Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:16]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)N(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 98.7 %

Procedure:
A mixture of 1-benzyloxycarbonyl-2,3-dihydro-6-nitroindole (1.0 g, 3.36 mmol) and tin(II) chloride dihydrate (3.78 g, 16.75 mmol) in ethanol (70 mL) was heated at 70° C., under an atmosphere of nitrogen, for 3 hours. The solution was cooled and the solvent evaporated under reduced pressure to give an off-white solid. The solid was partitioned between water (50 mL) and ethyl actate (100 mL) and the aqueous layer basified (pH 11) with 1M sodium hydroxide solution. The mixture was filtered to remove tin salts and the ethyl acetate was separated, dried (MgSO4) and evaporated under reduced pressure to give the amine as a yellow oil (0.89 g, 99%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH3:32][CH:33]([O:35][CH2:36][CH2:37][NH2:38])[CH3:34]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:38][CH2:37][CH2:36][O:35][CH:33]([CH3:34])[CH3:32])=[O:25])[C:6]1=[O:29]
Reactant: CC(C)OCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-[(1-methylethyl)oxy]ethanamine employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.67 (1H, br), 8.16 (1H, br s), 7.27 (3H, m), 7.10 (2H, t, J=9 Hz), 4.93 (2H, s), 4.00 (2H, s), 3.54 (1H, m, J=6 Hz), 3.40 (2H, m), 3.31 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.08 (6H, d, J=6 Hz); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2205.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C:7]([CH2:19][C@@H:20]2[O:22][C@@:21]2([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:8]([O:12][CH3:13])=[CH:9][CH2:10][CH:11]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCOC(C)=O.CCCCCC>[CH3:4][O:5][C:6]1[C@@:7]2([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:19][CH:20]3[O:22][C@@:8]2([O:12][CH3:13])[C@H:9]([CH2:10][CH:11]=1)[C@:21]3([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28]
Reactant: COC1=CCC=C(OC)C1(CC=C(C)C)C[C@@H]1O[C@@]1(C)CCC=C(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC1=CC[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
A DCM (100 mL) solution of 12 (1.88 g, 5.21 mmol, 1 equiv.) and 2,6-di-tert-butyl-4-methylpyridine (2.14 g, 10.4 mmol, 2 equiv.) was cooled to −78° C. in a 250-mL round-bottom flask, and trimethylsilyl trifluoromethanesulfonate (1.13 mL, 6.26 mmol, 1.2 equiv.) was slowly added. Immediately upon this addition, the solution turned bright yellow. After stirring at −78° C. for 45 min, the reaction was quenched with saturated aqueous NaHCO3 and allowed to warm to room temperature. The mixture was then extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a faintly yellow residue. Flash column chromatography (30 mL SiO2, 99:1 to 19:1 hexane:EtOAc) afforded 1.70 g (4.72 mmol, 90% yield) of 13 as a white, crystalline solid. 1H NMR (600 MHz; CDCl3): δ 5.34 (t, J=7.1 Hz, 1H), 5.03 (t, J=7.1 Hz, 1H), 4.52 (dd, J=5.5, 2.0 Hz, 1H), 3.74 (d, J=5.1 Hz, 1H), 3.48 (s, 3H), 3.46 (s, 3H), 2.36 (dd, J=14.7, 6.9 Hz, 1H), 2.22-2.17 (m, 2H), 2.03 (td, J=8.6, 6.4 Hz, 2H), 2.01-1.94 (m, 1H), 1.82 (d, J=12.4 Hz, 1H), 1.78 (dd, J=12.4, 5.1 Hz, 1H), 1.69 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H), 1.45 (td, J=13.0, 4.8 Hz, 1H), 1.22 (td, J=13.0, 4.6 Hz, 1H), 1.14 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 158.5, 131.6, 131.2, 124.9, 123.6, 112.7, 90.6, 78.9, 54.6, 51.4, 46.5, 44.4, 42.0, 39.4, 33.6, 32.8, 28.2, 26.4, 25.9, 22.9, 20.1, 18.00, 17.85. HRMS-ESI (m/z): [M+H]+ calculated for C23H36O3, 361.2737. found, 361.2730.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[O:28])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(SCc2cccc(Cl)c2)cn1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)Cc2cccc(Cl)c2)cn1
Reaction time: 3 h

Procedure:
To the stirred solution of 10.28 g of 5-(m-chloro-benzylmercapto)-2-pyridinecarboxylic acid methyl ester in 150 ml of methylene chloride, cooled in an ice bath, 7.5 g of m-chloroperbenzoic acid are added in small portions during 10 minutes. The mixture is stirred for 3 hours, washed twice with 10% aqueous potassium bicarbonate, dried and evaporated. The residue is recrystallized from ethanol, to yield the 5-(m-chlorobenzylsulfinyl)-2-pyridinecarboxylic acid methyl ester of the formula ##STR6## melting at 143°-144°.
Reaction SMILES: [CH3:1]CCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19][CH2:20][CH2:21][C:22](=O)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:16][CH:15]=1.C(OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19][CH2:20][CH2:21][C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH2:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(COCCC(=O)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CCOCc1ccc(OC)cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methlytriphenylphosphonium bromide (3.08 g, 8.61 mmol) with THF (50 mL) and add a hexane solution of n-butyllithium (3.8 mL, 2.5 M, 9.47 mmol). After the addition is complete stir at ambient temperature for 0.5 hour. Add 4-(p-methoxybenzyloxy)-1-(t-butyldimethylsilyloxy)butan-2-one (2.65 g, 7.82 mmol) in THF (10 mL) and stir for 0.5 hours. Quench the reaction with saturated ammonium chloride solution and partition it between diethyl ether and water, wash the organic layer with water and then with saturated sodium chloride solution. Dry over MgSO4 and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/19 ethyl acetate/hexane to give the title compound as an oil. Rf =0.25; silica gel, 1/9 ethyl acetate/hexane. 1H NMR (CDCl3, 300 MHz) δ0.05 (s, 6H), 0.91 (s, 9H) 2.33 (t, J=6.98 Hz, 2H), 3.56 (t, J=6.98 Hz, 2H), 3.81 (s, 3H), 4.08 (s, 2H), 4.45 (s, 2H), 4.87 (s, 1H), 5.09 (d, J=1.65 Hz, 2H), 6.88 (d, J=8.73 Hz, 2H), 7.25 (d, J=8.73 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1.[Br:18]Br.C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>CC(O)=O.C1COCC1.[Zn]>[Br:18][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=[C:2]([Cl:1])[C:14]=3[C:13]=2[CH:12]=1
Reactant: BrBr
Reactant: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(Cl)c2c1[nH]c1ccc(Br)cc12
Reaction time: 1 h

Procedure:
To a suspension of 1-chloro-5H-pyrido[4,3-b]indole-4-carboxamide (Example 10 Step 3) in AcOH (0.15 M) at room temperature was added Br2 (10 equiv) to provide a homogeneous mixture. After standing at room temperature a precipitate formed, and after 1 h, a suspension of Zn powder (excess) in THF was added in a cold water bath. After a period of 10 min, the reaction mixture was poured over THF/EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were washed with brine, dried over MgSO4 and filtered. After evaporation of the organic solvents, the residue was purified by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.CC(O[Na])=O.[Br:18]Br.Cl>C(O)(=O)C.C(OCC)(=O)C>[Br:18][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-Methoxy-2-nitro-phenol (10 g) was dissolved in glacial acetic acid (60 mL) and CH3CO2Na (8.2 g) was added. Next, bromine (3 mL) dissolved in glacial acetic acid (12 mL) was added drop wise to the stirring solution at room temperature. After complete addition of bromine, the mixture was stirred for 30 min at room temperature and then placed in an oil bath at 75° C. for 2 h. After reaction mixture cooled to room temperature, concentrated HCl (500 mL) was slowly added to the mixture followed by addition of ethyl acetate (500 mL). The layers were separated and the organic layer was washed with water, brine, dried (Na2SO4). Flash chromatography on silica gel eluting with 5% ethyl acetate-hexane afforded 8.8 g (60%) of the title compound as a solid. MS: 218 (MH+−30), HPLC tR: 2.40 min.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5][N:4]=1)#[N:2].[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>>[C:1]([C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:14][CH:15]=2)=[CH:7][C:6]([C:17]([F:20])([F:18])[F:19])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2cc(C(F)(F)F)cnc2C#N)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (74%, colourless oil). HPLC-MS m/z=414.1 (M+1), Rt: 4.8 min.
Reaction SMILES: [C:1](=[S:3])=S.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH:15](N)[CH2:16][CH3:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C([N:24](CC)CC)C>CC(C)=O.[Hg](Cl)Cl>[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][CH2:16][CH2:17][N:24]=[C:1]=[S:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: CCC(N)Oc1cccc(CN2CCCCC2)c1
Agent: Cl[Hg]Cl
Solvent: CC(C)=O
Product: S=C=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: -14 °C

Procedure:
A solution of carbon disulphide (3.3 ml) in acetone (8 ml) was added dropwise to a solution of 3-[3-(1-piperidinylmethyl)phenoxy propanamine (12.4 g) in acetone (30 ml) over a 15 minute period, between -5° and -10° C. The solution was cooled to -14° C. and mercury (II) chloride (13.6 g) in acetone (30 ml) was added, during 45 minutes. Triethylamine (16 ml) was added at 0° C. during 15 minutes, and the mixture was heated at reflux for 45 minutes. The resulting suspension was purified by filtration and the filtrate evaporated in vacuo. The residue was purified by column chromatography using methanol as eluant to give the title compound (6 g) as an amber oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:26].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:17])([CH3:18])[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)=[O:26]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C(C)(C)C(=O)O)cc1

Procedure:
In an analogous manner, by the reaction of ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride with 5-chloro-2-methoxybenzoyl chloride, there is obtained, via ethyl 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-2-methylpropionate (oil), 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-2-methylpropionic acid; m.p. 149°-150° C., after recrystallization from glacial acetic acid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.ClC(OC1C=CC(F)=CC=1)=O.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[O:29]>>[C:7]1([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[O:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)Oc1ccc(F)cc1
Product: Cc1ccc(OC(=O)NCCc2ccc(-c3ccccc3)cc2)cc1

Procedure:
The procedure is carried out in a manner similar to Example 4, replacing the 4-phenylbenzylamine with 2-(4-biphenyl)ethylamine and the 4-fluorophenyl chloroformate with 4-methylphenyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([O:33]C)=[O:32])[CH:20]=4)[N:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([OH:33])=[O:32])[CH:20]=4)[N:15]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4cccc(Cl)c4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCC(c4cccc(Cl)c4)CC3)c(-c3ccc(F)cc3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(4-(3-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylate (137.2 mg, 0.28 mmol, 1.00 equiv, 98%) in methanol (20 mL). This was followed by the addition of a solution of sodium hydroxide (57.8 mg, 1.45 mmol, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred for overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 43 mg (33%) of 2-(4-(3-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].O.C(OCC)(=O)C>C(C(C)=O)C>[ClH:1].[CH2:27]([CH:26]([N:25]1[C:2]2[N:7]3[N:8]=[C:9]([CH3:20])[C:10]([C:11]4[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=4[CH3:19])=[C:6]3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Product: Cl

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (1.5 g, 4.14 mmol) and 3-aminopentane (3 mL) in methyl ethyl ketone (15 mL) was heated under reflux for one hour. 3-Aminopentane (6 mL) was added thereto, followed by heating under reflux for further 4.5 hours. Water was added to the reaction mixture, followed by extcarting with ethyl acetate, The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane), to give the title compound (1.02 g) as a pale yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:54][CH2:55][CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[S:60][CH:61]=1.CCN(CC)CC>CN(C=O)C>[S:60]1[CH:61]=[C:57]([CH2:56][CH2:55][NH:54][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]1=2
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1csc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.50 g (1.26 mmol) of 2-adamantyl-oxycarbonyl-α-methyl-DL-tryptophan and 0.18 g (1.33 mmol) of 1-hydroxybenzotriazole hydrate in 8 mL of anhydrous DMF (under a N2 atmosphere) was treated in one portion with 0.27 g (1.41 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 2 hours, treated with 0.30 g (1.40 mmole) of 3-[2-aminoethyl)benzo [b]thiophene hydrochloride plus 0.25 mL (0.18 g, 1.79 mmol) of Et3N, and stirred for an additional 18 hours. The reaction mixture was partitioned between 100 mL of EtOAc and 150 mL of H2O. The layers were separated and the aqueous layer extracted with fresh EtOAc (3×75 mL). The combined organic layers were washed with 5% aqueous citric acid (3×150 mL), brine (1×150 mL), 5% aqueous NaHCO3 (3×150 mL), and brine again. The organic layer was dried (Na2SO4) and evaporated (vacuum) to an off-white foam. The residue was chromatographed (230-400 mesh SiO2 in a 21×300 mm column, eluted with 2% MeOH in CH2Cl2) to yield the purified product as a white foam, 0.40 g (57%); 1H NMR (CDCl3) δ1.47-1.92 (17H, m), 2.92 (2H, t, J 7 Hz), 3.25 (1H, d, J 15 Hz), 3.46-3.57 (3H, m), 4.79 (1H, br s), 5.14 (1H, br s), 6.27 (1H, m), 7.02 (2H, m), 7.11-7.86 (8H, m), 8.10 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](O)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([Cl:24])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Product: O=C(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
23 g of 3-chloro-2-(4-chloro-3-hydroxycarbonylphenyl)-5-trifluoromethylpyridine in 23 ml of thionyl chloride were refluxed for 5 hours. The excess thionyl chloride was then removed by distillation. The remaining dark brown oil was used without further purification for the subsequent reaction.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9](O)=[O:10])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([N:23]=[N+:24]=[N-:25])=[O:10])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.2 g (0.09 mol) of 3-allyl-4-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 13.2 ml (0.18 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 3-allyl-4-acetoxy-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 17.5 g (0.27 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 3-Allyl-4-acetoxy-cinnamic acid azide of melting point 87°-89° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:18][CH:19]=C)[CH2:9][C@H:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.C[OH:44]>>[CH3:1][O:2][C:3]([C@@:5]1([CH2:18][CH:19]=[O:44])[CH2:9][C@H:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:4]
Reactant: C=CC[C@]1(C(=O)OC)C[C@H](F)CN1C(=O)OC(C)(C)C
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@]1(CC=O)C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 5 h

Procedure:
1 g (3.5 mmol) (2R,4S)-2-allyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is dissolved in 60 mL dichloromethane/methanol 1:1, cooled to −78° C., flushed with oxygen for two minutes then treated with a flux of ozone until the solution turns light blue. The solution is allowed to warm up to room temperature after addition of 1 g (1.1 eq.) triphenylphosphine, stirred an additional 5 h and column chromatographed (silica gel, TBME/petroleum ether 3:2) to yield 870 mg of the desired product as a clear oil.