Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=CC(C#N)=CN=1.[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:23]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[Cl:39])[N:22]=2)[CH:14]=[CH:13][C:12]=1[N+]([O-])=O>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:23]1[N:22]=[C:21]([NH:20][CH2:19][CH2:18][NH:17][C:15]2[N:16]=[CH:2][C:12]([C:11]#[N:10])=[CH:13][CH:14]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[NH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazolyl-2-pyridyl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 2-chloropyridine-5-carbonitrile using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method describe in Step B of Example 1 from 3-(3-{[(benzofuran-2-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.52-7.42 (m, 3H), 7.26-7.09 (m, 8H), 6.39 (d, 1H), 4.46 (s, 2H), 4.39 (s, 2H), 3.68 (s, 3H), 2.88 (t, 2H), 2.57 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1[CH:52]=[C:51]([NH2:53])[CH:50]=[N:49][CH:48]=1>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:20]([NH:53][C:51]1[CH:52]=[N:47][CH:48]=[N:49][CH:50]=1)=[O:21]
Reactant: CCc1ccc(Nc2noc3c(C(=O)O)c(Cl)ccc23)cc1
Reactant: Nc1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1ccc(Nc2noc3c(C(=O)Nc4cncnc4)c(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylic acid (0.195 g, 0.615 mmol) was dissolved in DMF, followed by TEA (0.223 ml, 1.61 mmol) and HATU (0.285 g, 0.749 mmol). The mixture was allowed to stir for 5 min before adding pyrimidin-5-amine (0.0509 g, 0.535 mmol) and the mixture was heated to 50° C. overnight. The mixture was then cooled to RT, partitioned between EtOAc/brine, the layers were separated, and the aqueous was extracted with EtOAc (3×). The combined organics were washed with H2O and brine, filtered and concentrated. The crude material was purified by silica gel chromatography using 20:1 DCM/MeOH to give 6-Chloro-3-(4-ethylphenylamino)-N-(pyrimidin-5-yl)benzo[d]isoxazole-7-carboxamide as a light brown solid. MS calculated 393.8, found M+H+=394.1.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]([C:11]2([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:4]1([CH2:7][O:8][C:9]([C:11]2([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[O:10])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)OCC2CCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyano-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester (3.90 mmol; 1.72 g) in dichloromethane (12 mL) at 0° C. was added trifluoroacetic acid (12 mL) and the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was evaporated. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with a saturated sodium bicarbonate solution (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to yield 4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester. 1H-NMR (CDCl3): 7.55 (1H, d), 7.20 (1H, d), 3.90 (2H, dd), 3.35 (2H, m), 2.70-3.10 (3H, m), 2.60 (1H, m), 2.25 (1H, m), 0.70-2.20 (15H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH:13]([NH2:16])([CH3:15])[CH3:14].[BH4-].[Na+].Cl>CO>[CH3:14][CH:13]([NH:16][CH2:6][C:5]1[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:15]
Reactant: CC(C)N
Reactant: O=Cc1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)NCc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitro-6-fluorobenzaldehyde(1.21 g, 7.16 mmol) in dry methanol (15 ml), was added isopropyl amine (1 ml, 11.4 mmol) and the mixture stirred for 24 hours at room temperature in argon atmosphere. Then NaBH4 (0.3 g, 7.9 mmol) was added and the reaction mixture was stirred for 36 hours. The suspension was neutralized by addition of HCl 5N, then was extracted with diethyl ether (1×100 ml) and dried over MgSO4 and evaporated at reduced pressure to afford N-(1-methylethyl)-(2-nitro-6-fluorophenyl)methylamine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH2:14][C:15]([OH:17])=O)[CH2:10][C:11](O)=[O:12].[NH4+:18].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:15](=[O:17])[NH:18][C:11](=[O:12])[CH2:10]1
Reactant: [NH4+]
Reactant: O=C(O)CC(CC(=O)O)c1c(Cl)cccc1Cl
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CC(c2c(Cl)cccc2Cl)CC(=O)N1
Temperature: 190 °C

Procedure:
14.5 g (52 mmol) of 3-(2,6-dichloro-phenyl)-pentanedioic acid were dissolved in 140 mL of conc. NH4OH solution. All the volatiles were removed in vacuo and the resulting solid was heated to 190° C. for 6 h. The crude reaction mixture was taken up in CH2Cl2, the organic phase was washed with 0.1 M Na2CO3 solution, dried and evaporated to dryness. The resulting crude solid was triturate with Et2O, filtered and dried, yielding 9.37 g of the title compound.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[S:15])[CH:11]=[C:10]2[OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([S:15][CH2:2][CH3:3])=[CH:11][C:10]2=[O:16]
Reactant: COC(=O)c1cc(Br)c2oc(=S)cc(O)c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
Iodoethane (2.04 mL, 25.54 mmol), was added to a stirred suspension of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (2.3 g, 7.30 mmol) and potassium carbonate (1.21 g, 8.76 mmol) in acetone (100 mL) under argon. The resulting mixture was stirred at 60° C. for 2 hrs. The mixture was concentrated in vacuo, and the residue was pardoned between water and DCM. The aqueous layer was extracted into DCM, and the organic extracts were combined, washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in DCM. The solvent was evaporated to dryness to afford methyl 8-bromo-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (1.8 g, 72%) as an orange solid. Mass Spectrum: M+H+ 343.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][CH2:43][NH2:44])=[CH:40][CH:39]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][CH2:42][C:41]4[CH:45]=[CH:46][C:38]([CH3:37])=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-methylphenethylamine, m.p. 161-163° C. MS [(+)ESI, m/z]: 554 [M+H]+
Reaction SMILES: C[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1CCOC[CH2:12]1>CCOC(C)=O>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:12]=[O:11])=[N:3][CH:2]=1)([O-:10])=[O:9]
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1ccc([N+](=O)[O-])cn1
Reaction time: 4 h

Procedure:
5-Nitropyridine-2-carboxaldehyde was prepared from the nitro derivative, 2-methyl-3-nitropyridine, by the procedure employed for the synthesis of Example I, except that anhydrous dioxane was used as the solvent and the reaction time was 4 h. Yield: 2.0 g (42%); mp 66°-67° C. (lit. 66.5°-67.5° C.); TLC, Rf 0.85 (EtOAc); 1H NMR (90 MHz, CDCl3) δ 8.0 (d, 1H, 3-H, J3,4 =4.5 HZ), 8.30 (d, 1H, 4-H, J3,4 =4.5 Hz), 9.25 (s, 1H, 6-H), 10.45 (s, 1H, 2-CHO).
Reaction SMILES: O[C:2]([C:16]1[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([O:27][CH3:28])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C([SiH](CC)CC)C.[C:36](=O)(O)[O-:37].[Na+]>C(Cl)Cl>[CH3:36][O:37][C:19]1([O:27][CH3:28])[C:20]2[O:24][C:23]([CH3:25])([CH3:26])[CH2:22][C:21]=2[C:16]([CH:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][C:4]2[CH:5]=[CH:6][N:7]=[CH:8][CH:9]=2)=[CH:17][CH2:18]1
Reactant: COc1ccc(C(O)(Cc2ccncc2)c2ccccc2)c2c1OC(C)(C)C2
Reactant: O=C([O-])O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCl
Product: COC1(OC)CC=C(C(Cc2ccncc2)c2ccccc2)C2=C1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Under an argon atmosphere, a solution of Compound 47a (0.4 g) obtained in Step A in methylene chloride (3 ml) was cooled to −78° C., and then boron trifluoride ether complex (0.3 ml) and triethylsilane (0.52 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 47 (0.27 g, 56.7%) as a yellowish brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([OH:18])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[C:27]([C@@H:28](O)[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:28]([C:27]4[C:22]([Cl:21])=[C:23]([O:31][CH:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]5)[CH:24]=[CH:25][CH:26]=4)[CH3:29])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O
Product: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Yield: 98.1 %

Procedure:
The title compound was prepared from methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate (0.64 g, 1.8 mmol) and 1,1-dimethylethyl 4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarboxylate (0.78 g, 2.2 mmol) using a procedure analogous to Intermediate 2, Step C to give 1.22 g of the desired product. MS (ESI): 692.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=3[OH:32])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]1([CH2:39]N2CCCCC2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[OH-].[Na+].C(O)(=O)C>C1(C)C=C(C)C=C(C)C=1.C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:19]3[CH:24]=[C:23]([CH2:39][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=3[OH:32])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCN(CN2CCCCC2)CC1
Reactant: CCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1CN1CCCCC1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
2,4-Diphenyl-6-(2-hydroxy-4-hexyloxyphenyl)-s-triazine (42.5 g, 0.1 mol), dipiperidinomethane (17.5 g, 0.096 mol) and sodium hydroxide (0.8 g, 0.02 mol) are dissolved in 42 g of mesitylene. The mixture is heated with agitation at 160° C. for 18 hours. Acetic acid (8.5 g) is then added and the reaction mixture is heated for 30 minutes at 120°-130° C. Toluene (300 ml) is added and the heating is continued till the reaction product dissolves. The reaction mixture is then cooled to room temperature and the product crystallizes to give 21 g of reaction product. The crude product is recrystallized from 500 ml of toluene to yield 15 g of final product.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:23])([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:20])([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)=[O:9]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-aminophenylsulfur pentafluoride to afford an orange solid. HPLC (Condition 4), tR=6.43 min, UPLC-MS (Condition 3), tR=1.27 min, m/z=435.3/437.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C@H:13]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH2:12][C@@H:11]([NH:31]C(=O)OCC3C=CC=CC=3)[CH2:10]2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].CO>[N:1]1([CH2:6][C:7]([N:9]2[CH2:10][C@H:11]([NH2:31])[CH2:12][C@H:13]2[C:14]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)=[O:30])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157.7 %

Procedure:
A flask charged with benzyl (3R,5S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.20 g, 2.15 mmol), prepared as in Example 1, palladium on carbon (10%, 120 mg) and methanol (20 mL) and the mixture was placed under a hydrogen atmosphere (balloon). The mixture was stirred for 2 hours at ambient temperature, filtered and concentrated to give (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (1.44 g, 3.39 mmol), which was carried forward without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][C:18]1=[O:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)NCCCC(=O)O)cc1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2.0 g of 4-[(3-benzyloxy-4-methoxybenzoyl)amino]butyric acid are heated to reflux for 1 hour in 10 ml of acetic acid anhydride. After evaporation of the acetic acid anhydride, the residue is stirred at room temperature with diethyl ether. The mixture is filtered and the filter residue is washed with diethyl ether. There is obtained 1-(3-benzyloxy-4-methoxybenzoyl)-2-pyrrolidinone of melting point 92°-92° C.
Reaction SMILES: [C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35](S(C2C=CC(C)=CC=2)(=O)=O)[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35]([N:48]=[N+:49]=[N-:50])[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CO[C@H]1O[C@H](C(O)S(=O)(=O)c2ccc(C)cc2)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1O[C@H](C(O)N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
10 g of compound 2 and 3 g of NaN3 were dissolved in 100 cc of DMF. Reaction was allowed to proceed for 24 hrs at 70° C. after which the reaction mass was poured into 1 liter of water. Compound 5, obtained as a solid, was recrystallized from acetone giving 8 g (quant.) after drying over P2O5. M.p. 111° C.; 1H NMR (CDCl3): δ 8.22, 8.07, 7.92 (d,d,d, 2H each, benzoyl), 7.38-7.66 (m, 9H, benzoyl), 6.0—5.96 (m, 2H, H2,3), 5.8 (m, 1H, H4), 5.13 (d, 1H, H1), 4.47 (m, 1H, H5), 3.69 (s, 3H, OMe), 3.62 (AB, 2H, H6.6′).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[OH:31][CH:28]1[CH2:29][CH2:30][N:25]([C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[CH:8]3)=[O:17])[CH2:26][CH2:27]1
Reactant: OC1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCC(O)CC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Piperidin-4-ol to give (4-Hydroxy-piperidin-1-yl)-[1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-methanone. LC-MS: m/e 410 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([OH:14])=O.ClC(OCC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:25][C:24]1[CH:32]=[CH:33][C:34]([Cl:35])=[C:22]([Cl:21])[CH:23]=1)[CH3:31])=[O:14]
Reactant: CN(CCCN)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)COc1nc2ccccc2o1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCNC(=O)COc1nc2ccccc2o1)Cc1ccc(Cl)c(Cl)c1
Temperature: -15 °C
Yield: 42.3 %

Procedure:
To the solution of 54 mg (0.28 mmol) (1,3-benzoxazol-2-yloxy)acetic acid in 3 ml chloroform 28 mg (0.28 mmol) 4-methylmorpholine is added. The mixture is cooled to −15° C., 30 mg (0.28 mmol) ethyl chloroformate is dropped to it and the mixture is stirred under cooling for 15 minutes. Then the solution of 83 mg (0.34 mmol) N-(3,4-dichlorobenzyl)-N-(methyl)propane-1,3-diamine in 2 ml chloroform is added and the reaction mixture is stirred for 30 min under cooling and 1 hour at room temperature. The chloroform solution is extracted with 2×10 ml water, the organic phase is dried over sodium sulfate and evaporated in vacuum to obtain 50 mg title compound as an oil. LC/MS[MH+]=422 (C20H21Cl2N3O3 422.31).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C@H:16]1[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:6])=[O:5])([CH3:3])[CH3:2]>[Pd].CO.C1COCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:9]=1
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To 10% palladium on carbon (1.3 g) was added 50F (5.7 g) in methanol (150 mL) and THF (50 mL) under a stream of nitrogen. The vessel was flushed and degassed with nitrogen gas (3×) and a balloon containing hydrogen gas was introduced. The reaction was stirred at rt for 4.0 h. The catalyst was filtered through Celite® and washed with methanol several times. The filtrate and the combined washings were evaporated and dried to give 5.5 g of 50G. 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 1.10 (d, J=6.60 Hz, 3H) 1.21-1.30 (m, 12H) 2.01-2.13 (m, 2H) 3.20 (s, 3H) 3.29-3.40 (m, 1H) 3.44-3.53 (m, 1H) 3.65 (ddd, J=10.17, 7.97, 5.50 Hz, 1H) 3.70-3.78 (m, 1H) 5.64 (d, J=8.25 Hz, 1H) 6.46-6.55 (m, 2H) 7.41 (d, J=7.70 Hz, 1H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN1CCC(c2cccc(O)c2)CC1
Product: CCCCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1

Procedure:
Beginning with 3-(1-butyl-piperidin-4-yl)-phenol and methanesulfonyl chloride. MS m/z (rel. intensity, 70 eV) 311 (M+, 3), 268 (bp), 189 (20), 131 (18), 79 (12);