Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[O:26][CH:25]=[N:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[O:26][CH:25]=[N:24][CH:23]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1(c2cnco2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnco2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.200 mmol) was dissolved in 1 ml DMF. Sodium hydride (24 mg, 0.600 mmol) was added at 0° C. and the reaction mixture was stirred at RT for 10 min. 5-(2-methyloxiran-2-yl)oxazole (35 mg, 0.280 mmol) in DMF (1 mL) was added dropwise over 10 min. and the reaction mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. Ice cold water was added to the reaction mixture and then extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (4×10 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain the 20 mg of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(oxazol-5-yl)propan-2-ol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.09 (s, 1H), 7.18 (s, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 6.8 (s, 1H), 4.7 (m, 1H), 4.35 (m, 3H), 3.9 (m, 1H), 3.56 (m, 1H), 3.25 (m, 2H), 3.09 (s, 3H), 2.37 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provides enantiomers II-142a-b.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([CH3:50])[C:43]([Br:51])=[C:42]1[C:52](O)=[O:53])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:55]([NH2:60])[C:56]([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.CCOC(C)=O.O>[CH2:34]([N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([CH3:50])[C:43]([Br:51])=[C:42]1[C:52]([NH:60][CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1c(Br)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)CN
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)c(C(=O)NCC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
HATU (12.6 g, 33.24 mmol) and DIPEA (12.4 ml, 69.25 mmol) were added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (10 g, 27.77) in DMF (110 mL) and it was stirred for 10 min at same temperature and then neopentyl amine (3.92 ml, 33.24 mmol) was added to the reaction mixture warmed to RT and then stirred for 15 h. Reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 91.9% yield, white color solid) which directly used without further purification. Methyl iodide (3.17 mL, 51.04 mmol) was added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 25.52 mmol), (100%) NaH (1.2 g, 51.04 mmol) in THF (100 mL) and stirred for 2 h at RT. The reaction mass was poured onto crushed ice, extracted with EtOAc (2×200 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 10% ethyl acetate/hexane Rf-value 0.6) to afford title compound (10 g, 88.05% yield, white solid).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:20])/[C:15](OCC)=[O:16])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CO.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[O:1]([CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:20])/[CH2:15][OH:16])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)/C(C)=C/CCCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: C/C(=C\CCCCO[Si](C)(C)C(C)(C)C)CO
Reaction time: 1 h
Yield: 100 %

Procedure:
To a methylene chloride solution (200 ml) of Ester 4 (15.84 g; 0.0528 mol), a 0.95 M diisobutylaluminiumhydride-hexane solution (139 ml; 0.132 mol) is added at 0° C. and the whole is stirred for 1 hour. After stirring, methanol (7 ml; 0.160 mol) and sodium sulfate decahydrate (68.0 g; 0.211 mol) are added thereto and the whole is stirred at room temperature for 30 min. Sodiumsulfatedecahydrate is filtered using Chloroform (21), and the solvent is distilled off under reduced pressure to produce Alcohol 5 (13.60 g; 0.0528 mol) of 100% in yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[CH3:27])[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][C@H:15]1[CH3:27])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate (31.0 mg, 0.075 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=555.5 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH3:26])[C:14]1([CH2:24][OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH3:12][N:13]([CH3:26])[C:14]1([CH2:24][OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:9])[CH2:16][CH2:15]1
Reactant: CN(C)C1(CO)CCSc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)C1(CO)CCS(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
248 mg of 70% m-chloroperbenzoic acid was added to a 20 ml of methylene chloride solution containing 222 mg of 4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran dissolved therein, and stirred at room temperature for 30 minutes. The reaction solution was washed with 5% aqueous sodium thiosulfate solution, saturated sodium bicarbonate solution and brine in this order, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crystals were recrystallized from a solvent mixture of ethyl acetate and isopropyl ether. 53 mg of the title compound was obtained as colorless crystals. ##STR33## Melting point: 132°-133° C. IR(KBr)cm-1 : 3245, 1070, 1000
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:42](=[O:44])[CH3:43])[CH2:19][CH2:20]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1
Reactant: CC(=O)Cl
Reactant: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc(CN3CCN(C(C)=O)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution containing 1 equivalent of (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime (Example 48) in dry DCM at 0° C. were added 1.5 equivalent of triethyl amine and 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phase was dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography to give the expected product, (3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers, in 70% yield (94.4% purity by HPLC). The pure Z-isomer could be separated by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent, and was obtained in 40% yield (98.0% purity by HPLC).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.O>O1CCOCC1.Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:40])[CH3:39]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1cccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a deoxygenated solution of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E66 (200 mg, 0.39 mmol) in anhydrous 1,4-dioxane (10 ml) was added tributyl(1-ethoxyvinyl)tin (155 mg, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The resultant mixture was refluxed under argon for 20 h. Further tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) was added and refluxing continued for a further 24 h. On cooling, water (15 ml) and 5N hydrochloric acid (10 drops) were added and the mixture stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel,
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4](Br)[N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)CCC.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]2[CH:23]=[N:24][CH:25]=[CH:26][N:27]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnccn3)nc(-c3cnccn3)c2s1
Temperature: 95 °C
Yield: 6.6 %

Procedure:
To a solution of 1-(4,6-dibromo-thiazolo[5,4-c]pyridin-2-yl)-3-ethyl-urea (0.06 g, 0.16 mmol) in DMF (3 mL) was added 2-(tributylstannyl)pyrazine (0.10 mL, 0.32 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen for 10-15 min followed by addition of Pd(PPh3)4 (0.018 g, 0.015 mmol). The resulting solution was again degassed for 15-20 min followed by heating up to 95° C. overnight. After completion of reaction (TLC monitoring), the reaction mixture was cooled, added water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organics was dried over Na2SO4 and evaporated to dryness under high vacuum. The crude residue was purified over silica-gel (100-200 M, 2% MeOH-DCM) to get the desired product (0.004 g, 7%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[ClH:18].Cl.[O:20]=[C:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:22]1.C(N(CC)CC)C>C(O)CC(C)C>[ClH:1].[ClH:18].[NH2:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:23]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21](=[O:20])[CH:22]=3)[CH2:30][CH2:31]2)[N:11]=1
Reactant: CC1(C)CC(=O)C=C(N2CCCNCC2)C1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Solvent: O
Product: COc1cc2nc(N3CCCN(C4=CC(=O)CC(C)(C)C4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 1.7 g (0.007 mol) of 2-chloro-4-amino-6,7-dimethoxyquinazoline, 2.2 g (0.007 mol) of (3-oxo-5,5-dimethyl-1-cyclohexen-1-yl)-homopiperazine dihydrochloride monohydrate, 3.55 g (0.035 mol) of triethylamine and 30 ml of anhydrous isoamyl alcohol is heated at the boiling point under reflux for 10 hours. After cooling, the triethylamine hydrochloride is filtered off with suction and washed with isoamyl alcohol. The alcohol phases are concentrated at 50° C. in vacuo and the residue which remains is dissolved in 200 ml of chloroform. After washing twice with water, the chloroform solution is dried with sodium sulphate and evaporated to dryness. The residue can be taken up in 20 ml of absolute ethanol. Hydrogen chloride, dissolved in ethyl alcohol, is added to this solution, followed by absolute ether, while cooling with ice, until the onset of turbidity. The 1-(4-amino-6,7-dimethoxyquinazolin-2-yl)-4-(3-oxo-5,5-dimethyl-1-cyclo-hexen-1-yl)-homopiperazine dihydrochloride which precipitates is filtered off with suction and washed with absolute ether. Yield: 2.1 g (60%) of melting point 259°-261° C. (decomposition). A sample recrystallised from ethanol/methanol (2:1) has a melting point of 260°-261° C. (decomposition).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:15]=[C:14]([C:16]([CH3:18])=[CH2:17])[CH:13]=[CH:12][C:10]=1[NH2:11].C(N(CC)CC)C.C(OC(=O)C)(=O)C>CC(C)=O.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.CO>[Cl:8][C:9]1[CH:15]=[C:14]([C:16]([CH3:18])=[CH2:17])[CH:13]=[CH:12][C:10]=1[N:11]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)c1ccc(N)c(Cl)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(N2C(=O)C=CC2=O)c(Cl)c1
Temperature: 15 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Maleic anhydride (50 g) was dissolved in 120 ml of acetone. While this solution was being kept at 15° C., 83 g of 2-chloro-4-isopropenylaniline was added thereto. The resulting reaction mixture was stirred at 15° C. for 2 hours. Then, 0.9 g of cobalt acetate tetrahydrate, 16 g of triethylamine, and 57 g of acetic anhydride were added, with stirring, to the above reaction mixture. Thereafter, the reaction mixture was heated to 60° C., stirred at that temperature for 21/2 hours, and then cooled to room temperature. After the addition of 50 ml of methyl alcohol, the reaction mixture was slowly poured into 2,000 ml of vigorously stirred water. The precipitate so formed was separated by filtration and then washed with water, with an aqueous sodium carbonate solution, and thoroughly with water. Finally, the precipitate was washed with 150 ml of methyl alcohol and then dried at 50° C. under reduced pressure to obtain 109 g of N-(2-chloro-4-isopropenylphenyl)maleimide in an 89% yield. The analytical data were as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:17]([CH2:18][C@H:19]2[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:16]2[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:15]=2[N:14]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:12][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[N:17]([CH2:18][C@H:19]2[O:24][CH2:23][CH2:22][NH:21][CH2:20]2)[C:16]2[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:15]=2[N:14]=1)[C:8]([NH:9][CH3:10])=[O:11]
Reactant: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CNCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (770 mg, 1.54 mmol) was dissolved in DCM (10.0 mL). Afterward, TFA (2.00 mL) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 1 hr and then concentrated under reduced pressure. The crude (S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt product was used without further purification (790 mg) in the next step. It was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; particle size: 5 μm). MS m/z 401.3 [M+H]+ (ESI), Rt 1.37 min.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(O[C:27](OCC)(OCC)[CH2:28][CH3:29])C>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:27]([CH2:28][CH3:29])=[N:23][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (50 mg) in triethylorthopropionate (5 ml) was heated at 150° C. for 18 hours. The excess triethylorthopropionate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-4′-(5-ethyl-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O:14][C:15]1[C:16](=[O:47])[C:17](=O)[C:18]=1[NH:19][C:20]1[CH:21]=[N:22][N:23]([CH3:45])[C:24]=1[NH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C.C(N(CC)CC)C.C(OCC)C>C(O)C.CCCCCC>[CH3:45][N:23]1[C:24]([NH:25][C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:20]([NH:19][C:18]2[C:15](=[O:14])[C:16](=[O:47])[C:17]=2[NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH:21]=[N:22]1
Reactant: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1ncc(Nc2c(NCCNC(=O)OC(C)(C)C)c(=O)c2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 93.3 %

Procedure:
To a suspension of tert-butyl 2-aminoethylcarbamate (288 mg) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (718 mg) in ethanol (20 ml) was added triethylamine (0.209 ml), and the mixture was stirred under reflux for 4 hours. To the reaction mixture were added diethyl ether and hexane. The crystalline precipitate was collected by filtration and dried in vacuo to give tert-butyl 2-[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]ethylcarbamate (830 mg) as a solid.
Reaction SMILES: S(Cl)(Cl)=O.FC(F)(F)[C:7]1[CH:8]=[C:9]([CH:13]=[C:14](C(F)(F)F)[CH:15]=1)[C:10](O)=[O:11].CC1C=CC([NH2:27])=CC=1[N+]([O-])=O.C(N(CC)CC)C.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(Cl)=O>C(Cl)(Cl)Cl>[C:10]([NH2:27])(=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:7][CH:8]=1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Thionyl chloride (576.0 g, 4.8 mol) was added over a period of 15 min to a solution of 3,5-bis trifluoro methyl benzoic acid (Lancaster) (250.0 g, 0.97 mol) in chloroform (2.5 L) at room temperature. The reaction mixture was heated to reflux temperature for 1 hour. The excess of thionyl chloride was removed by co-distillation with chloroform under reduced pressure. After the end of the distillation, the resulting 3,5-bis trifluoro methyl benzoyl chloride was cooled down to room temperature and dissolved in 400 ml chloroform. A solution of 4-methyl-3-nitroaniline (92.0 g, 0.60 mol) in chloroform (1.2 L) was cooled to −5° C. and triethyl amine (304.8 g, 3.0 mol) was added. 3,5-bis trifluoro methyl benzoyl chloride in chloroform was added drop wise at −5° C. over a period of 60-75 min. The resulting suspension was stirred for 1 hr at −5° C. The suspension was distilled to a residual volume of 800 ml and filtered, washed with chilled chloroform (200 ml) and dried in vacuum to give 160.0 g of novel (3,5-bis trifluoromethyl)-N-(4-methyl-3-nitrophenyl)-)-benzamide (68%) as cream colored crystals (98.2% purity by HPLC) MR-123-130° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:13][OH:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:3]1=[O:28].CN(C1C=CC=CN=1)C.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:4]2[C:5](=[O:15])[C:6]([CH2:13][O:14][CH:40]([CH2:39][CH:38]=[O:44])[C:41]([OH:43])=[O:42])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[C:3]2=[O:28])=[CH:17][C:18]=1[C:24]([F:25])([F:27])[F:26])#[N:21]
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC(CC=O)C(=O)O)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 0.20 g of 4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 3 mL of pyridine was added 6 mg of dimethylaminopyridine and 0.052 g of succinic anhydride. The mixture is stirred for 12 hours then evaporated to dryness. The crude product is washed with water and extracted with DCM. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 50/50 cyclohexane/ethyl acetate to give the desired compound.