Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.O[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([C:21]1[C:20]([O:5][CH2:6][C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:27]
Reactant: N#Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Temperature: 100 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[CH:31]=[CH:30][C:29]=3[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[CH:31]=[CH:30][C:29]=3[S:37](=[O:40])(=[O:39])[NH:38][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[Cl:41])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-4-[(2'-sulfamoyl-5'-propylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step E) and 2-chlorobenzoic acid (2.0 equivalents), CDI (2.0 equiv), and DBU (2.0 equiv) according to the procedure of Example 51 to give an 86% yield of the desired material as a cream-colored solid after flash chromatography, mp 67°-69° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 711 (M+1)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:32][CH:31]([NH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)=[O:35])[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH:31]([NH:33][C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:35])[CH2:32]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(NC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
0.59 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (b) above] was suspended in 0.94 ml of anisole, and 3.32 ml of trifluoroacetic acid and 0.15 ml of trifluoromethanesulfonic acid were added dropwise to the suspension, whilst ice-cooling, after which the mixture was stirred at the same temperature for 1 hour. At the end of this time, 1,2-dichloroethane was added to the reaction mixture, and the solvent was removed by distillation under reduced pressure. The residue was then washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to give 0.44 g of the title compound, in the form of an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4].[ClH:14]>CN(C)C=O.O1CCOCC1>[Cl-:14].[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cl
Agent: COC(=O)c1ccc(C=NO)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxycarbonylbenzaldehyde oxime (896 mg) in N,N-dimethylformamide (10 ml) was added 4N-hydrochloride acid in 1,4-dioxane (1.38 ml) and oxoneR (1.69 g). The suspension was stirred at ambient temperature for 16 hours and poured into ice-water. The object compound was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-Methoxycarbonylbenzaldehyde oxime chloride (1.05 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]3([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3ccccc3)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (250 mg, 0.59 mmol, prepared in Example 53A-E), phenylboronic acid (108 mg, 0.9 mmol), tetrakis(triphenylphosphine)palladium (68 mg, 0.06 mmol), and 2M Na2CO3 (885 μL, 2 mmol) were mixed in dioxane (4 mL). The reaction vessel was placed under an argon atmosphere and stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude product. The crude product was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a yellow solid (172 mg). MS (m/e)=366.2 (M+H-tBu)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[OH-].[K+].[CH:14]#[CH:15]>CS(C)=O>[CH:14]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:10])[CH3:11])=[CH2:15]
Reactant: C[Si](C)(C)CCCCCCO
Reactant: C#C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCCCCC[Si](C)(C)C
Yield: 99 %

Procedure:
In a similar manner to Example 1, 75 g (0.43 mol) of 6-(trimethylsilyl)hexanol, 7.5 g of KOH and 75 g of DMSO were reacted at 80° C. with acetylene. 6-(Trimethylsilyl)hexyl vinyl ether was obtained in 99% yield.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[OH:16])[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[N:6]=[CH:7][CH:8]=[CH:9]2
Reactant: Oc1cccc2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=P(Cl)(Cl)Oc1cccc2cccnc12
Temperature: 25 °C
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.58 mL, 1 equiv) and quinolin-8-ol (Aldrich, 900 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.86 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow syrup (870 mg, 54%). This crude product was used for next step directly.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4([CH3:30])[CH2:27][O:26]C(C)(C)[O:24]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O>[CH3:30][C:23]([OH:24])([CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:34])([F:1])[F:33])=[CH:32][CH:31]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:27][OH:26]
Reactant: CC1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(O)(CO)COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.9 %

Procedure:
4-[4-(Trifluoromethoxy)phenoxy]-1-{4-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}piperidine (223 mg, 0.463 mmol), ethanol (10 mL), and concentrated hydrochloric acid (2 mL) were mixed and stirred at room temperature for 14 hours. Water was added to the reaction mixture, followed by neutralization with sodium carbonate. Ethyl acetate was added to the mixture to conduct extraction. The organic layer was washed with water three times. The organic layer was concentrated under reduced pressure, obtaining 196 mg (yield: 96%) of the objective compound.
Reaction SMILES: [ClH:1].[CH2:2]=O.[CH:4]1[CH:9]=[C:8]2[CH:10]=[CH:11][O:12][C:7]2=[CH:6][CH:5]=1>C1C=CC=CC=1>[Cl:1][CH2:2][C:11]1[O:12][C:7]2[CH:6]=[CH:5][CH:4]=[CH:9][C:8]=2[CH:10]=1
Reactant: c1ccc2occc2c1
Reactant: C=O
Reactant: Cl
Solvent: c1ccccc1
Product: ClCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 1 l R.B. flask was equipped with a mechanical stirrer, addition funnel, and gas inlet tube. The flask was charged with 212 ml of conc. HCl, 127 ml of benzene, and 38.14 g of paraformaldehyde, then cooled to 0° C. and saturated with hydrogen chloride gas. While maintaining the temperature at 0°-1° C. add the 50.0 g (0.423 mol) of 2,3-benzofuran in a slow dropwise fashion. When the addition was complete, the mixture was stirred 21/2-3 hours at room temperature.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][C@H:3]1[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(C(C)C)C(C)C.Cl[C:48]([O:50][CH3:51])=[O:49].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:34]([O:33][C:31]([NH:30][C@H:3]1[C@@H:2]([NH:1][C:48]([O:50][CH3:51])=[O:49])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:4]1)=[O:32])([CH3:36])([CH3:35])[CH3:37]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.7 %

Procedure:
To a solution of di-tert-butyl (4-{(3R,4S,5S)-4-amino-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (1.27 g, 2.43 mmol) in DCM (50.0 mL) at 0° C., DIPEA (983 mg, 7.60 mmol) was added followed by a solution of methyl chloroformate (244 mg, 2.59 mmol) in DCM (10 mL). The solution was stirred at 0° C. for 30 min., then at room temperature for additional 30 min., then the reaction was quenched with 1.0 M aq. Na2CO3 in water (75.0 mL, 75.0 mmol). The organic layer was separated, washed with brine, then dried over Na2SO4, filtered and concentrated to give the crude sub-title compound as a yellow foamy solid (1.545 g, 109%). The crude product was used directly in the next step without further purification. LCMS calc. for C28H46N5O8 (M+H)+: m/z=580.3. Found: 580.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:12]([I:14])[CH3:13].C(O)(C)C>C(#N)C>[IH:14].[CH2:12]([NH+:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][CH:2]1[CH3:1])[CH3:13]
Reactant: CCI
Reactant: CC1CCC2CCCCC2N1
Solvent: CC(C)O
Solvent: CC#N
Product: CC[NH+]1C(C)CCC2CCCCC21
Product: I
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-Ethyl-2-methyldecahydroquinolinium hydroiodide was prepared according to the method described below. To a solution 100 gm (0.65 mol) of 2-methyldecahydroquinoline (trans and cis) in 350 ml acetonitrile, 111 gm (0.72 mole) of ethyl iodide was added. The mixture was stirred (using an overhead stirrer) at room temperature for 96 hours. Then, an additional ½ mole equivalent of ethyl iodide was added and the mixture was heated at reflux for 6 hours. The reaction mixture was concentrated on a rotary evaporator at reduced pressure and the obtained solids were rinsed with 500 ml ethyl ether to remove any unreactive amines and excess iodide. The reaction afforded a mixture of two N-ethyl-2-methyl-decahydroquinolinium hydroiodide salts (mono-ethyl derivatives) and a small mixture of the quaternized derivatives. The products were isolated by recrystallization from isopropyl alcohol several times to give the pure trans-fused ring N-ethyl-2-methyl-decahydroquinolinium hydroiodide and the pure cis-fused ring N-ethyl-2-methyl-decahydroquinolinium hydroiodide (see the scheme below).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[H-].[Na+].[CH3:20][OH:21]>>[Br:1][C:2]1[C:3]([O:21][CH3:20])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: CO
Reactant: FC(F)(F)c1nccn1-c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ncc(-n2ccnc2C(F)(F)F)cc1Br
Yield: 80 %

Procedure:
3-Bromo-2-chloro-5-(2-trifluoromethylimidazol-1-yl)pyridine (318 mg, 0.97 mmol) in methanol (12 ml) was treated with sodium hydride (54 mg, 60% dispersion in oil, 1.41 mmol) and refluxed for 3 hrs. After cooling and concentration, the residue was purified by silica chromatography, to give the product as a yellow solid (252 mg, 80% yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67](C(OCCCC)=O)[CH2:66][CH2:65]1>O1CCCC1.ClCCl>[NH:67]1[CH2:68][CH2:69][CH:64]([NH:63][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[CH:4]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:65][CH2:66]1
Reactant: CCCCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCNCC1)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, 2.5 mmol, 1 equiv), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv), N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1 tetrahydrofuran/dichloromethane (50 mL) was added text-butyl 4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at room temperature. After 16 h, the reaction mixture was filtered, and the filtrate was concentrate. The resulting residue was dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (50 mL) at room temperature. After 2 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (508 mg, 42%). LCMS (ESI) m/z: 481.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1 H), 8.85 (d, J=7.6 Hz, 1 H), 8.60 (s, 1 H), 8.38 (d, J=8.8 Hz, 1 H), 7.98 (d, J=8.8 Hz, 1 H), 7.84 (br s, 2 H), 7.72-7.79 (m, 3 H), 7.32 (d, J=7.6 Hz, 2 H), 7.15 (m, 1 H), 4.02 (m, 1 H), 3.27-3.32 (m, 2 H), 2.95-3.05 (m, 2 H), 1.87-1.94 (m, 2 H), 1.41-1.48 (m, 2 H).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>O>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: CO
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The second process mode comprises: condensating N-formyl-L-aspartic aicd anhydride with L-phenylalanine in water containing methanol in an amount of 6 equivalents or less to L-phenylalanine at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture successively with hydrochloric acid without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol and thereby to precipitate α-APM hydrochloride; separating the α-APM hydrochloride; and neutralizing said hydrochloride as required, thereby preparing α-APM or its hydrochloride.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)C(=O)C)C>CN(C)C(=O)C>[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]1
Reactant: CC(C)Br
Reactant: COCC1(Nc2ccccc2)CCNCC1
Agent: CCN(CC)C(C)=O
Solvent: CC(=O)N(C)C
Product: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Yield: 42.6 %

Procedure:
A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamide and 72 parts of N,N-dimethylacetamide is stirred and refluxed for 10.25 hours. After cooling, the formed N,N-diethylethanamine hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Oc1ccccc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 130 mg (0.468 mmol) 6-chloro-4-phenoxy-nicotinic acid ethyl ester, 0.040 ml (0.47 mmol) morpholine and 0.065 ml (0.47 mmol) triethylamine in 7 ml tetrahydrofuran was stirred at reflux for 40 h. After cooling to room temperature the reaction mixture was filtered, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and concentrated. Flash column chromatography afforded 66 mg (43%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1C=N[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S.[CH3:33][N:34](C)C=O>CO.[Cu]Br>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:31][CH2:30][CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:29][CH2:28]3)=[N:34][CH:33]=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: CN(C)C=O
Agent: [Cu]Br
Agent: S
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper(1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeOH, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide(g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[C:15]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[N:16]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (172 mg, 1.4 mmol) in 5 ml of THF was added dropwise to a solution of 2,4-dichloro-6-phenyl-[1,3,5]triazine (452 mg, 2 mmol) (ref: WO 0125220, p.190) and diisopropylethylamine (0.35 ml, 2 mmol) in 15 ml of THF at room temperature then stirred for 18 hours. The reaction was filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography (SiO2) eluting with 8:2 dichloromethane: ethyl acetate to afford 233 mg of the desired product. HPLC: Rt 6.803 mins. MS: m/z 313.0 (M+H)