Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][NH:11][N:10]=1.S(=O)(=O)(O)O>CC(O)(C)C>[C:3]([N:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:10]1)([CH3:9])([CH3:4])[CH3:2]
Reactant: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: CC(C)c1nnc2ccc(-c3cn(C(C)(C)C)nc3-c3ccc(F)cc3F)nn12
Yield: 47.5 %

Procedure:
The 6-(3-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.300 g, 0.881 mmol, Example #L.1.1) was suspended in t-BuOH (3.0 mL) then sulfuric acid (0.15 g, 1.5 mmol) was added. The mixture was heated using a CEM® microwave at about 130° C. for about 10 min (250 psi maximum pressure, 10 min ramp, 300 max watts). The reaction mixture was concentrated under reduced pressure then purified by flash chromatography on silica gel using 9:1 DCM/MeOH as an eluent to give the title compound (0.083 g, 24%): LC/MS (Table 1, Method a) Rt=2.90 min; MS m/z: 397.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
At 0° C., NaH (1.88 g, 46.2 mmol) was added to a solution of 5-fluoro-1H-indole (5.2 g, 38.5 mmol) in 40 mL DMF. After 10 min at 0° C. tert-butyldimethylsilyl chloride (6.96 g, 46.2 mmol) was added and the mixture allowed to stir at 0° C. for an additional 1 h. The mixture was warmed to room temperature and stirred overnight, then diluted by the addition of water and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography to give the title compound (6.5 g, 67.7%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:17])[CH:12]1[O:16][CH2:15][CH2:14][CH2:13]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCC1CCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2CCCO2)cc1
Temperature: 0 °C

Procedure:
0.3 mol (46.2 g) of para-chloronitrobenzene and 1 mol (101 g) of tetrahydrofurfurylamine are heated for three hours in an oil bath at 150° C. The reaction medium is then poured into 500 ml of ice-cooled water. The expected product initially precipitates in the form of a thick oil which rapidly crystallises. After it has been filtered off, washed with water, recrystallised from ethanol and dried in vacuo, the product melts at 74° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:19]=[C:18]2[CH3:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:26]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:19]=[C:18]2[CH3:25])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:26])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)n(-c2ccc(NCCN3CCOCC3)c(F)c2)c(C)n1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1cc(=O)n(-c2ccc(N(C)CCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 20.1 %

Procedure:
To a suspension of 3-(3-fluoro-4-((2-morpholinoethyl)amino)phenyl)-2,6-dimethyl pyrimidin-4(3H)-one (0.24 g, 0.69 mmol) and K2CO3 (0.48 g, 3.47 mmol) in acetonitrile (15 mL) was added CH3I (0.30 g, 2.11 mmol). The mixture was stirred at rt for 36 h, then filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH (V/V)=50:1) to give the title compound as a white solid (50 mg, 20%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([Mg]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([C:10]1([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
1-Boc-3-azetidinone (1) (2.0 gm, 11.68 mmol) was dissolved in dry THF (20 ml) under nitrogen and cooled to 0° C. Then the solution was added 2.0 M solution of Benzyl magnesium bromide (2) in THF (8.76 ml, 17.52 mmol) under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction completion was monitored by TLC. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product was then purified by column chromatography to give compound 3 (2.15 gm, 70%). 1H NMR (400 MHz, DMSOd6) δ: 1.40 (s, 9H), 2.25 (s, 2H), 4.00 (d, 2H), 4.35 (d, 2H), 6.05 (s, 1H), 7.18 (m, 3H), 7.25 (d, 2H); MS: m/z 263.90 (M+1)+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25].CC(O)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:26][CH2:24][CH3:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (200 mg, 0.64 mmol, 1 equiv), ethanamine (58 mg, 1.05 mmol, 2 equiv) and AcOH (62 mg, 1.05 mmol, 2 equiv) were dissolved in DCM (15 mL), and the mixture was stirred at r.t. for 2 h. Then NaBH3CN (101 mg, 1.9 mmol, 3 equiv) was added to the mixture and stirred for 16 h at r.t. The reaction mixture was washed by brine, dried over Na2SO4, and concentrated to give the title compound as a gray oil (250 mg, 100%). ESI-MS (M+1)+: 340.3. 1H NMR (400 MHz, CDCl3) δ: 7.73˜7.63 (m, 3H), 7.42˜7.31 (m, 1H), 7.16˜7.09 (m, 2H), 4.30˜4.21 (m, 1H), 3.91 (s, 2H), 2.73 (q, 2H), 2.31˜2.23 (m, 2H), 1.93˜1.83 (m, 2H), 1.49˜1.36 (m, 2H), 1.27˜1.18 (m, 2H), 1.15 (t, 3H), 1.12˜1.05 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]([CH2:30][C:31]1[CH2:35][CH2:34][CH2:33][CH:32]=1)[C:24]([C@@:26]1([CH3:29])[CH2:28][O:27]1)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]1([CH2:30][C@H:23]([NH:22][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:24]([C@@:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCC2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (2.00 g, 6.78 mmol) and (S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0° C. was added HATU (3.00 g, 8.36 mmol) followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N2O6, found 473.3 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:19])([O-:15])=[O:14]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2[N+](=O)[O-])C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-nitrobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-nitrobenzamido) -2-methyl - 1,2,3,4-tetrahydroisoquinoline; m.p. 196.5°-198° C. after purification from ethanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:33]12([C:43](Cl)=[O:44])[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:43]([C:33]23[CH2:42][CH:37]4[CH2:36][CH:35]([CH2:41][CH:39]([CH2:38]4)[CH2:40]2)[CH2:34]3)=[O:44])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 22 °C
Reaction time: 12 h
Yield: 40.8 %

Procedure:
In a round bottom flask were added 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg), triethylamine (20 uL) and anhydrous dichloromethane (1 mL). 1-Adamantylcarbonyl chloride (17 mg) was added, and the reaction was stirred at 22° C. for 12 hours. The reaction mixture was washed with said aq NaHCO3, said aq NaCl, dried (MgSO4) and evaporated under reduced pressure. The crude reaction was chromatographed with acidic silica to provide 12 mg (42%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:38][CH2:37][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[C@H:34]([OH:35])[CH3:36]
Reactant: C[C@@H](O)[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.63 g, 3.64 mmol) synthesized in Example (106c) was dissolved in methanol (20 mL), and D-allo-threoninol (1.05 g, 9.99 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.00 g, 7.23 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.70 g, yield 87%) as a white foam.
Reaction SMILES: [I-].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: c1c[nH]cn1
Reactant: C[N+](C)(C)Cc1cccn1C1CCCCC1
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: CCOCC
Product: c1cc(Cn2ccnc2)n(C2CCCCC2)c1

Procedure:
A solution of (1-cyclohexyl-pyrrol-2-yl)methyl trimethylammonium iodide (3.48 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 3 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. An excess of ethereal hydrogen chloride was added and the resulting solid was filtered off and crystallised from methanol/ethyl acetate to give 1-cyclohexyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride as a hygroscopic solid (0.80 g), m.p. 147°-149°.
Reaction SMILES: [N:1]1[C:6](C)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][CH2:8][N:1]2[C:6](=[N:1][CH2:2][CH2:3][CH2:4]2)[CH2:5][CH2:4]1
Reactant: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: C1CCC2=NCCCN2CC1

Procedure:
Reaction of the Product of Step 3 with 2,6-Lutidine in the Presence of a Catalytic Amount of DBU. A mixture of 5.0 g of product of Step 3 and 2.13 g 2,6-lutidine is heated at 143° C. for 30 minutes. Two drops of DBU are added and the reaction mixture is heated for additional 1.5 hours, cooled and worked up as in (b) above to give 4.23 g of the desired product. The reaction can also be carried out with an excess of 2,6-lutidine and a catalytic amount of DBU without solvent or in the presence of toluene as a solvent giving similar results.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][N:26]([CH2:28][C:29]([OH:31])=[O:30])[C:25](=[O:32])[CH2:24]2)=[CH:19][CH:18]=1.O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:27][N:26]([CH2:28][C:29]([O:31][N:34]3[C:38](=[O:39])[CH2:37][CH2:36][C:35]3=[O:40])=[O:30])[C:25](=[O:32])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CN1CC(c2ccc(F)cc2)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(CN1CC(c2ccc(F)cc2)CC1=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A total of 31.5 g (150 mmol) of dicyclohexylcarbodiimide is added in portions to a solution of 35.6 g (150 mmol) of 2-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid and 17.2 g (150 mmol) of N-hydroxysuccinimide in 570 ml of dioxan, during which operation the temperature of the reaction mixture should be maintained below 30° by cooling in an ice bath. When the exothermic reaction has ceased, the reaction mixture is stirred for 16 hours at room temperature, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated to dryness by evaporation under reduced pressure at 70°. The residue is dissolved in 200 ml of ethyl acetate, and diethyl ether is added until the solution starts to turn cloudy. The crystalline precipitate which forms directly is filtered off with suction, washed with diethyl ether and dried. N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide having a melting point of 120°-123° is obtained.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3[nH]2)CC1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3[nH]2)CC1
Yield: 33.8 %

Procedure:
Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 4 (100 mg, 0.25 mmol) and Intermediate 3 (98 mg, 0.33 mmol) as a yellow solid. M.P.: 88-92° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.39 (s, 1H), 7.89-7.81 (m, 3H), 7.69-7.58 (m, 2H), 7.40-7.32 (m, 1H), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12-3.05 (m, 1H), 3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CS(C)=O.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A mixture of 2-chloro-5-(4-chlorophenyl)pyridine (500 mg, 2.23 mmol), DMSO (2.0 mL) and 1-isopropylpiperazine (3 mL, 23.4 mmol) was stirred and heated on a 100° C. oil-bath overnight. The reaction mixture was poured into water (75 mL), and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of ethyl acetate and methanol (4:1). Collecting the proper fractions afforded 600 mg (85%) of 1-[5-(4-chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[CH3:56][C:55]1[CH:54]=[C:53]([CH3:57])[NH:52][C:51](=[O:58])[C:50]=1[CH2:49][NH:48][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1cccc(F)c1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cccc(F)c2C(F)(F)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-fluoro-2-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DMF (25 ml) cooled in an ice bath was added HATU (2.19 g, 5.77 mmol) and DIPEA (1.67 ml, 9.61 mmol). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 904 mg, 5.29 mmol) was added and the reaction was warmed room temperature for 4 h. The reaction mixture was then poured onto distilled water (300 ml) and stirred for 1 h after which time the precipitate was collected via vacuum filtration using microfibre paper. The resulting solid was triturated using diethyl ether and filtered to afford the title compound as a pale brown solid (1.19 g, 72%). LC-MS 100%, m/z=343.0, 1H NMR (500 MHz, DMSO) δ 11.48 (s, 1H), 8.54 (t, J=4.8 Hz, 1H), 7.71 (dd, J=13.3, 8.0 Hz, 1H), 7.56-7.45 (m, 1H), 7.20 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 4.25 (d, J=4.9 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [C:1]1([NH:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[I:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[NH:18]C1C=CC=CC=1>ClC1C=CC=CC=1>[C:1]1([NH:11][C:12]([NH:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[I:15])=[NH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CNc1cccc2ccccc12
Reactant: Ic1ccccc1Nc1ccccc1
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1ccccc1I)Nc1cccc2ccccc12
Yield: 33.5 %

Procedure:
A solution of 1-naphthylcyanamide (182 mg, 1.08 mmol) and o-iodophenylaniline hydrochloride (279 mg, 1.09 mmol) in chlorobenzene (5 ml) was heated at 135°-140° C. for 14 hours. It was concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was dried over Na2SO4 and concentrated. The resulting light green residue was recrystallized from 95% EtOH-H2O to give N-(1-naphthyl)-N'-(o-iodophenyl)-guanidine (140 mg, 33%) as off-white needles. mp 154°-155° C.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:30][CH2:31][CH2:32][OH:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]([CH2:31][CH2:32][OH:33])[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: OCCNCc1ccccc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25]O)[CH2:20][CH2:19]2)[CH:5]=1.C([N:36](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>CO.C1COCC1>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][NH2:36])[CH2:20][CH2:19]2)[CH:5]=1
Reactant: OCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Yield: 53.6 %

Procedure:
In the same way as that described in Example 6 using 1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-4-[1-(4-fluorophenyl)-2-hydroxyethyl]piperazine (113 mg, 0.25 mmol), triethylamine (70 μL, 0.50 mmol), methanesulphonyl chloride (39 μL, 0.50 mmol) and THF (5 mL). The crude mesylate was converted to the amine in the same manner as that used in Example 6, using ammonia (2.5 mL of a 2M solution in MeOH, 5.0 mmol). The amine (60 mg, 53%) was isolated as a pale yellow foam. 1H NMR (250 MHz, CDCl3) δ1.89-2.01 (2H, m), 2.27-2.85 (14H, m), 4.10 (1H, dd, J=10.1 and 3.8 Hz), 7.00 (2H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.13-7.16 (2H, m), 7.34 (2H, dd, JHB-HA =8.7 Hz and JHB-F =5.5 Hz), 7.47 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=1.9 Hz), 8.37 (1H, br s), 8.47 (2H, s). MS (ES+) (448, M+1).