Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].[CH2:24]([C:52]([OH:54])=[O:53])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([C:49](O)=[O:50])([C:46]([OH:48])=[O:47])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45]>C(Cl)Cl.C1COCC1>[O:23]=[C:18]1[CH2:19][CH2:20][C:21](=[O:22])[N:17]1[O:16][C:49]([C:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:52]([OH:54])=[O:53])[C:46]([OH:48])=[O:47])=[O:50]
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 33.4 %

Procedure:
DCC (187 mg, 0.908 mmol) in DCM (2 mL) was added to a solution of N-hydroxysuccinimide (99 mg, 0.862 mmol) and docos-21-ene-1,11,11-tricarboxylic acid (Intermediate 45: 400 mg, 0.908 mmol) in DCM (7 mL) and THF (0.7 mL). The reaction was stirred overnight before the solvent was evaporated. The residue was purified by HPLC (Sunfire C18 30×50 mm; 55-80% ACN/water+0.1% TFA) to yield the title compound (155 mg, 0.288 mmol, 32%): by LCMS Method E Rt=1.51 min, M+H 538.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.46 (m, 28H) 1.60-1.87 (m, 3H) 1.91-2.17 (m, 5H) 2.38 (t, J=7.03 Hz, 2H) 2.86 (br. s., 4H) 3.68 (dd, J=11.25, 7.34 Hz, 1H) 3.78 (dd, J=11.31, 5.20 Hz, 1H) 3.99-4.10 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C1C[O:13][CH2:12][CH2:11]1>>[CH2:2]1[CH:12]([OH:13])[CH2:11][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:1]1
Reactant: CC(=O)c1ccccc1
Reactant: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR12## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybornane [J. Chem. Soc. 49, 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and was stirred for 16 hours. Acetophenone (2.36 g, 24.6 mmol) as a solution in THF (10 mL) was added to the preceding solution over one hour, stirred for fifteen minutes after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hours, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) phenethyl alcohol. 2.17 g (92% yield) 88% ee.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH:19]1[C:24]([NH2:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH:19]3[C:24]([NH2:26])=[O:25])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CSCCN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)C1CSCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 3-thiomorpholinecarboxamide (CAN 103742-31-0, 68.9 mg, 472 μmol) as starting materials and isolated (119 mg, 77%) as white solid; LC-MS (UV peak area, ESI) 100%, 362.1540 [MH+].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:22][CH2:21][C:16]3([NH:20][CH2:19][CH2:18][CH2:17]3)[CH2:15]2)[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25](=O)(O)[O-].[Na+]>C(O)=O>[CH3:25][N:20]1[C:16]2([CH2:21][CH2:22][N:14]([C:10]3[CH:11]=[N:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:15]2)[CH2:17][CH2:18][CH2:19]1
Reactant: O=C([O-])O
Reactant: c1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCCC12CCN(c1cncc(Oc3ccccc3)c1)C2
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a stirring solution of 7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (420 mg, 1.42 mmol) in 37% aqueous solution of formaldehyde (5 mL) was added 98% formic acid (3 mL) under nitrogen. The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, then basified with saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford a thick brown viscous liquid. This was distilled using a Kugelrohr apparatus (2 mm, 180° C.) to give a very pale cream-colored syrup (400 mg, 90.9%).
Reaction SMILES: [H-].[Na+].[C:3]12[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8][C:7](=[O:14])[O:6][C:4]2=[O:5].I[CH2:16][CH3:17]>CN(C)C=O>[CH2:16]([N:8]1[C:7](=[O:14])[O:6][C:4](=[O:5])[C:3]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:9]12)[CH3:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Sodium hydride (28 g of a 55% oil dispersion) was added in portions to a stirred, cooled (4° C.) solution of isatoic anhydride (100 g) and iodoethane (104 g) in anhydrous dimethylformamide (600 ml). The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (1 l) and water (500 ml). The organic layer was separated, washed with brine (2×100 ml), dried (sodium sulphate) then evaporated to give a semi-solid which was triturated with diethyl ether to afford N-ethyl isatoic anhydride as a tan powder (70 g). N-Ethyl isatoic anhydride (64 g), glycine (27 g) and glacial acetic acid (500 ml) were heated at reflux for 4 hours. The solvent was evaporated and the residue was partitioned between dichloromethane (1.5 l) and saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with 1M sodium hydroxide (200 ml), dried (magnesium sulphate), evaporated then the residue triturated with diethyl ether to afford the title compound as a beige solid (53 g). mp 169°-170° C. (ethyl acetate). Rf 0.50 in dichloromethane/methanol (9:1) on silica plates. 1H NMR (360 MHz, CDCl3) δ1.21 (3H, t, J=7 Hz), 3.73-3.83 (3H, m), 4.13-4.22 (1H, m), 6.97 (1H, broad s), 7.26-7.36 (2H, m), 7.56 (1H, ddd, J1 =2 Hz, J2 =J3 =8 Hz), 7.89 (1H, dd, J1 =2 Hz, J2 =8 Hz). Found: C, 64.25; H, 5.92; N, 13.67. C11H12N2O2 requires C, 64.69; H, 5.92; N, 13.72%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[N:5]=[C:4]([O:10][CH2:11][C:12](OC)=[O:13])[C:3]=1[Cl:16].[CH3:17][CH:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[N:5]=[C:4]([O:10][CH2:11][C:12]([O:25][CH:18]([CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:13])[C:3]=1[Cl:16]
Reactant: CCCCCCC(C)O
Reactant: COC(=O)COc1nc(F)c(Cl)c(N)c1Cl
Product: CCCCCCC(C)OC(=O)COc1nc(F)c(Cl)c(N)c1Cl
Temperature: 130 °C

Procedure:
Methyl (4-amino-3,5-dichloro-6-fluoro-2--pyridinyloxy)acetate (1375 g of 98.0 percent assay, 5.02 moles) was combined with 1901 g (14.6 moles of 1-methylheptanol (2-octanol) in a 5 liter flask equipped with a stirrer, a 30 centimeter (cm) Vigreaux column and distillation head, and a thermometer. The solution was heated to about 130° C. at 10 kiloPascals (kPa) pressure to remove any water present in the system. A 1.3 g portion of tetrabutyl titanate catalyst was added and the mixture was heated at about 150° C. under 60 kPa pressure for 6 hours, distilling out the nethanol as it formed. The pressure was slowly reduced to about 3.3 kPa and the excess 1-methylheptanol was removed by distillation along with any other volatiles. The residue, which amounted to 1857 g, was the title compound. It was found to be 97.4 percent pure and to contain 0.2 percent unreacted methyl ester and 0.1 percent 1-methylheptanol. The yield was, accordingly, 98 7 percent of theory.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:36])=[N:33][CH:34]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[N:33][CH:34]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1

Procedure:
Neat TFA (0.04 mL, 0.55 mmol) was added to a DCM solution (1 mL) of tert-butyl 3-(5-(2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (34 mg, 0.06 mmol). After 16 h the resulting mixture was concentrated in vacuo, dissolved in DCM and 1N HCl in ether was added. The resulting solution was concentrated in vacuo and the DCM/HCl process was repeated 2×. The resulting solid was characterized as the corresponding HCl salt of the title compound.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 4-methylphenol:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To the solution of 4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-pyridin-2-ylamine (83 mg, 0.33 mmol) in DCM (3.0 mL) is added benzoyl isocynate (96 mg, 0.65 mmol). The resulting mixture is heated at 50° C. for 1 hour. The solvent is then carefully removed in vacuum and to the residue are added K2CO3 (54 mg, 0.39 mmol) and ethanol (2 mL). The reaction mixture is then heated at 85° C. for 30 min. Solvent is again removed in vacuum and the residue is purified through a Silica column eluting with 0-100% EtOAc/Heptane to give the titled compound (72 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH:15]=O)[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](/[CH:8]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN(C)/C=C/c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-bromo-2-methyl-3-nitropyridine (3.0 g, 13.8 mmol) and N—N-dimethylformamide-dimethylacetal (DMF-DMA) in 45 ml of DMF was heated at 90° C. for 4 hours, and cooled to room temperature. The solvent was evaporated and the residue dissolved in dichloromethane (DCM), which was washed with saturated NaHCO3 and brine, and chromatographed (EtOAc/Hexanes 1:10) to give a red solid, 2.86 g, in 76% yield.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]5)=[CH:36][CH:37]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:14]1=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c2)c2ccccc21
Reaction time: 2 h
Yield: 11 %

Procedure:
The title compound was synthesized according to the method of Example A45, except substituting (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (35 mg, 0.084 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (42 mg, 0.109 mmol). The solvent was removed and the Boc-protected amine purified by column chromatography (silica gel, CH2Cl2/MeOH, 95:5) to give an impure product which dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. The reaction was stirred for 2 h, the solvent removed and the residue purified by prep-HPLC to give the title compound as a white powder (4.0 mg, 11%); 1H NMR (400 MHz, CD3OD) δ 7.88-7.85 (m, 3H), 7.46 (s, 1H), 7.18-7.12 (m, 3H), 7.03-6.97 (m, 2H), 6.65 (t, J=7.7 Hz, 1H), 6.04 (d, J=7.5 Hz, 1H), 3.51-3.48 (m, 4H), 3.42-3.39 (m, 4H), 3.35 (s, 3H), 2.29-2.25 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 450.2, calcd for [C28H27N5O+H]+ 450.23.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([F:37])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][CH:14]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]([P:74](=[O:85])([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])([F:73])[F:72])=[CH:67][CH:66]=1>C1COCC1>[C:1]([O:5][C:6](=[O:38])[C:7]([F:36])([F:37])[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([C:71]([P:74]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])([O:75][C:76]([CH3:77])([CH3:79])[CH3:78])=[O:85])([F:72])[F:73])=[CH:67][CH:66]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a solution of methyl 4-[1-{4-[2-(tert-butoxy)-1,1-difluoro-2-oxoethoxy]benzyl}-2-(4-fluorophenyl)-2-oxoethyl]benzoate (0.176 g, 0.333 mmol)) in degassed THF (1.7 ml), were added at −20° C. 18-crown-6 (0.15 g) and potassium tert-butoxide 1 M in THE (0.379 ml ). Di(tert-butyl) [4-(bromomethyl)phenyl](difluoro)methylphosphonate (0.156 g, 0.378 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated ammonium acetate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 20% giving 0.140 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](C(N2C(CC3CCCCC3)C(=O)N3CC4C=CC=CC=4CC3C2=O)C(NCCC2C=CC(F)=CC=2)=O)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:46]>>[C:1]([NH2:2])(=[O:46])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(C(=O)NCCc2ccc(F)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Product: NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
This compound was prepared by stirring 2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide (305 mg, 0.51 mmol) in 10 ml of concentrated sulfuric acid. After 1 hour the solution was poured into 40 g of ice. The ice melted and the white solid was filtered, dried, and the crude product was purified by flash chromatography (1:20 methanol/dichloromethane; Rf =0.25) to give 60 mg (20%) of 4-{(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-[2-4-fluoro-phenyl)-ethylcarbamoyl]-methyl}-benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[NH:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH:11][CH3:12])=[C:2]([Cl:1])[C:3]=1[F:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1c([N+](=O)[O-])cc(C(=O)OC)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 5.30 g (21.32 mmol) of 3-chloro-2-fluoro-4-methylamino-5-nitro-benzoic acid in 53 mL of THF and 13.75 ml of MeOH is cooled to a temperature of 0° C. Then, 13.86 ml (27.72 mmol) of trimethylsilyl-diazomethane (2 M in diethylether) were added portion wise at a temperature of 0° C. The mixture is stirred 30 min at a temperature of 0° C. and 30 min at ambient temperature. The reaction mixture is evaporated with acetic acid in the trap. The yellow residue is titurated in diethyl ether and after decantation, 4.3 g (16.37 mmol, 77%) of a yellow solid is isolated. The Et2O phase is evaporated and 1.5 g of impure product is recovered. The crude product is used directly in the next step without purification. 1H-NMR (CDCl3, 300 MHz): ? ppm=3.30 (d, 3H), 3.95 (s, 3H), 7.80 (s br, 1H), 8.70 (d, 1H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[NH:19][CH3:20])=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[N:19]([CH3:20])[C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1NC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 150 °C
Yield: 89.9 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(2-methylamino-5-trifluoromethylphenyl)-benzamide (1.64 g), p-toluenesulfonic acid monohydrate (1.76 g), and xylene (50 ml) was stirred under reflux at 150° C. for 1 hour. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.40 g of 2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 68).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9][CH2:10][C:11]#[N:12])=[N:5][C:4]2[CH2:13][CH2:14][O:15][CH2:16][C:3]1=2.[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[C:11]([CH2:10][N:9]([CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH2:16][O:15][CH2:14][CH2:13][C:4]=2[N:5]=1)[C:31](=[O:32])[CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:35][CH:34]=2)[CH2:25][CH2:26]1)#[N:12]
Reactant: N#CCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: N#CCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (5.4 mg) from [(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-amino]-acetonitrile and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C24H26FN5O4 467.5. found 468.5 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (br. s., 1H) 9.80 (br. s., 1H) 7.96-8.19 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.58 (s, 2H) 4.50 (s, 2H) 4.26-4.46 (m, 4H) 3.80-3.92 (m, 3H) 3.61-3.75 (m, 1H) 3.52 (br. s., 2H) 3.17 (br. s., 1H) 3.09 (br. s., 1H) 2.00 (br. s., 4H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].Br[CH2:30][C:31](OC)=[O:32]>CN(C)C=O>[O:32]=[C:31]1[CH2:30][S:28][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26][NH:27]1
Reactant: COC(=O)CBr
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NNC(=O)CS1)OCO3
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
A mixture of 1.00 g (2.50 mmol) of the starting material XVIII, 20 ml of dimethylformamide and 0.94 g (6.14 mmol) of methyl bromoacetate was stirred at 70° C. for 1.5 h. After dilution with water the precipitated crystals were filtered off and purified by refluxing in ethyl acetate to yield 0.41 g (37%) of the title compound; Mp.: 294-295° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]([O-])(=O)=O.[K+]>S(=O)(=O)(O)O.O>[Br:14][C:5]1[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 2-methyl-1,3-dinitro-benzene (10 g) and 1:1 concentrated sulfuric acid-water (100 mL) at 80° C. was added potassium bromate (10.1 g) portionwise over 2-21/2 hr. The mixture was stirred at 80° C. for an additional 2 hr and cooled to room temperature. The mixture was poured into 500 g ice and then extracted with diethyl ether (300 mL). The ether layer was washed with 10% sodium bicarbonate solution (250 mL), brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (4:96) to afford 5-bromo-2-methyl-1,3-dinitro-benzene (5.3 g).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(Br)C(=O)NOCc1ccccc1
Yield: 87 %

Procedure:
Prepared in 87% yield (3.53 g, 11.3 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (3.0 g, 13 mmol) with O-benzylhydroxylamine hydrochloride (2.13 g, 13 mmol) via general procedure A. Rf=0.58 (3:1, hexanes:EtOAc); mp=88.6-91.1° C.; 1H-NMR (500 MHz, CDCl3): δ 9.05 (br s, 1H), 7.45-7.34 (m, 5H), 4.94 (s, 2H), and 1.93 (s, 6H); 13C-NMR (126 MHz, CDCl3): δ 169.7, 134.9, 129.6, 129.1, 128.8, 78.4, 59.5, and 32.6; FT-IR (neat) 3195 (br), 3034, 2954, 2890, 1652 (s), 1505, 1469, 1454, 1112, 1032, 1004 cm-1. HRESI-MS: calcd □ for C11H18BrN2O2 (M+NH4)+ 289.0546, observed 289.0543.