Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.CC(O)=[O:29].O.C([O-])(O)=O.[Na+]>Br.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:25]([NH2:26])=[O:29])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccc(F)cc2)ccc1=O
Reactant: CC(=O)O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccc(F)cc2)ccc1=O

Procedure:
A solution of 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (30 mg) in 28% hydrogen bromide solution of AcOH (2 ml) was stirred at 25° C. for 3 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHCl3 and MeOH. The fractions were concentrated in vacuo to obtain 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (30 g) as white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=2)[CH:5]=[CH:6][C:7]=1F.BrC1C=C(C(OCC)=O)OC=1C1C=CC=C([C:40]#[N:41])C=1>>[C:26]([C:21]1[CH:20]=[C:19]([C:10]2[CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:13][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:40]#[N:41])[CH:3]=2)[CH:24]=[C:23]([F:25])[CH:22]=1)#[N:27]
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(C#N)c2)o1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2ccc(F)c(Cl)c2)o1
Product: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(C#N)c2)o1

Procedure:
The synthesis of the title compound takes place in analogy to the synthesis of the compound from Example 15A starting with the compound from Example 8A. 190 mg (56% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11]([CH2:14][NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)([CH3:13])[O:10][C:9]2=[O:38])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[N:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54](Cl)=[O:55]>ClCCl>[C:35]([C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:25]2[O:24][C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][C:11]4([CH3:13])[O:10][C:9](=[O:38])[N:8]([C:5]5[N:6]=[CH:7][C:2]([NH:1][C:54]([C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][N:48]=6)=[O:55])=[CH:3][CH:4]=5)[CH2:12]4)=[O:37])=[CH:22][CH:21]=3)=[N:27][C:26]=2[CH:28]=1)#[N:36]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(N)cn5)C(=O)O4)cc3)oc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(NC(=O)c6ccccn6)cn5)C(=O)O4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-{[3-(5-aminopyridin-2-yl)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (10 mg, INTERMEDIATE 23) and diisopropylethylamine (7 μl) in 4 ml of dichloromethane was added picolinoyl chloride (3 mg). The mixture was stirred at room temperature for 1 h. The sample was purified directly via column chromatography on a Biotage Horizon 12M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound (4 mg, 34%). Mass spectrum (ESI) 616.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 9.01 (s, 1H), 8.69 (d, J=3.9 Hz, 1H), 8.47 (d, J=8.4 Hz, 2H), 8.33 (d, J=8.3 Hz, 2H), 8.31 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.92 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.41 (bs, 1H), 6.65 (bs, 1H), 4.94 (bs, 1H), 4.04 (d, J=10.3 Hz, 1H), 3.99 (dd, J=14.2, 6.6 Hz, 1H), 3.83 (dd, J=14.4, 6.4 Hz, 1H), 3.47 (sept, J=7.0 Hz, 1H), 1.67 (s, 3H), 1.46 (d, J=6.9 Hz, 6H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:22])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (840 mg, 1.8 mmol) produced in Synthesis Example 27 in DMF (7 mL) was added hydrazine monohydrate (purity of 80%, 285 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (770 mg, yield 92%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([N:11]2[CH2:38][CH2:37][CH2:36][C@H:12]2[C:13]([NH:15][C@H:16]([CH:34]=[O:35])[CH2:17][CH2:18][CH2:19][N:20](C(OCC2C=CC=CC=2)=O)[C:21](=[NH:23])[NH2:22])=[O:14])=[O:10])[CH:2]=1.[ClH:39]>[Pd].O1CCCC1>[ClH:39].[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([N:11]2[CH2:38][CH2:37][CH2:36][C@H:12]2[C:13]([NH:15][C@H:16]([CH:34]=[O:35])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])=[O:14])=[O:10])[CH:2]=1
Reactant: N=C(N)N(CCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)CCc1cccnc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Palladium on carbon (10%, 93 mg) was added to a well-stirred, nitrogen-blanketed mixture of N60 [N-(3-(3-pyridyl)propanoyl)-L-prolyl]-Nδ -benzyloxycarbonyl-L-arginine aldehyde (935.0 mg, 1.79 mmol) and 1N hydrochloric acid (0.90 mL) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for about 5 minutes before the nitrogen blanket was removed and replaced with hydrogen at one atmosphere. After about 5 hours, an additional equivalent of 1N hydrochloric acid (0.90 mL) was added and the mixture was suction-filtered through Celite and concentrated down to dryness to give 800.1 mg (97%) of the title compound as a dense, white solid, m.p. 126°-144° C. (sealed tube, decomposes between 190°-210° C.); 1H NMR (D2O) δ 8.69 (s, 1H), 8.65 (d, J=5.9 Hz, 1H), 8.53 (d, J=7.7 Hz, 1H), 8.01 (t, J=6.1 Hz, 1H), 4.38-4.34 (m, 1H), 4.11-3.81 (series of m, 1H), 3.63-3.51 (m, 3H), 3.18-3.14 (m, 2H), 2.95-2.80 (m, 2H), 2.27-2.21 (m, 2H), 2.00-1.50 (series of m, 5H); 13C NMR (D2O) ppm 176.75, 176.00, 175.23, 174.64, 156.55, 149.10, 143.54, 142.65, 140.87, 129.02, 124.66, 118.79, 95.08, 92.48, 79.24, 78.46, 62.78, 62.54, 62.30, 55.89, 51.43, 50.00, 49.34, 45.53, 42.79, 41.94, 35.72, 31.91, 31.81, 28.92, 27.56, 26.38, 25.98, 24.82, 24.62, 22.56; IR (KBr, cm-1) 3344-2876, 1654, 1554, 1448, 1248, 1000, 682. MS m/z (MH+ -2HCL) calcd 89.2301, obsd 389.2305.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:2][N:3]([CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNCCCCCl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCCCl)P(=O)(Cl)Cl
Temperature: -40 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
N-methyl-N-(4-chlorobutyl)amine hydrochloride (2.0 g, 12.73 mmol) was dissolved in 20 mL of anhydrous CH2Cl2 and cooled to −40° C. Phosphorous oxycloride (1.2 mL, 12.73 mmol) was added neat followed by the drop wise addition of triethyl amine (3.6 mL, 25.46 mmol) in 5 mL of CH2Cl2. Warmed reaction to 0° C. and slowly to room temperature. Allowed reaction to stir at room temperature for 6 hours. The reaction mixture was poured over ice, added saturated ammonium chloride and separated layers. Extracted water layer 3× with CH2Cl2, combined organic layers, dried over anhydrous sodium sulfate and concentrated under reduce pressure. Purified by silica gel flash chromatography (3:1 Hex/EtOAc) to yield a clear oil (2.57 g, 85%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:28][CH2:29][C:30](=[O:33])[CH2:31][CH2:32]4)=[CH:23][CH:22]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)benzenesulfonylchloride (J. Med. Chem. 1992, 35, 1853) and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4H), 3.10-3.60 (m, 2H), 3.44 (t, J=6.0 Hz, 4H), 4.95 (dd, J=12.3, 6.0 Hz, 1H), 6.80-7.00 (m, 4H), 7.27 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H), 9.77 (brs, 1H), 12.09 (brs, 1H); MS (ES) m/z: 459.9 (MH+); HRMS Calcd. for C21H21N3O5S2 M+): 459.0923. Found: 459.0930.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([NH:6][CH2:7][CH3:8])=[O:5])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: CCNC(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
Into a round bottom flask was added 2-amino-N-ethyl-3-fluoro-benzamide (2.00 g, 11.0 mmol) and N-methylpyrrolidinone (10 mL, 100 mmol). N,N-diisopropylethylamine (2.29 mL, 13.2 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.51 mL, 13.2 mmol) and the mixture was heated at 100° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in DCM (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-70% EtOAc/hex as the eluting solvent. The product was placed in hexane and stirred overnight. The mixture was filtered to obtain 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide as a yellow solid (1.79 g, 50%). m.p.=233-234° C.; LCMS (m/e) 329 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.22 (s, 1H), 7.40-7.22 (m, 3H), 6.20-6.10 (m, 1H), 3.53-3.42 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:20])[N:12]([CH2:14][CH:15](OC)[O:16]C)[CH3:13])[CH:6]=1)([CH3:4])[CH3:3].Cl>O>[CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:15]([OH:16])[CH2:14][N:12]([CH3:13])[C:11]2=[O:20])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: COC(CN(C)C(=O)Nc1cc(C(C)(C)C)on1)OC
Agent: Cl
Solvent: O
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Yield: 87.1 %

Procedure:
A round bottom flask was charged with 2.6 grams of the 3-[5-(1,1-dimethylethyl)-3-isoxazoly]-1-methyl-(2,2-dimethoxyethyl)urea (prepared above), 150 milliliters of water and 1.5 milliliters of concentrated hydrochloric acid (HCl). The resulting mixture was heated until one phase formed, and crystals coated out on the sides of the flask and cooled; and the scrapings of the crystals and the solution were filtered. The crystalline precipitate was washed twice with separate portions of H2O, and then air dried to yield 1.9 grams of white crystals of 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-1-methyl-4-hydroxy-2-imidazolidinone. M.P. 173°-177° C., IR spectra (mull.) bands at 3400, 3140, 1700, and 1590 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=c1cc(Cl)c(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(-c3ccccc3)c(Cl)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a mixture of 5-chloro-6-phenylpyridazin-3(2H)-one (207 mg, 1.0 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (415 mg, 3.0 mmol), and followed by addition of 1-(bromomethyl)-4-methoxybenzene (241 mg, 1.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. Water (25 mL) was added to the reaction mixture and stirred for 1 hour. The product was collected by filtration and dried overnight under reduce pressure to yield 278 mg (81%) of 5-chloro-2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one as a tan solid. MS (ESI) 327 (M+H).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:53]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH:69]N)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:55][C:56](=[O:58])[NH2:57]>>[NH:53]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH:69][C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:55][C:56](=[O:58])[NH2:57]
Reactant: COC(=O)[C@H](CCCCNC(=O)CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NN
Product: COC(=O)[C@H](CCCCNC(=O)CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Yield: 71.4 %

Procedure:
By using 3.60 g of Boc-Ser(Bzl)-Thr(Bzl)-Lys(CO-CH2CH2COOH)-OCH3 and 2.21 g of Boc-Asn-Leu-NHNH2, and the same procedure as in Reference Example 7 was repeated to obtain 3.37 g (yield: 71.4%) of the above-mentioned objective product.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24](O)=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH2:28].C1COCC1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1

Procedure:
2-[3-Cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)-phenyl]-N-methylacetamide (154 mg) is prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid (186 mg, 0.5 mmol) and 1 M solution of methylamine in THF (0.5 ml, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:10])[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]([F:26])([F:25])[F:24])[CH:20]([C:27](O)=[O:28])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.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>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:10][C:27]([CH:20]2[CH:21]([C:23]([F:25])([F:24])[F:26])[CH2:22][N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19]2)=[O:28])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1N
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1C(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: COC(=O)c1cncn1NC(=O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of compound 2 (2.0 g, 14.1 mmol), 1-Benzyl-4-trifluoromethyl-pyrrolidine-3-carboxylic acid (4.06 g, 14.9 mmol) and DIEA (10 mL, 42.5 mmol) in DMF (30 mL) was added HATU (8.1 g, 21.2 mmol). The resulting reaction mixture was stirred at r.t. overnight. The reaction was monitored by LC-MS. The reaction was quenched with water (100 mL) when it was complete. The aqueous solution was extracted with EtOAc (80 mL×3). The combined organic phase was washed with brine and concentrated to afford the crude product. The residue was purified by silica gel column (eluted with PE/EA=5:1 to 1:2) to afford compound 13 (4.8 g, 85.6% yield) as white oil. LC-MS: m/z 397 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.00 (br. s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.34˜7.28 (m, 5H), 3.81 (s, 3H), 3.78˜3.72 (m, 2H), 3.41˜3.38 (m, 1H), 3.30˜3.24 (m, 2H), 3.14˜3.12 (m, 1H), 2.71˜2.67 (m, 1H), 2.58˜2.53 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)[CH:25]=1)(=[O:23])=[O:22]>>[O:3]=[C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)[CH:25]=1)(=[O:23])=[O:22])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)[CH:25]=1)(=[O:23])=[O:22]
Reactant: O=C=NCCCCN=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 64.2 %

Procedure:
Compound 236 was prepared following the procedures outlined in Example 208 using 1,4-diisocyanatobutane (5.24 mg, 0.0374 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 168.2, 54.7 mg, 0.0749 mmol). Purification by preparative HPLC gave the title compound (27.5 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88-7.86 (d, 2H), 7.75 (s, 2H), 7.63 (t, 2H), 7.55-7.51 (m, 4H), 4.48 (m, 2H), 3.38-3.31 (m, 1H), 3.61-3.42 (m, 17H), 3.35-3.30 (m, 4H), 3.13 (s, 6H), 3.08-3.02 (m, 7H), 1.45 (m, 2H). MS (m/z): 1145.04 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11]Br>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: Nc1cc[nH]n1
Product: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 3,4,5-trifluorobenzyl bromide. The title compound was obtained as a brown oil (Yield=31%). MS ISP (m/e): 228.2 (100) [(M+H)+].
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[C:13]=2[C:24]=1[CH3:25])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:25][C:24]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:15][O:16][C:12]=2[C:11]([CH3:26])=[C:10]([CH3:27])[C:9]=1[NH2:8]
Reactant: Cc1ccc(C2COc3c(C)c(C)c(NCc4ccccc4)c(C)c32)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)nc1
Yield: 85 %

Procedure:
Using N-benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 278, the title compound was synthesized in the same manner as in Reference Example 30. Yield 85%. Melting point: 125-127° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](F)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:32]1[C:33](CC(C2SC=CC=2)=O)=[C:34]([CH:38]=[CH:39][C:40]=1F)[C:35](Cl)=[O:36]>>[CH2:15]1[C:26]2[C:27](=[CH:28][CH:29]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]6[CH:33]=[CH:32][CH:40]=[CH:39][CH:38]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:25]=2)[CH2:12][CH2:11][NH:10]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: O=C(Cc1c(C(=O)Cl)ccc(F)c1Br)c1cccs1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared in a manner analogous to Example 66, using 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 3-bromofluoro-2-thiophenecarbonylmethylbenzoyl chloride. HRMS: calc. C28H19N6OSFBr calcd for C31H22F2N6O: 532.1823, found: 533.1921 (M+H)+ 585.0508 found 585.0515+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: Nc1cccc2nccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Yield: 55.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, quinoxalin-5-ylamine (Intermediate 482) (540 mg, 3.7 mmol), 2-nitro-benzenesulfonyl chloride (986 mg, 4.46 mmol), pyridine (0.9 ml, 7.44 mmol) and DCM (10 ml) gave the title compound (679 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.Cl.[NH2:21][OH:22].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:22][N:21]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 81.3 %

Procedure:
α,β-Dibromo-4-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (8.3 g, 83%) as colorless crystals.