Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[F:4][C:5]([F:16])([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.C(O[CH2:24]/[CH:25]=[CH:26]/[C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](/[CH:39]=[CH:40]/[CH3:41])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)(=O)C(C)(C)C.Cl>C(OCC)C.[Cu]Cl>[F:4][C:5]([F:16])([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH2:41]/[CH:40]=[CH:39]/[C@H:36]2[CH2:37][CH2:38][C@H:33]([C@H:30]3[CH2:29][CH2:28][C@H:27](/[CH:26]=[CH:25]/[CH3:24])[CH2:32][CH2:31]3)[CH2:34][CH2:35]2)=[CH:9][CH:8]=1
Reactant: C/C=C/[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/COC(=O)C(C)(C)C)CC2)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: Cl[Cu]
Agent: Cl
Agent: II
Solvent: CCOCC
Product: C/C=C/[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.12 g of magnesium shavings were covered with 5 ml of absolute diethyl ether while gassing with nitrogen and then, after the addition of a crystal of iodine, covered with a solution of 1.3 g of 4-(trifluoromethoxy)benzyl bromide in 25 ml of diethyl ether. After completion of the addition the mixture was heated to reflux for a further 30 minutes. The reaction mixture was transferred into a dropping funnel and then added dropwise at 0° C. and while gassing with nitrogen to a solution of 0.9 g of 3E-[trans-4-(trans-4-[1E-propenyl]cyclohexyl)cyclohexyl]-allyl pivalate, 0.03 g of copper-(I) chloride and 25 ml of absolute diethyl ether. After completion of the addition the reaction mixture was stirred at room temperature for a further 30 minutes, then treated with 20 ml of 25% hydrochloric acid and the organic phase was separated. The aqueous phase was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed in succession with 500 ml of water, 250 ml of concentrated potassium carbonate solution and again with 500 ml of water, dried over magnesium sulphate, filtered and subsequently concentrated. The residue was purified by chromatography on silica gel with hexane. Recrystallization from acetone gave 0.5 g of pure 1-trifluoromethoxy-4-[4E-(trans-4-(trans-4-[1E-propenyl]cyclohexyl)cyclohexyl)-3-butenyl]benzene with m.p. (C-N) 63° C. and cl.p. (N-1) 149° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+].[CH:24]([O:27][C:28]([O:30][CH:31](I)[CH3:32])=[O:29])([CH3:26])[CH3:25]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH:31]([O:30][C:28]([O:27][CH:24]([CH3:26])[CH3:25])=[O:29])[CH3:32])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CC(C)OC(=O)OC(C)I
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cncn34)C[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(c2csc3cncn23)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a solution of 48 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 73 mg of 1-(isopropoxycarbonyloxy)ethyl iodide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give the title compound in a yield of 22 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(3-chlorophenyl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials and isolated (8 mg, 21%) as colorless oil; MS (ESI, m/z): 380.1, 382.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23](OC)=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:28][NH2:29]>CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]([NH:28][NH2:29])=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: NNC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylate (47 mg, 0129 mmol) was suspended in a mixture of methanol (1 ml) and hydrazine hydrate (1 ml). 3 drops of DMF were added and the mixture stirred at 60-70° C. for 2 hours. The volatiles were removed in vacuo. The resulting material was suspended in AcOEt/Hexanes, filtered and dried to afford 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carbohydrazide as solid (47 mg, 100% yield). LCMS (ES): 95% pure, m/z 364 [M+1]+.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>C1COCC1.CCOCC>[O:10]=[C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]1[P:20](=[O:21])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1CCc2ccccc2C1=O
Temperature: -65 °C

Procedure:
A solution of α-tetralone (10 g, 68 mmol) in anhydrous THF (120 ml) is added dropwise to 1M lithium diisopropylamide solution (75 .mol, 75 ml) stirred at -65° C. under nitrogen. After stirring for 45 minutes, diethyl chlorophosphate (12.90 g, 75 mmol) is added to the enolate formed and the temperature of the mixture is progressively raised to 0° C. over a period of 50 minutes. After cooling to -70° C., the mixture is transferred to 2M lithium diisopropylamide solution (150 mmol, 75 ml). The solution obtained is stirred for 2 hours at 10° C. and then treated with acetic acid (272 mmol, 15.5 ml) in ether (250 ml). The mixture is filtered and the filtrate is concentrated. The title compound is obtained by purification on a flash column (eluant: cyclohexane/EtOAc=60/40).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[S:21])#[N:5]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1ccc(C#N)c(NC(=S)NC(=O)c2ccccc2)c1

Procedure:
Prepared as in Example 1a from 2-amino-4-methylbenzonitrile and benzoyl isothiocyanate as a pale-yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J=8.0 Hz, 1H), 7.51-7.58 (m, 3H), 7.67 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.98-8.01 (m, 2H), 11.88 (s, 1H), 12.49 (s, 1H). MS 296 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc2cccnc2c1
Solvent: C1CCOC1
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-methylquinoline (1.63 g, 11.4 mmol) in dry THF (10 mL), cooled by ice/water, is added phenyllithium (1.9M in cyclohexane/ether 70/30, 6.0 mL, 11.4 mmol) dropwise over 5 min. After 15 min, the cooling bath is removed, and the solution is stirred at rt for 5 h. The reaction is quenched by adding MeOH, and stirring is continued overnight. Water is added, the mixture is extracted with EtOAc (3×35 mL), and the combined extracts are dried over MgSO4. The drying agent is filtered off, and air is bubbled into the solution for 7 d. The solvent is evaporated; the residue is dissolved in warm (50° C.) EtOAc/hexanes and filtered warm. The filtrate is concentrated and dried in vacuo to obtain the crude title compound that is used directly for the next step. Further purification is possible by chromatography on silica gel (Jones Flashmaster, eluting with hexanes:EtOAc 3:1→2:1→1:1). 1H NMR (CDCl3, 400 MHz) 2.58 (s, 3H), 7.31 (d, J=3.7 Hz, 1H), 7.36-7.49 (m, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 8.16 (t, J=8.0 Hz, 2H). MS (ES+): m/z 220.3 (100) [MH+]. HPLC: tR=2.7 min (Platform II, nonpolar 5 min).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.[F:24][C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:25]=2[F:24])[N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: Fc1cccc(CBr)c1F
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1cc(Cc2cccc(F)c2F)nc1[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4.2 g (14.5 mmol) 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide in 50 ml tetrahydrofuran were added 10.9 ml (17.4 mmol) of a 1.6M butyl lithium solution in hexane at −75° C. After stirring for 20 min 3.6 g (17.4 mmol) 2,3-difluorobenzylbromide was added at −75° C. and the mixture was allowed to reach room temperature overnight. The mixture was partitioned between water and ethyl acetate, re-extracted with ethyl acetate and the combined organic layers are dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate=4:1) to yield 3.0 g (49%) of 2-(tert-butyl-dimethyl-silanyl)-4-(2,3-difluoro-benzyl)-imidazole-1-sulfonic acid dimethylamide as a light yellow solid; MS (ISP): 416.1 ((M+H)+.).
Reaction SMILES: O1CC=CC(=O)C1.C(N(CC)CC)C.CC(C)(O)C#N.[CH3:21][C:22]1([CH3:44])[O:27][C:26]([CH3:29])([CH3:28])[C:25](=O)[CH:24]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[N+:39]([O-:41])=[O:40])[C:23]1=O>C(#N)C.CCOCC>[CH3:21][C:22]1([CH3:44])[CH2:23][C:24]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[N+:39]([O-:41])=[O:40])=[CH:25][C:26]([CH3:29])([CH3:28])[O:27]1
Reactant: CC1(C)OC(C)(C)C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C1=O
Agent: CC(C)(O)C#N
Agent: O=C1C=CCOC1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)C=C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])CC(C)(C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2,2,6,6.tetramethyl.5.(4.chloro.2.nitrobenzoyloxy)-3,6-dihydro-2H-pyran-3-one (5.97 g, 16.9 mmol) and triethylamine (4,70 ml, 33.8 mmol) in 30 ml of acetonitrile is added acetone cyanohydrin (0.5 ml), and the mixture is stirred at RT for 24 hours. The reaction mixture is diluted with ether and extracted with aqueous 5% K2CO3. The aqueous layer is made acidic with conc. HCl and extracted with ether. The combined organic layers are dried and evaporated to give light yellow crystals, which are purified to yield 2,2,6,6.tetramethyl-4-(4-chloro-2-nitrobenzoyl) -2H-pyran-3,5-(4H,6H)-dione (compound 8, Table A).
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[OH:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23](O)=O.[ClH:35]>CCOCC>[ClH:35].[F:16][C:12]1[C:11]2[O:17][C:23]([C:22]3[CH:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[C:20]([O:19][CH3:18])[CH:21]=3)=[N:9][C:10]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(F)c1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: Cl
Solvent: CCOCC
Product: COc1cc(-c2nc3cccc(F)c3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 7 mL trimethylsilyl polyphosphate was added 2-amino-6-fluorophenol (166 mg, 1.31 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (300 mg, 1.31 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in ether and reconcentrated to give a tan solid. The free base was dissolved in ether and HCl (1N in ether) was added. The solution was filtered to give 7-fluoro-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole hydrochloride as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.71 (d, 1H), 8.00 (t, 1H), 7.97–7.84 (m, 4H), 7.70 (d, 1H), 7.49–7.37 (m, 3H), 4.00 (s, 3H); MS (ESI) 321 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9]C(C)(C)C)=[O:8])[N:4]([C:14](=[O:37])[C@@H:15]([NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16])[C:3]1=[O:38].Cl.O1CCOCC1>>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[N:4]([C:14](=[O:37])[C@@H:15]([NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16])[C:3]1=[O:38]
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O)C(=O)OCc1ccccc1
Yield: 90.8 %

Procedure:
0.8 g of tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 20 ml of a 13% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 0.65 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (0.65 g) and 20 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.5 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 86.2% The physico-chemical properties of this product are identical with those of the sample obtained in Example 5-(2).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.CI.[CH3:11]COC(C)=O.CC(O)=O>[OH-].[Na+]>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CI
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (66.7 g, 0.497 mol) was dissolved in aq. NaOH (41.6 g of solid in 365 mL of H2O). The mixture was then treated with CH3I (100.1 g, 0.704 mol) and was stirred at room temperature for 18 h. TLC (petroleum ether: EtOAc=4:1) indicated that the reaction was complete. The resulting mixture was adjusted to pH=5˜6 with HOAc (30 mL). The solid formed was collected and dried on vacuum to give title compound (40 g, 54%) as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[N:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([C:30]4[N:29]=[C:28]([CH3:27])[O:32][N:31]=4)=[CH:41][CH:40]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Agent: Cl
Product: Cc1nc(-c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCCCC4c4coc5cccc-5c4)CC3)cc2)no1

Procedure:
The title compound, yellow solid (111 mg, 87%), MS (ISP) m/z=513.3 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][NH:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2[CH:35]=[CH:36][CH:37]=[N:38]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>C1COCC1>[CH:37]1([NH:38][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([N:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([NH:4][CH2:3][CH:2]([CH3:23])[CH3:1])[C:13]=4[N:12]=[CH:11]3)=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a stirred solution of 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzoic acid (63 mg, 0.2 mmol) which was prepared according to intermediate example 4-1 in THF (5 mL), at rt was added HATU (85 mg, 0.22 mmol), DIPEA (29 mg, 0.22 mmol) and cyclopropylamine (12.8 mg, 0.22 mg) in one portion. After stirring for 4 h, the solution was evaporated and the remaining solid was purified by flash chromatography to yield N-cyclopropyl-4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzamide as an off-white solid (24 mg, 33.8%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:29])([CH3:30])[CH2:31][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1
Reactant: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@](O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 5-(4-trifluoromethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one (0.68 g, 2.76 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.50 g, 2.30 mmol) in DMF (5 ml), potassium carbonate (0.38 g, 2.76 mmol) was added followed by stirring at room temperature for 16 hours, and then water was added. The solution was extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (R)-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (1.06 g, quantitative yield) as a white amorphous form.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[CH:24]=[C:23]([C:33]([F:36])([F:35])[F:34])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[S:28][C:27]([C:25]2[CH:24]=[C:23]([C:33]([F:34])([F:35])[F:36])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.8 %

Procedure:
To a cooled and stirred solution of 3′-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.22 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH) yielded the title compound as a light yellow solid (0.13 g, 27%). MS (ISN) 494.3 [(M−H)−]; mp 226.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.N[C:35]1[CH:36]=[C:37]([C:41](=O)C)[CH:38]=[CH:39][CH:40]=1>CS(C)=O>[CH2:41]([N:22]([CH2:21][CH2:20][OH:24])[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1)[C:37]1[CH:36]=[CH:35][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CC(=O)c1cccc(N)c1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)Cc3ccccc3)c2C1
Reaction time: 8 h
Yield: 97.3 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. 1-(3-aminophenyl)ethanone (-, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-(benzyl(2-hydroxyethyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (16.5 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([N:1]=[C:16]=[S:17])=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(-c2ccccc2N)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccccc2N=C=S)cc1

Procedure:
Reaction of 2-amino-4'-methoxybiphenyl (10 g) with thiophosgene (8.7 g) in dioxane (25 ml) and water (80 ml) at 0° C. for 3 hours gave 4'-methoxy-2-biphenylylisothiocyanate as a pale yellow oil.