Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:25][NH:26][C:27]([NH2:29])=[O:28].C[O-].[Mg+2].C[O-].CO>C(OCC)(=O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[CH:12]=2)[C:3]([NH:29][C:27]([NH:26][CH3:25])=[O:28])=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid methyl ester (500 mg, 1.37 mmol) and methyl urea (305 mg, 4.12 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 5.9 mL, 4.12 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., diluted with ethyl acetate (10 mL), and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl-urea (253 mg, 45%) as a white foam: mp 59-62° C. (foam to gel); EI-HRMS m/e calcd for C17H21F3N2O4S (M+) 406.1174, found 406.1178.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]3[NH:23][CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]3[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cnc2[nH]ccc2c1NC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C=O)cnc21
Reaction time: 0.5 h
Yield: 42 %

Procedure:
4-[(1-Benzylpiperidin-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (672 mg, 2.01 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 436 mg, 10.0 mmol) under cooling with ice, and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred with [2-(chloromethoxyl)ethyl]trimethylsilane (885 μL, 5.00 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (392 mg, yield 42%).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:30]2[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2c(F)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 100 °C
Yield: 14.5 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 27] (0.080 g, 0.219 mmol), 8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (0.094 g, 0.230 mmol), PdCl2(dppf) DCM adduct (9.0 mg, 11.0 μmol) and Cs2CO3 (0.143 g, 0.438 mmol) in dioxane (8.0 mL) and water (2.0 mL) was heated at 100° C. overnight. The cooled mixture was diluted with EtOAc and filtered. The filtrate was washed with water, dried and concentrated. The residue was purified by reverse-phase preparative HPLC, followed by purification by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 50%-100%), to give 3-fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H) -yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as an off-white solid (0.018 g, 15% yield). Mass spectrum m/z 551 (M+H—H2O)+. 1H NMR (500 MHz, MeOH-d4) δ 7.66 (d, J=10.4 Hz, 1H), 7.51 (s, 1H), 7.47-7.34 (m, 3H), 7.29 (t, J=7.2 Hz, 2H), 7.22-7.11 (m, 1H), 7.09-6.97 (m, 1H), 6.90 (t, J=8.1 Hz, 1H), 3.81-3.63 (m, 3H), 2.06 (br. s., 3H), and 1.77-1.58 (m, 6H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:22]([Cl:25])=[N:23][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:18][C:19]3[CH:20]=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:22]([Cl:25])=[N:23][CH:24]=3)=[N:3][CH:4]=[C:5]([O:16][CH3:17])[CH:6]=2)[N:9]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cnc(Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Reaction time: 0.67 h
Yield: 14.3 %

Procedure:
To a 5 mL microwave vial, 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0550 g, 0.234 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Step 2, 0.0579 g, 0.261 mmol) were dissolved into DMF (1 mL). NaHMDS (Aldrich, 1 M in THF, 0.935 mL, 0.935 mmol) was added slowly at 0° C. and the dark red mixture was stirred at that temperature for 40 min. The mixture was poured into sat'd NH4Cl (20 mL) and stirred for 5 min. The resulting solid was collected via filtration, washed with water and purified by preparative HPLC using a Phenomenex Gemni 5 micron C18 100×30 mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fractions were combined and concentrated. The residue was taken into sat'd NaHCO3. The aqueous pH was adjusted to pH 4-5 and the resulting solid was collected to give N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)methanesulfonamide (0.0146 g, 14% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (br. s., 1H) 9.62 (br. s., 1H) 8.61 (d, J=14.08 Hz, 2H) 8.41 (br. s., 1H) 8.20 (br. s., 1H) 7.68-8.09 (m, 2H) 3.86 (br. s., 3H) 3.13 (br. s., 3H) 2.45 (br. s., 3H). m/z (ESI, positive ion) m/z: 436.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:11][C:12]([CH2:33][CH3:34])=[C:13]([CH:32]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:29][CH2:30][CH3:31])=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24]C)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CN1CCCC1=O.O.COC(C)(C)C>[CH2:1]([O:8][C:9]1[C:10]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:11][C:12]([CH2:33][CH3:34])=[C:13]([CH:32]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:29][CH2:30][CH3:31])=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)O
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-benzoate (119 g, 181 mmol) in N-methylpyrrolidone (476 mL), add potassium hydroxide (21.2 g, 378 mmol) and stir 25 min at 120° C. Allow the mixture to cool and then dilute with water (240 mL) and methyl-tert-butylether (100 mL). Adjust to pH=2.5 with 12 N hydrochloric acid. Separate the phases and wash the aqueous phase with methyl-tert-butylether (3×35 mL). Wash the combined organic extracts twice with water and once with brine. Concentrate the organic extracts in vacuo. Recrystallize the resultant residue from acetonitrile, filter, and dry to yield (78 g, 67%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.60-7.47 (m, 3H); 7.37-7.20 (m, 6H); 7.12-7.02 (m, 4H); 6.60 (s, 1 H); 5.00 (s, 2H); 4.20 (m, 4H); 3.00 (m, 2H); 2.61 (q, J=7.7 Hz, 2H); 2.33 (m, 2H); 1.59 (m, 2H); 1.18 (t, J=7.7 Hz, 3H); 0.98 (t, J=7.7 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1
Reactant: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COc1cc(=O)n(Cc2nc3cc(CN)ccc3n2CCCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a cooled (0° C.) suspension of [1-(4-hydroxy-butyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (74 mg, 0.15 mmol) in DCM (3 mL) was added TFA (337 μL, 4.38 mmol). The solution was allowed to stir for 6 h at room temperature, followed by the removal of the volatiles in vacuo. The resulting trifluoroacetate was dissolved in methanol (3 mL) followed by the addition of acetyl cloride (104 μL, 1.46 mmol). After 10 minutes the solution was concentrated. This procedure was repeated allowing the reaction to run for 3 hrs. The solution was concentrated in vacuo and the residue stripped with methanol (twice) to yield 1-[5-Aminomethyl-1-(4-hydroxy-butyl)-1H-benzoimidazol-2-ylmethyl]-4-methoxy-1H-quinolin-2-one; HCl salt (65 mg, 100%) as an off white solid:
Reaction SMILES: [Cl-].C([N+]1C=CC(C(=O)NCC(C2C=CC=CC=2)COCC2C=CC(C(F)(F)F)=C(C(F)(F)F)C=2)=CC=1)C1C=CC=CC=1.[OH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1.Cl.[F:54][C:55]([F:79])([F:78])[C:56]1[CH:57]=[C:58]([CH:71]=[C:72]([C:74]([F:77])([F:76])[F:75])[CH:73]=1)[CH2:59][O:60][CH2:61][CH:62]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:63][NH2:64].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:54][C:55]([F:78])([F:79])[C:56]1[CH:57]=[C:58]([CH:71]=[C:72]([C:74]([F:75])([F:77])[F:76])[CH:73]=1)[CH2:59][O:60][CH2:61][CH:62]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:63][NH:64][C:48](=[O:50])[C:47]1[CH:46]=[CH:45][C:44]([OH:43])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1)c1cc[n+](Cc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)c1ccc(O)cc1
Yield: 61.3 %

Procedure:
In the same manner as in the case of synthesis of Compound 30, a residue was given from 4-hydroxybenzoic acid (0.33 g, 2.4 mmol), the compound produced in Example 17 (0.83 g, 2.0 mmol), triethylamine (0.28 mL, 2.0 mmol), WSC.HCl (0.46 g, 2.4 mmol) and CH2Cl2 (10 mL). The oily residue was crystallized from petroleum ether to give the Compound 56 (0.61 g, 61%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:16][CH:17]=1)[CH2:19][CH2:20][Cl:21]
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)Oc1ccc(N(CCCl)CCCl)cc1
Yield: 83 %

Procedure:
To a suspension of succinic anhydride (225 mg, 2.25 mmol) in CHCl3 (10 ml) was added under stirring, 4-[N,N-bis(2-chloroethyl)-amino]phenol (compound 6, FIG. 7; 203 mg, 0.75 mmol) followed by triethylamine (75 mg, 0.75 mmol). The mixture was stirred overnight and the solvent evaporated. The crude residue was dissolved in EtOAC/Et2O/H2O and under stirring the pH was adjusted to 3. The organic layer was washed with water, brine, dried (MgSO4), and evaporated. The resulting oil was crystallised from Et2O/hexane and the white solid was filtered off and dried under vacuum to obtain the desired end product (210 mg; yield 83%). Melting point 98-100° C.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:11])[CH:6]([N:8]=[N+]=[N-])[CH3:7])([CH3:3])[CH3:2]>[Ni].C(O)(C)C>[CH:1]([NH:4][C:5](=[O:11])[C@@H:6]([CH3:7])[NH2:8])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)C(C)N=[N+]=[N-]
Agent: [Ni]
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@@H](C)N

Procedure:
A 14.3 g sample of (R)-ethyl-2-azidopropionate was taken up in 50 mL of isopropylamine and allowed to stand for 24 hours. After stripping excess amine, 14.8 g of pure N-isopropyl-2-azidopropionamide was obtained. The amide thus obtained, 3.12 g, was stirred with 5.0 g of Raney nickel catalyst in 40 mL of isopropanol until nitrogen evolution ceased. The solution was filtered and concentrated in vacuo at 40° C. to give 2.5 g of crude N-isopropyl-D-alanine amide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[C:21](=[O:33])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[C:21](=[O:33])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (Aldrich, 704 mg, 4.0 mmol) in dichloromethane (20 mL), was added oxalyl chloride (Aldrich, 0.70 mL, 8.0 mmol) dropwise, followed by two drops of DMF. The reaction mixture was stirred at room temperature for 2 h, and concentrated in vacuo. Toluene (20 mL) was added and the reaction mixture was evaporated in vacuo to remove the excess oxalyl chloride. The residue was dissolved in dichloromethane (20 mL). Half of this acid chloride solution was added to a mixture of 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (306 mg, 1.5 mmol) in dichloromethane (5 mL) and TEA (0.5 mL, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The precipitate that formed was collected by filtration, and washed with methanol, to afford the desired product (363 mg, 67% yield) as a solid. MS(ESI+) m/z 363.25 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[CH:46][CH:47]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 66 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35].C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2c(C)nc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1
Temperature: 100 °C

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoacetate [Aldrich] (2 ml) then heated to 100° C. for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with aq. ammonia-methanol-dichloromethane) to obtain the title compound as a white solid;
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[Cl:10][C:4]1[CH:3]=[C:2]([NH2:1])[CH:9]=[CH:8][C:5]=1[C:6]1[NH:13][N:12]=[N:11][N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2nnn[nH]2)c(Cl)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-amino-2-chloro-benzonitrile (Aldrich, 765 mg, 5 mmol) in toluene (10 mL), sodium azide (423 mg, 6.5 mmol) and triethylamine hydrochloride (895 mg, 6.5 mmol) was added and the mixture was stirred vigorously at 115° C. overnight. The mixture was cooled and poured into water. The aqueous layer was adjusted to PH=5 by the addition of 6 N HCl and the solid formed was filtered and dried. 175 mg,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[S:16][C:17]=3Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[S:16][C:17]=3[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Br)cn2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3N3CCCCC3)cn2)cc1
Yield: 26.9 %

Procedure:
According to Scheme 5 Step 2: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-bromothiazol-2-yl)pyridin-2-amine (2.16 mmol, 1.00 g), piperidine (8.64 mmol, 0.89 mL) and Et3N (12.9 mmol, 1.81 mL) in DMF (10 mL) was microwaved for 30 minutes at 150° C. The reaction mixture was diluted with AcOEt and water. The aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(piperidin-1-yl)thiazol-2-yl)pyridin-2-amine (0.58 mmol, 263 mg, 26%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[OH:20][NH:19][CH2:11][CH2:10][O:9][CH:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)[CH2:6][CH:7]=[CH2:8]
Reactant: NO
Reactant: C=CCC(OCC=O)C1(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCC(OCCNO)C1(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
{[1-(1-Methylcyclopropyl)but-3-en-1-yl]oxy}acetaldehyde (C54) (27.7 g from the previous step, ≦165 mmol) was dissolved in a 2:1 mixture of ethanol and water (39 mL). Sodium acetate (63.1 g, 770 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 32.1 g, 462 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (2×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 12% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 4.1 g, 22.4 mmol, 48% over two steps. 1H NMR (400 MHz, CDCl3) δ [7.49 (t, J=5.6 Hz) and 6.91 (t, J=3.6 Hz), total 1H], 5.82-5.92 (m, 1H), 5.00-5.10 (m, 2H), {[4.52 (dd, half of ABX pattern, J=16.4, 3.2 Hz) and 4.35 (dd, half of ABX pattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=13.2, 5.6 Hz) and 4.09 (dd, half of ABX pattern, J=12.8, 6.0 Hz)], total 2H}, 2.59-2.64 (m, 1H), 2.25-2.45 (m, 2H), 1.02 (s, 3H), 0.42-0.56 (m, 2H), 0.18-0.29 (m, 2H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:14]=2[C:13]([F:12])([F:27])[F:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, yellow solid, MS: m/e=395.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,4-bis(trifluoromethyl)benzoic acid.