Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][CH2:40][N:39]2[C:43](=[O:46])[CH2:44][CH2:45][CH:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[C:43](=[O:46])[CH2:44][CH2:45][CH:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC2CNCCN12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(=O)CCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 59.6 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.187 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 78.6 mg (0.561 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 71 mg of the title compound as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[N:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:40]([O:42][CH3:43])=[O:41])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To the solution of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and methyl chloroformate (5.2 mg, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 132 as off-white solid. MS m/z 446.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.55 (s, 1H), 8.72 (d, 1H), 8.18 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H), 7.90 (d, 2H), 7.84 (d, 1H), 7.50 (d, 2H), 7.35 (dd, 1H), 3.72 (s, 2H), 3.54 (s, 3H), 3.43 (t, 4H), 3.03 (t, 3H), 2.65 (s, 3H).
Reaction SMILES: C([N:8]1[C:12]2=[C:13]([NH:28][S:29]([CH:32]3[CH2:34][CH2:33]3)(=[O:31])=[O:30])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OC(=O)C)C>C(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:14]2[C:13]([NH:28][S:29]([CH:32]3[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[C:12]3[NH:8][CH2:9][CH2:10][N:11]3[C:16](=[O:17])[C:15]=2[CH3:18])=[C:21]([F:27])[CH:22]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Borontribromide (20 mg, 0.0001 mol) was added to a stirred solution of cyclopropanesulfonic acid [1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-8-yl]-amide (1A: 30 mg, 0.0001 mol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with methanol and concentrated. The concentrate was partitioned between ethyl acetate and water. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (4% methanol in DCM) afforded 7 mg of the product (28% yield).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH2:26]3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:46][C:47]([CH3:49])=[O:48]>O1CCCC1.C(O)(=O)C>[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH:26]3[C:47]([OH:48])([CH3:49])[CH3:46])[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)=O
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a stirred solution of 60 μL of hexamethyl disilazane in 10 mL of dry tetrahydrofuran at 0° under argon was added dropwise 190 μL of butyllithium (1.37M in hexane). To this solution at -78° was added a solution of 106 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 1 mL of tetrahydrofuran over a 3 min period. The reaction mixture was stirred for 10 min after which time 25 μL of acetone was added. After 20 min, 50 μL of acetic acid was added, the reaction mixture was evaporated to a small volume, and partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was subjected to preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with ether-petroleum ether (1:2) to afford 21 mg (17.4%) of solid 3 -phenylthio-6-(2-hydroxyprop-2-yl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester. IR (neat): 3400, 1765, 1685, 1545 cm-1 ; NMR (220 MHz; CDCl3): δ 1.17 (3H, s), 1.25 (1H, s), 1.32 (3H, s), 2.30 (1H, J=18, 3.5), 2.8-3.0 (2H, m), 3.11 (1H, dd, J=6, 3), 4.5 (1H, m), 6.93 (1H, s), and 7.2-7.6 (15H, m).
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[NH:10][C:11]1[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.[C:28]([O:31][CH2:32][C:33]1[C:38]([N:39]2[C:51](=[O:52])[C:50]3[S:49][C:48]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=4[C:42]=3[CH2:41][CH2:40]2)=[CH:37][C:36]([F:53])=[CH:35][C:34]=1Br)(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:28]([O:31][CH2:32][C:33]1[C:38]([N:39]2[C:51](=[O:52])[C:50]3[S:49][C:48]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=4[C:42]=3[CH2:41][CH2:40]2)=[CH:37][C:36]([F:53])=[CH:35][C:34]=1[C:15]1[CH:16]=[C:11]([NH:10][C:2]2[CH:3]=[C:4]3[N:9]([N:1]=2)[CH2:8][CH2:7][O:6][CH2:5]3)[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 120 °C
Yield: 49.9 %

Procedure:
A mixture of 150a (260 mg, 0.70 mmol), (2-bromo-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}phenyl)methyl acetate 218a (225 mg, 0.50 mmol), PdCl2(dppf) (55 mg, 0.075 mmol), 2 M Na2CO3 solution (1.5 mL) in DME (8 mL) was heated at 120° C. under microwave irradiation for 0.5 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 150b (154 mg, 50%). MS: [M+H]+ 618.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>C(C1C=CC=CC=1)(C)(C)C>[C:1](=[NH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)c1ccccc1
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 28 %

Procedure:
91.1 g of benzophenone, 150 ml of tert-butylbenzene and 2 g of 200-mesh silica-alumina (Nikki Kagaku K.K., N-635) were fed to the same reactor as in Example 11. The reactor was heated, and ammonia gas was continuously fed to the reactor at a feed rate of 1.5 Nl/min, while keeping the contents at 170° C, and reaction was carried out under 8 atm. for one hour. The withdrawn gas was cooled and condensed tert-butylbenzene was refluxed into the reactor. After the completion of the reaction, benzophenoneimine was obtained in yield of 28%.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][C:33]1C2C(=CC=CC=2)NC=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH3:33]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CCCN[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O)C[C@]12O
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and tryptamine (7.1 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-propylamino)-cholestan-3β-ol as a white solid (7.3 g, 59%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 21% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1.C12CC(C=C1)C(=O)N2>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)([NH:9][CH:10]=[O:11])[CH2:6][N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@@H]1CC=C(CO)C1
Agent: O=C1NC2C=CC1C2
Product: NC1=NCC(NC=O)(N[C@@H]2CC=C(CO)C2)C(Cl)=N1

Procedure:
By the method of Example 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate--methanol gave title compound as white crystals, mp. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, =CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920 -4.4°, [α]57820 -5.2°, [α]54620 -4.8°, [α]43620 -20.0°, [α]36520 -60.4° (c 0.25, methanol).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCN(C(C)C)C(C)C.Cl[C:43]([O:45][CH3:46])=[O:44]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:19][C:15]1[CH:14]=[C:13]([CH:12]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH2:11][CH2:10][CH2:9][NH:8][C:43]([O:45][CH3:46])=[O:44])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(CCCN)c2cccc(F)c2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCCC(c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A 100 mL round bottom flask was charged with 0.092 g of TFA salt of (3S)-tert-butyl 3-(4-amino-1-(3-fluorophenyl)butyl)piperidine-1-carboxylate, 0.152 g of DMAP, 10 mL of CH2Cl2, and 2 mL of DIPEA. The mixture was cooled with an ice bath and then a solution of methyl chloroformate (0.280 g) in CH2Cl2 (3 mL) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 25 mL/min) to afford 0.0306 g (38%) of (3S)-tert-butyl 3-(1-(3-fluorophenyl)-4-(methoxycarbonylamino)butyl)piperidine-1-carboxylate. Isomer 1 and 2, MS ESI +ve m/z 431 (MNa+), 409 (MH+), tR=1.91, 1.98 min in 3 min chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:29][CH2:28][CH2:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-4-chloro-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:57][C:58](=[O:71])[C@H:59]([CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:70])[NH2:69])[NH:60][N+]([O-])=O)C1C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:60][C@H:59]([C:58]([OH:71])=[O:57])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:69])[NH2:70])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinone-6-yl)propionate (187 mg, 0.5 mmol) and N-nitro-L-arginine benzyl ester di-p-toluenesulfonate (327 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added triethylamine (0.25 ml, 1.7 mmol). The mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off and the residue was chromatographed on a column of silica gel (5 g) using methanol-chloroform (1:19, v/v) as eluent. The eluate was evaporated and the residue was dissolved in acetic acid (2 ml). With palladium black catalyst (30 mg), the solution was hydrogenated at room temperature for 10 hours. After completion of the reaction, the catalyst was removed and the solvent was distilled off. Methanol (5 ml) was added to the residue and the resulting solution was ice-cooled. A solution of ferric chloride (324 mg, 2 mmol) in water (1 ml) was added and the mixture was stirred for 15 minutes. The resulting mixture was passed through a column of Amberlite XAD-2 (3 g) with water to remove the inorganic matter. Elution with methanol gave a crude compound, which was then concentrated. The residue was chromatographed on a Sephadex LH20 column (1.5×45 cm) [eluent: ethanol-0.1 M acetic acid (3:2, v/v)]. The eluate was distilled off to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-arginine (37 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH3:14].N1(C(N2CCCCC2)N2CCCCC2)CCCC[CH2:20]1.O>C(Cl)Cl.[Fe].C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH:14]=[CH:20][NH:11]2
Reactant: C1CCN(C(N2CCCCC2)N2CCCCC2)CC1
Reactant: Cc1c(Cc2ccccc2Cl)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1Cc1cccc2[nH]ccc12
Yield: 62.1 %

Procedure:
A mixture of 16 g (0.06 mol) of 2-(2-chlorobenzyl)-6-nitrotoluene and 24.4 g (0.09 mol) of tripiperidinomethane is heated for 5 hours at 120° C. in a water jet vacuum with interconnection of a distillation assembly. Then the mixture is taken up in 200 ml of a mixture of 5 parts of toluene and 3 parts of glacial acetic acid and under stirring is added to a suspension of 144 g of iron powder and 362 g of silica gel in 800 ml the same toluene-glacial acetic acid mixture. The reaction mixture is refluxed for 1 hour under an argon atmosphere. After cooling it is diluted with methylene chloride and filtered off from a precipitate. The filtrate in succession is washed with 10% sodium carbonate solution, 5% sodium bisulfite solution and saturated common salt solution and then dried on sodium sulfate. The solution is concentrated by evaporation, the residue after chromatography on silica gel with a mixture of 4 parts of cyclohexane and one part of ethyl acetate and recrystallization from cyclohexane yields 9 g (58% of theory) of 4-(2-chlorobenzyl)-indole, melting point 76°-77° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>>[C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(I)cc(I)c(OCC(=O)O)c1I
Agent: [Na+]
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I

Procedure:
27.3 g (49 mmol) of 3-cyano-2,4,6-triiodophenoxyacetic acid is stirred in 100 of 2N sodium hydroxide solution for 3 hours at 50° C. The resultant alkaline solution is filtered over active carbon for purifying and decolorizing and then brought to pH 2 by adding 2N hydrochloric acid. After several hours of stirring in an ice bath, the yield is 23.9 g (85% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH:30][CH2:31][CH:32]([CH2:34]O)[OH:33].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 4 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate as a white solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]1([N:17]([C@H:35]2[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.[CH:53]([N:56](C(C)C)[CH2:57][CH3:58])(C)[CH3:54].C(NCC)C>CN(C=O)C>[CH:11]1([N:17]([C@H:35]2[CH2:36][CH2:37][C@H:38]([CH3:41])[CH2:39][CH2:40]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH3:29])[CH2:30][C:31]([N:56]([CH2:57][CH3:58])[CH2:53][CH3:54])=[O:32])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An equimolar mixture of HOBt, ({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-acetic acid was added EDAC (1.5 eq) and diisopropylethyl amine (1.2 eq) and dry DMF (10 mL/mmol). The solution was stirred 30 min at rt and then diethyl amine (1.5 eq) was added and stirring was continued over night.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[CH3:26])=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]=3[C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=3[CH3:26])=[CH:4][CH:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Cc1cc(C#N)ccc1-c1c(-c2ccc(Br)cc2)ccn1CCC(=O)O
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(C#N)ccc1-c1c(-c2ccc(-n3ccnc3)cc2)ccn1CCC(=O)O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
To a mixture of 3-(3-(4-bromophenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrol-1-yl)propanoic acid (400 mg, 0.98 mmol) and imidazole (200 mg, 2.94 mol) in DMSO (5 mL) was added L-proline (33.8 mg, 0.294 mmol), CuI (111.7 mg, 0.588 mmol) and K2CO3 (270 mg, 1.96 mmol), then the resultant mixture was stirred at 100° C. overnight. After being cooled down to room temperature, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL×3). The combined filtrate was washed with saturated NaHCO3 aqueous solution (30 mL), and the aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine, dried over MgSO4, concentrated. The residue was purified by silica gel column (DCM: MeOH=30:1-20:1) to afford 3-(3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrol-1-yl)propanoic acid (190 mg, yield 48.9%) as a solid.