46.2 %

Procedure:
A solution of 400 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 50 ml of dimethylformamide and 50 ml of water was treated with 2.5 g of hydroxylamine hydrochloride and 2.5 g of potassium carbonate and the solution obtained was heated to 100° C. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water and dried. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate/petroleum ether to give 190 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-1-hydroxy-4-(1-methyl-3-indolyl)pyrrole-2,5-dione of melting point 238°-240° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with methanesulfonic acid 4-amino-phenyl ester (synthesis: S. Kobayashi, et al.; Synlett. 2000, p 883) as a mixture of cis and trans diastereomers. MS (m/e): 340.121 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[CH:17])=[CH:13][CH:14]=2)[C:9]([CH3:19])([CH3:18])[CH2:8][C:7]=1[CH3:20])=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)[C:9]([CH3:19])([CH3:18])[CH2:8][C:7]=1[CH3:20])=[O:5])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)=C2C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C1=C(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)cc3)ccc21

Procedure:
Following General Procedure B and using 6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 200, 0.106 g, 0.38 mmol), 4-iodo phenyl acetic acid methyl ester (0.106 g, 0.38 mmol), triethyl amine (2 mL), copper(I)iodide (0.02 g, 0.105 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 12-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.075 g, 47%).
Reaction SMILES: Cl.[CH:2]1([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][C:11](=[O:15])[NH:10]3)[CH2:5][CH2:4][CH2:3]1>CO.[Pd]>[CH:2]1([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][C:11](=[O:15])[NH:10]3)[CH2:3][CH2:4][CH2:5]1
Reactant: O=c1ccc2c(C3CCC3)[nH]nc2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CCc2c(n[nH]c2C2CCC2)N1
Temperature: 65 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
To an aliquot of 3-cyclobutyl-2,7-dihydro-pyrazolo[3,4-b]pyridin-6-one-hydrochloride salt (0.20 mg, 0.87 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg). The reaction mixture, in a hydrogenation bottle, was pressured with 45 psi H2, and then the reaction mixture was heated to 65° C. (internal). After 14 hr, the reaction was cooled to room temperature, filtered through a plug of diatomaceous earth, and concentrated under reduced pressure. Partial purification of this material was accomplished by MPLC using a 10 g ISCO column, eluting with 2% MeOH/CH2Cl2 with 0.2% NH4OH. The product-containing fractions with biproduct were collected and concentrated. This material was further purified by trituration with Et2O. The product was filtered off and dried under reduced pressure to afford the title compound (40.0 mg, 23% yield) as a colorless solid. Rf=0.54 (10% MeOH/CH2Cl2). 400 MHz 1H NMR (CD3OD) d 3.54 (dddd, J=8.8, 8.7, 8.7, 8.7 Hz, 1H), 2.75 (apt t, J=7.5 Hz, 2H), 2.58 (apt t, J=7.5 Hz, 2H), 2.33-2.23 (m, 4H), 2.07 (dddd, J=18.7, 9.5, 9.5, 9.5 Hz, 1H), 7.75-7.48 (m, 1H). LRMS m/z (APCI+) 192 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[F:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cc([Mg]Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(F)c2)CC1
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 ml, 7.5 mmol, 0.5M in THF) was added, under nitrogen, to 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 5.1 mmol). After 24 hours, saturated ammonium chloride solution was added then the organic solvent was removed in vacuo. The mixture was extracted with ethyl acetate, then this extract was washed with brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of ethyl acetate/petrol (0% to 20%) to afford the title compound (511 mg, 30%). 1H NMR (Me-d3-OD) δ 1.48 (9H, s), 1.67 (2H, br.d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99 (2H, br.d), 7.27 (1H, dd), 7.38 (1H, dd), 7.42 (1H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].Cl>CO.CCOCC.C(O)(=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:8][C:9]2=[O:11])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1Cc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 200 ml of methanol containing 2-aminophenylacetic acid (13.8 mmole), 1.82 ml (15.2 mmole) 1-benzyl-4-piperidone, and 4 ml acetic acid was added 20 g of 3 Angstrom molecular sieves and 1.91 g (30.4 mmole) of sodium triacetoxyborohydride at room temperature. The reaction mixture was protected from moisture and stirred overnight. After 12 hours, an additional 500 mg of sodium triacetoxyborohydride was added and stirring was continued for 4 hours more. Saturated sodium bicarbonate solution was added and most of the methanol was removed under reduced pressure. The aqueous solution was neutralized with acetic acid and extracted with ethyl acetate solution. The combined extracts were dried (sodium sulfate) and concentrated. Chromatography of the crude reaction product on silica gel (chloroform-methanol-concentrated ammonium hydroxide elution, 96:4:0.4, v/v) afforded 296 mg of a waxy solid. This material was dissolved in a solution of methanol and ether and treated with HCl gas. The resulting precipitate was collected, washed with ether and dried to give the title compound as a solid: m.p. 266°-270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[CH:10]1[CH:15]=[C:14]([CH:16]([CH:19]=O)[CH:17]=O)[N:13]=[CH:12][CH:11]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:19]=[C:16]([C:14]3[CH:15]=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:17]=[N:9]2)[N:3]=1
Reactant: NNc1cccc(Br)n1
Reactant: O=CC(C=O)c1ccccn1
Solvent: CCO
Product: Brc1cccc(-n2cc(-c3ccccn3)cn2)n1
Temperature: 70 °C

Procedure:
2-Bromo-6-hydrazinopyridine (500 mg, 2.7 mmol) was dissolved in ethanol (10 mL) and 2-(2-pyridyl)malondialdehyde(403 mg, 2.7 mmol) was added. The reaction was heated at 70° C. for 16 h. The solvents were removed the ethanol in vacuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:4) to afford 2-bromo-6-(4-pyridin-2-yl-1H-pyrazol-1-yl)pyridine as a light yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 9.0 (s, 1H), 8.62-8.61 (d, J=3 Hz 1H), 8.27 (s, 1H), 7.97-7.94 (d, J=9 Hz, 1H), 7.74-7.57 (m, 3H), 7.39-7.37 (d, J=3 Hz, 1H) 7.19-7.15 (t, 1H). MS (ESI) 301.0 (M++H), 303.0 (M+H+2).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH:12]([C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
1.1 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide were dissolved in 40 ml of ethanol. 0.1 g of 10% palladium-on-carbon was added and the mixture was hydrogenated at room temperature and under atmospheric pressure for 2 hours. The catalyst was filtered off. The filtrate was evaporated to give 0.74 g of crude product which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. After evaporation of the solvents there was obtained 0.44 g of 4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide as an oil; MS: m/e 286 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].[K].Cl[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:14][CH:13]=1)[CH2:10][CH3:11].FC1C=CC=CC=1C1C=CC(CCC(CCC2C=CC(C3C=CC=CC=3F)=CC=2)=O)=CC=1.[BH4-].[Na+].OC(C1C=CC(C2C=CC=CC=2F)=CC=1)CC.Cl>CN(C)C=O.C1C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][S:5][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:14][CH:13]=1)[CH2:10][CH3:11]
Reactant: COC(=O)CS
Reactant: CCC(Cl)c1ccc(-c2ccccc2F)cc1
Agent: CCC(O)c1ccc(-c2ccccc2F)cc1
Agent: Cl
Agent: O=C(CCc1ccc(-c2ccccc2F)cc1)CCc1ccc(-c2ccccc2F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCC(SCC(=O)OC)c1ccc(-c2ccccc2F)cc1

Procedure:
101.5 gm (0.905 mol) of potassium tert. butylate, suspended in 500 ml of dimethylformamide, were admixed, while stirring and cooling under exclusion of air, with 96.0 gm (0.905 mol) of thioglycolic acid methyl ester. To the solution of the potassium salt, the mixture was admixed with 205.9 gm (0.822 mol) of 1-chloro-1-(2'-fluoro-4-biphenylyl)propane [prepared by reduction of 2'-fluoro-4-biphenylylethylketone with sodium borohydride and subsequent reaction of the obtained 1-hydroxy-1-(2'-fluoro-4-biphenylyl)-propane with hydrochloric acid in benzene], and the mixture was stirred for 4 hours at room temperature. Subsequently, 2 liters of water were added, and the reaction product was isolated by extraction with ethyl acetate, and washing, drying and evaporating of the extract. Yield: 254 gm (97% of theory); oil, Rf -value: 0.5 (cyclohexane-ethyl acetate=9:1 on silicagel-polygram-plates).