Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C@@H:48]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:49][OH:50].C(N(CC)CC)C>C(Cl)Cl>[OH:50][CH2:49][C@@H:48]([NH:47][C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=1)=[O:19])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
To a solution of 2-phenyl-4-quinoline-carboxylic acid (0.33 g, 1.3 mmol, Aldrich Chemical Company) in methylene chloride (5 mL) was added benzotriazol-1-yloxytris-(dimethyamino)phosphoniumhexafluorophosphate (BOP) (0.63 g, 1.43 mmol). The resulting mixture was shaken at room temperature for 5 min. (S)-(-)-2-arnino-3-phenyl-1-propanol (0.2 g, 1.3 mmol) was added along with triethylamine (0.2 mL, 1.43 mmol). The resulting mixture was shaken at room temperature for 24 h. Methylene chloride (10 mL) was added and the organic layer was washed with NaHCO3, H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oil. The oil was purified by flash chromatography (silica gel, 30-80% EtOAc/hexane) to yield the title compound as a white solid (0.3 g, 60%). MS (ES+) m/e 383.5 [M+H]+, 405 [M+Na]+, 787 [2M+Na]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[F:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (900 mg, 1.989 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (406 mg, 1.989 mmol), HBTU (905 mg, 2.387 mmol) and Et3N (1.386 mL, 9.94 mmol) in DCM was stirred at room temperature overnight. The reaction did not go to completion overnight. An additional equivalent of each reagent was added and the reaction stirred over the weekend. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified using flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). However, this product batch was not pure. It was purified with a Gilson HPLC. Product crashed out from the HPLC solution. The solid was filtered to obtain N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (120 mg) as a solid. The mother liquor was purified with a Gilson HPLC to obtain another batch of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (160 mg). LC-MS m/z 638.4 (M+H)+, 0.89 min (ret time).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]([O:18][C:19]([Cl:22])(Cl)Cl)=[O:17]>>[Cl:15][C:16]([O:18][CH:19]([Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)OC(Cl)c1ccccc1
Reaction time: 2 h

Procedure:
7.5 g (0.07 mole) benzaldehyde and 0.3 g (0.004 mole) pyridine are introduced in an apparatus similar to that of example 1. The mixture is brought to 45° C. and 8.5 g (0.043 mole) trichloromethyl chloroformate added drop by drop over 10 minutes. After 2 hours of stirring at 45° it is confirmed by NMR analysis that all the aldehyde has been converted to the α-chlorinated chloroformate with formula: ##STR7##
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([OH:23])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:57][C:58]([F:74])([F:73])[CH2:59][NH:60][CH2:61][C:62]1[CH:63]=[C:64]2[C:69](=[CH:70][CH:71]=1)[C@H:68]([NH2:72])[CH2:67][CH2:66][CH2:65]2>C1COCC1>[S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([NH:72][C@H:68]1[C:69]2[C:64](=[CH:63][C:62]([CH2:61][NH:60][CH2:59][C:58]([F:57])([F:73])[F:74])=[CH:71][CH:70]=2)[CH2:65][CH2:66][CH2:67]1)=[O:23])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: N[C@@H]1CCCc2cc(CNCC(F)(F)F)ccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
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: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CNCC(F)(F)F)ccc32)cc1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (214 mg, 0.64 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (340 μl, 1.92 mmol, 3.0 eq.) and HATU (292 mg, 0.77 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((2,2,2-trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A53) (0.64 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 0.7% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 22% (80 mg, 0.14 mmol); MS, Rt=3.2 min; m/z=575.0 [MH]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3cc(Cl)ccc23)CC1
Product: Cc1ccccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
From the compound of step 4 (100 mg, 211 μmol), the title compound was prepared analogously as described in example 1, step 2, using 2-methylphenol. Yield: 29 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH2:17][CH3:18])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH2:17][CH3:18])=[O:4]
Reactant: CCc1c(C(=O)NC)c2ccc(OC)cc2n1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(C(=O)NC)c2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide 73f (0.267 g, 1.08 mmole) in 15 ml CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3.25 ml, 3.25 mmole). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NH4OH to make pH˜10. The mixture was diluted with H2O and extracted with 10% CH3OH in CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue purified by flash column chromatography (3-5% CH3OH in CH2Cl2) to give pale yellow color solid (0.170 g, 68%). 1H NMR (CDCl3) δ7.40 (1H, d, J=8.5 Hz), 6.65 (1H, s), 6.59 (1H, d, J=8.5 Hz), 3.53 (3H, s), 3.28 (2H, q, J=7.5 Hz), 2.82 (3H, s), 1.13 (3H, t, J=7.5 Hz). ESIMS (MH+): 233.15.
Reaction SMILES: [C:1]([C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[CH3:13][Si](Cl)(C)C>CO>[C:1]([C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:13])=[O:6])#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(C(=O)O)c1C#N
Solvent: CO
Product: COC(=O)c1cccc(C)c1C#N
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
2-Iodo-3-methylbenzoic acid (1.50 g, 5.70 mmol) was dissolved in DMF (15 mL) and treated with CuCN (0.625 g, 7.0 mmol). The solution was heated at 85° C. for 1 h, cooled and poured into water (25 mL). The solution was cooled to 0° C. and 2-cyano-3-methylbenzoic acid precipitated from the solution was isolated by filtration to yield 0.651 mg of a white solid (71%). Crude 2-cyano-3-methylbenzoic acid (0.50 g, 3.1 mmol) was dissolved in MeOH (10 mL) and cooled to 0° C. This solution was treated with excess trimethylsilyl chloride (5.0 mmol) and allowed to warm to RT where it was stirred for 5 h. The methanol was removed under vacuum and the residue was treated with water (20 mL) and extracted with ethyl acetate and concentrated to yield methyl 2-cyano-3-methylbenzoate (0.44 g, 2.52 mmol). To this solid was added DMF (5 mL), Sc(OTf)3 (0.01 g, 0.02 mmol), and diaminopropane (0.22 g, 3.0 mmol). The resulting mixture was heated at 85° C. for 0.5 h, cooled and the cyclic intermediate 5-Methyl-2,3-dihydro-1H-4,9a-diaza-fluoren-9-one was isolated by trituration with ether. This compound (0.112 g, 0.5 mmol) was dissolved in ethanol containing excess hydrazine hydrate (3.0 mmol). This solution was stirred at RT for 20 h and 4-(3-amino-propylamino)-5-methyl-2H-phthalazin-1-one was isolated by flash chromatography (MeOH/DCM/Et3N).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[Cl:10][CH2:11][CH2:12]Cl.[OH-].[K+]>>[Cl:10][CH2:11][CH2:12][O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: COc1ccccc1O
Reactant: ClCCCl
Agent: [K+]
Agent: [OH-]
Product: COc1ccccc1OCCCl
Yield: 52.2 %

Procedure:
A mixture of 52.88 g (0.426 mol) of guaiacol (34), 50 ml (0.426 mol) of 1,2-dichloroethane, 88.3 g (0.639 mol) of potassium hydroxide and heated at reflux for 24 h. The mixture was concentrated and extracted into ethyl acetate and evaporate the solvent and purified by column chromatography to gave 41.47 g (52%) of 1-(2-Chloroethoxy)-2-methoxy benzene (35) as a white solid, mp 42-43° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[F:13]>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:13]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(N)cc1F
Yield: 93.8 %

Procedure:
A mixture of N-methyl-2-fluoro-4-nitrobenzamide (52a) (2.89 g, 14.6 mmol) and iron (5.04 g, 90 mmol) in ethyl acetate (40 ml) and acetic acid (40 ml) was refluxed for 1 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield N-methyl-2-fluoro-4-aminobenzamide (52b) (2.3 g, 13.7 mmol, 94%) as an off-white solid. 1H NMR (acetone-d6, 400 MHz) δ 2.86 (d, J=4.3 Hz, 3H), 5.50 (bs, 2H), 6.37 (dd, J1=14.7 Hz, J2=2.1 Hz, 1H), 6.50 (dd, J=8.5, 2.1 Hz, 1H), 7.06 (bs, 1H), 7.68 (dd, J=8.8 8.8 Hz, 1H); 13C NMR (acetone-d6, 100 MHz) δ 25.8, 99.6 (d, J=13.8 Hz), 109.2 (d, J=12.8 Hz), 110.0 (d, J=1.6 Hz), 132.5 (d, J=4.8 Hz), 153.5 (d, J=12.6 Hz), 162.2 (d, J=242.5 Hz), 164.0 (d, J=3.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]2=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a 25 mL screw-cap vial were added dichloromethane (CH2Cl2; 10 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (250 mg, 1.36 mmol), and triethylamine (Et3N, 300 mg, 3 mmol). To this mixture was added 4-chlorobenzenesulfonyl chloride (315 mg, 1.5 mmol), and the resulting mixture was shaken at room temperature for 3 h. The crude reaction mixture was partitioned between CH2Cl2 and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by reverse phase chromatography to yield the title compound as a white solid (321 mg, 66%): mp 207-210° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.08-8.02 (m, 3H), 7.53-7.47 (m, 2H), 3.23 (s, 3H), 3.21 (s, 3H); ESIMS m/z 360 ([M+H]+).
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:18])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.C(OC(=O)[NH:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)[CH3:27])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[ClH:1].[F:18][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:26]([NH2:25])[CH3:27])=[CH:29][CH:30]=1)[CH2:12][CH2:11]2
Reactant: FC1(F)CC1COc1ccc2c(c1)CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 800 mg (2.94 mmol) 6-(2,2-difluoro-cyclopropylmethoxy)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (example XXXII.2) and 806 mg (3.23 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 8 mL THF are added 504 μL (8.81 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C. and 934 mg (4.41 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μl water, the solvent is removed and and the residue is purified by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[Br:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cccc(Br)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cccc(Br)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-bromophenol: ESMS m/e: 552.7 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=1)=[O:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:33][CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:45])[F:46])[CH:38]=2)=[O:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmol; 57.92 g) in THF (400 mL), add NMM (3 equiv; 631.52 mmol; 69.66 mL). Cool to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmol; 30.26 mL) dropwise maintaining the temperature below −5° C. After 30 min at from −5 to 10° C., add 2-amino-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmol) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min and then 1 h at RT. Partition between water and EA; wash the organic layer with water then saturated NaCl aqueous (brine), dry over anhydrous MgSO4, filter and concentrate in vacuo. Suspend the crude in MTBE and stir for 2 h. Filter the solid and dry in vacuo to give the title compound (64.44 g; 70.79%). 1H NMR (300 MHz, DMSO): 8.37-8.26 (m, 3H), 7.74-7.68 (m, 1H), 4.61 (d, J=5.5 Hz, 2H), 3.91 (d, J=12.9 Hz, 2H), 2.75-2.64 (m, 2H), 2.46-2.37 (m, 1H), 1.69-1.60 (m, 2H), 1.39 (s, 12H).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[F-].[K+].O>CS(C)=O>[N:23]1([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=3)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=2[C:21]#[N:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCCNCC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2N2CCCCCC2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5—Chloro-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (70 mg, 0.2 mmol) and azepane (40 mg, 0.4 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (2 ml) and potassium fluoride (0.35 mg, 0.6 mmol) was added to the DMSO solution. The resulting mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (15 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product was isolated by chromatography on silica gel column. MS:395, r.t.: 2.6 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:46]([O:48][C:49]1[CH:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](O)=[O:52])[CH3:47]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:51](=[O:52])[C:50]3[CH:54]=[CH:55][CH:56]=[CH:57][C:49]=3[O:48][CH2:46][CH3:47])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1C(=O)O
Reactant: COc1ccc(-c2nc(CN)co2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1

Procedure:
A 3.5 g quantity of the [2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 was suspended in 70 ml of acetone. To the obtained suspension were added 2.3 g of 1-hydroxybenzotriazole, 3.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3.8 g of 2-ethoxybenzoic acid, and the mixture was heated and refluxed for one hour. The reaction mixture was cooled, and acetone was distilled off under reduced pressure. Water was added to the residue, and extraction was then performed with ethyl acetate. The organic layer was washed with water twice, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give 4.6 g of white powdery N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>C1COCC1>[O:19]=[C:17]1[O:10][C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:8][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)CCC(=O)NNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.4 mmol) of 3-(N′-phenyl-hydrazinocarbonyl)-propionic acid were dissolved in 10 ml of THF and 213 mg (0.7 mmol) of triphosgene were added. The reaction mixture was stirred at room temperature overnight. Then a saturated sodium hydrogencarbonate solution was added, and the mixture was evaporated to dryness under reduced pressure. The residue was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 315 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:27](=[O:28])[C:26]1[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 8.1 %

Procedure:
2,4-dinitroaniline (18.05 g), triethylamine (12.97 g) and benzene (750 ml) were placed in a reaction vessel and stirred under the nitrogen atmosphere. To the reaction mixture, 3,5-dinitrobenzoyl chloride (25.00 g) was added and refluxed under heating for 6 hours. The reaction mixture was filtered in hot state and the filtrate was cooled to deposit crystals of 2',3,4',5-tetranitrobenzanilide which was collected by filtration. The product of 2',3,4',5-tetranitrobenzanilide (3.00 g) thus obtained, platinum/carbon (5%) (0.18 g) and dioxane (85 ml) were placed in a pressurized vessel and allowed to react under the hydrogen pressure of 1 to 3 kg/cm2 at 80° C. for 10 hours. After cooling, the catalyst was removed by filtration and dioxane was distilled off under the reduced pressure to obtain powder of 2',3,4',5-tetraaminobenzanilide.