Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: C1CNCCN1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCNCC2)c(=O)n(C)c1=O

Procedure:
Example 43 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and piperazine. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.0 Hz, 1H) 7.56 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.93 (m, 1H) 3.77 (m, 1H) 3.51 (s, 3H) 3.25 (s, 3H) 3.17 (m, 4H) 2.98 (m, 1H) 2.52 (m, 1H). [M+H] calc'd for C17H19FIN5O3, 488. found, 488.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7]([NH:17]C(=O)C)=[C:6]([CH:21]([CH3:23])[CH3:22])[CH:5]=1)([CH3:3])[CH3:2].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7]([NH2:17])=[C:6]([CH:21]([CH3:23])[CH3:22])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(C)C)cc(C(C)C)c2c1oc1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N
Temperature: 25 °C
Yield: 81.8 %

Procedure:
N-(1,3-diisopropyldibenzo[b,d]furan-4-yl)acetamide (15 g, 48 mmol) was suspended in the mixture of Concentrated HCl (125 mL) and MeOH (125 mL). The mixture was refluxed for 2 h and then cooled to room temperature. Saturated sodium carbonate was used to neutralize the solution. The residue was collected by filtration and redissolved in DCM. After dried over sodium sulfate, the solution was concentrated to give 1,3-diisopropyldibenzo[b,d]furan-4-amine (10.5 g, 81% yield) as brown solid.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH3:21])=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH3:21])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(-c5ccccc5)cc4)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12)c1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (0.30 g) were added methanol (4.0 mL), THF (4.0 mL), and a 1 M aqueous sodium hydroxide solution (3.0 mL), followed by stirring at 65° C. for 2 hours and then at room temperature for 3 days. To the reaction mixture was added a 10% aqueous citric acid solution (4.0 mL), and the precipitated solid was collected by filtration, washed with water and a mixture of diethyl ether/hexane (1/1), and dried at 60° C. under reduced pressure to obtain 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20]C)=[O:19])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.CO.[OH-].[Li+].Cl>O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([OH:20])=[O:19])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc3ccc(N)cc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc2ccc(C(=O)Nc3cccc(C(=O)O)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 51 mg (0.16 mmol) of compound 111 was added 1 mL of methanol. 1 mL of water, and 800 μL of 1N lithium hydroxide (aqueous). The reaction was allowed to stir for 16 hours at ambient temperature. The pH of the solution was lowered to 3 with 1N HCl (aqueous) and the volatiles removed in vacuo. The resulting solid was suspended in water and collected by vacuum filtration. This provided 16 mg of compound 115.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=313.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([OH:49])[CH:33](O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].O>C1(C)C=CC=CC=1>[CH2:32]1[O:49][C:11]2([CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[O:13][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CCCCCCCCCCCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)NC(c3ccccc3)C2)O1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 14.6 g (58.0 mmol) of 2,6-diphenyl-4-piperidone and 12.2 g (64 mmol) of p-toluenesulfonic acid monohydrate in 500 mL of toluene is refluxed and the azeotroping water is collected in a Dean Stark trap. When 1 mL of water is collected, 15.0 g (58.0 mmol) of 1,2-hexadecanediol (Aldrich) is added and the reaction is refluxed until another 1 mL of water is collected. The reaction mixture is cooled to room temperature and made basic with 50% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous phase is extracted with toluene (2×100 mL). The combined organic phases are dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. 11.0 g (38% yield) of the title compound is isolated after purification by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) followed by recrystallization from ethanol: mp 63°-70° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:10]2[O:9][C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:19])[CH2:3][CH2:4]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.027 g, 0.092 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.014 g, 0.092 mmol) in ethanol (0.5 mL), piperidine (0.00092 mL, 0.0093 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 47%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28]C=CC=1>C1COCC1.[Cu](I)I>[CH:24]1([C:29]#[C:28][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)\[C:11]3[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=3)[N:6]=2)[CH2:30][CH2:31]1
Reactant: C#Cc1ccccc1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(Br)n1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
To a solution of 3-[(Z)-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (210 mg, 0.514 mmol, 1 eq) in degased THF (2 mL) was added in a microwave tube under argon tetrakis(triphenylphosphine)palladium (0) (59.4 mg, 0.051 mmol, 0.1 eq), copper iodide (14.6 mg, 0.077 mmol, 0.15 eq) N,N-diisopropylethylamine (0.358 ml, 2.06 mmol, 4 eq) and phenylacetylene (157 mg, 1.54 mmol, 3 eq). The mixture was stirred at room temperature for 2 days. The mixture was concentrated, diluted with ethyl acetate and filtered over a celite cartridge. The solvent was evaporated and the residue was purified by chromatography on silica gel to afford 3-[(Z)-({[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}imino)(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (148 mg, 73% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([O-])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH:28]=[CH:27][N:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:2][C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][C@@H:9]1[C:21]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[CH2:30][CH2:29][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:22])=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])C1
Reactant: c1cn(CCC2CCCCN2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCCCC2CCn2ccnc2)C1
Temperature: 25 °C
Reaction time: 122 h
Yield: 30.3 %

Procedure:
1,4-Di-N-tert-butoxycarbonylpiperazine-2(R)-carboxylate (prepared as described in Preparative Example 2) (0.6946 g, 2.1 mmoles), 2(R/S)-[2-(1H-imidazol-1-yl)ethyl]piperidine (0.49 g, 2.73 mmoles) (prepared as described in Preparative Example 57, Step D) (INO972). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.524 g, 2.73 mmoles), 1-hydroxybenzotriazole (0.3693 g, 2.73 mmoles) and 4-methylmorpholine (0.2765 g, 0.3005 mL, 2.73 mmoles) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25° C. for 122 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3%(10% conc. ammonium hydroxide in methanol)dichloromethane as the eluant to give the title compound (0.3127 g, 30%): CIMS: m/z 492.4 (MH+): δ11 (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-H,), 7.05 (1H, s, Im-H4) and 7.63 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 28.2, 28.2, 28.2, 28.4, 28.4, 28.4: CH2: 19.1, 25.9, 26.2, 31.9, 40.8/41.3, 41.7, 43.0, 44.0: CH: 46.0, ˜52.1, 128.4, 137.2: C:˜80.4, 80.6, ˜154.3, ˜154.3 and 169.8.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=O.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27])#[N:16]>>[O:25]=[C:24]1[NH:1][C:2]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)([CH3:7])[C:3](=[O:5])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=1
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: COC(=O)C(C)(N)c1ccc(O)cc1
Product: CC1(c2ccc(O)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O

Procedure:
This product is prepared as in Example 5, starting from 10.71 g of methyl 2-amino-2-(4-hydroxyphenyl)propionate using 4-cyano-3-trifluoromethylphenyl isocyanate. 16.83 g of product are obtained (Yd=82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=[C:6]2Cl.C1(O)C=CC=CC=1.[NH3:29]>>[NH2:29][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:7]=1
Reactant: COc1cccc(-c2cc(Cl)c3cc(OC)ccc3n2)c1
Reactant: N
Solvent: Oc1ccccc1
Product: COc1cccc(-c2cc(N)c3cc(OC)ccc3n2)c1
Temperature: 180 °C

Procedure:
A mixture of 6-methoxy-2-(3-methoxyphenyl)-4-chloroquinoline (5.90 g, 19.68 mmol) and phenol (20 g) was heated with stirring at 180° C. and ammonia was passed through the reaction mixture during 11 h. Phenol was then removed by steam distillation. The mixture was filtered and the filtrate was basified to pH 8 by adding 8% Na2CO3 aqueous solution. The solid formed was collected by filtration and dried to give the desired 4-amino-6-methoxy-2-(3-methoxyphenyl)quinoline, 5.313 g (96.3%); mp 148-149° C.; 1H NMR (DMSO-d6) δ 3.85, 3.90 (each: 3H, s, OCH3), 6.67 (2H, s, exchangeable, NH2), 7.00 (1H, dd, J=2.9 and 8.1 Hz, ArH), 7.10 (1H, s, ArH), 7.28 (1H, dd, J=2.9 and 8.8 Hz, ArH), 7.40 (1H, t, J=8.1 Hz, ArH), 7.53 (1H, d, J=2.9 Hz, ArH), 7.61 (1H, 1H, d, J=8.1 Hz, ArH), 7.64 (1H, t, J=2.2 Hz, ArH), 7.77 (1H, d, J=8.8 Hz, ArH). Anal. Calcd. for (C17H16N2O2): C, 72.84; H, 5.75; N, 9.99. Found: C, 72.82; H, 5.51; N, 10.12.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][NH:19][C:11](=[O:13])[CH:10]([OH:14])[C@H:9]([NH2:8])[CH2:15][CH2:16][S:17][CH3:18])[CH:23]=1
Reactant: NCCc1cccnc1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Product: CSCC[C@@H](N)C(O)C(=O)NCCc1cccnc1

Procedure:
The product of example 3A and 1-amino-2-(3-pyridyl)ethane were processed as in example 2 to provide the title compound.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:28]=[CH:29][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:25][CH:26]=1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(-c2cccs2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(-c2cccs2)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (17 mg, 0.11 mmol) and diisopropylethylamine (55 uL, 0.32 mmol) in MeOH (2 mL) was added 2-(4-isocyanatophenyl)thiophene (43 mg, 0.22 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (5 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, 2H, J=8.0 Hz), 7.42 (d, 2H, J=8.0 Hz), 7.29 (s, 2H), 7.05 (s, 1H), 4.65-4.63 (m, 1H), 3.77-3.53 (m, 2H), 3.23 (s, 9H), 2.58-2.48 (m, 2H); MS ESI 362.1 [M+H]+, calcd for [C18H23N3O3S+H]+ 362.46.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH3:22])[C:20]([C:19](=[O:24])[C:18]([F:26])([F:25])[F:17])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 50 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that heptane/ethyl acetate (10:1) was used. Yield: 50%; MS: m/z=392/394 (M).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:1][N:4]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCCl
Reactant: NCCN
Product: CCCCN(CCCC)CCN(CCCC)CCCC

Procedure:
A three-necked round-bottomed flask (3 L) equipped with a Friedrich's condenser and an overhead mechanical stirrer is placed in a cooling bath. The flask is charged with dimethylformamide (DMF, 500 mL), potassium carbonate (2.1 mol), and potassium iodide (0.1 mol). The mixture is allowed to stir until the potassium iodide was dissolved (giving a faint yellow tint) and the potassium carbonate was fairly homogenized. Ethylenediamine (0.5 mol) is then added to the reaction mixture. 1-Chlorobutane (2.2 mol) is added drop-wise to the resulting reaction mixture from a pressure-equalizing addition funnel under efficient mechanical stirring. During the addition of the alkyl halide, the exothermic reaction which may occur is controlled by cooling the round-bottomed flask bath with the cooling bath so as to maintain the reaction temperature below room temperature (e.g., using a chiller temperature ˜5° C.). After all the alkyl halide has been added and any exotherm subsides, the cooling bath is replaced by a heating mantle or oil bath. The reaction mixture is then heated (˜50° C. reaction temperature; ˜70-80° C. bath temperature) under efficient stirring. After heating overnight, the reaction set-up is modified for vacuum distillation and unreacted alkyl halide and a majority of the DMF (about 400-450 mL) is removed. The resulting residual mixture in the reaction flask is partitioned between water and ethyl acetate in a separatory funnel to separate the polyalkylated product from the inorganic salts. The aqueous fraction is extracted three times with ethyl acetate and the combined ethyl acetate solutions are sequentially washed with water and brine solution. The ethyl acetate extract is dried over sodium sulfate, filtered and concentrated using a rotary evaporator. The resulting oily residue can be distilled under reduced pressure to isolate a purified fraction of tetrabutylethylenediamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17]OS(C)(=O)=O.O>CN(C=O)C>[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@H]1CCCO1
Reactant: O=C1CCc2cc(O)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OC[C@H]3CCCO3)ccc21

Procedure:
A solution of 5-hydroxyindanone (80 mg) and methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester (107 mg) in DMF (1 mL) was stirred at 70° C. for 16 h. After adding water it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. In this way the product was obtained with molecular weight 232.28 (C14H16O3); MS (ESI): 233 (M+H+).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].O>N1C=CC=CC=1>[C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCCn1ccc(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccn(CCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Yield: 24.1 %

Procedure:
Trityl chloride (0.358 g, 1.28 mmol) was added to a solution of 1-(4′-aminobutyl)uracil (contaminated by 11% 1,3-bis(4′-aminobutyl)uracil) (0.168 g) in anhydrous pyridine (15 mL). The reaction mixture was heated at 50° C. for 44 h, left to cool to room temperature, poured into cold water (50 mL) and extracted with DCM (3×25 mL). The organic extracts were washed with brine (40 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by silica gel column chromatography, using Jones Chromatography Isolute SI columns with a gradient elution of 0→5% CH3OH in CHCl3. The fractions with Rf=0.51 (10% CH3OH/CHCl3) gave the title compound as a white crystalline solid (94 mg, ca 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:28][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 83.8 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and phenethylamine (121 mg, 1.0 mmol) to give 330 mg of the title compound(84%): mp>250° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 8.21 (t, 1H, J=5.6 Hz), 7.09~7.39 (m, 7H), 5.07 (m, 1H), 3.24~3.33 (m, 2H), 2.64~2.73 (m, 3H), 2.25~2.32 (m, 2H), 1.80~1.95 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>CN(C)C=O>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH:6][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
L-Tryptophan methyl ester hydrochloride (1.05 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to Procedure A (0-25° C., dimethyl-formamide reaction solvent) and the product purified by chromatography on silica gel eluted with 10%, 20%, 30%, 40%, 50% and 60% ethyl acetate-hexanes giving a yellow foam. Yield, 79%; HPLC (60/40) 7.43 minutes (96%);