Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5](I)=[CH:4][N:3]=1.[C:30]([Cu])#[N:31]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5]([C:30]#[N:31])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(N)ncc1I)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: N#C[Cu]
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 7 (700 mg, 1.35 mmol) in DMF (40 mL), cyanocopper (243 mg, 2.7 mmol), tetrakis(triphenylphosphine) palladium(0) (779 mg, 0.68 mmol), and copper iodide (180 mg, 0.95 mmol) were added and the resulting mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH-DCM to afford the product, (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 8.
Reaction SMILES: [F:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:27](=O)[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].[NH3:30]>C(O)C>[F:1][CH2:2][C:3]1[NH:30][C:27]([CH3:28])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CF
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-oxobutanoate (1.45 g, 10 mmoles), ethyl 2-(3-nitrophenylmethylene)-3-oxobutanoate (2.63 g, 10 mmoles) and aqueous ammonia (1.1 ml, d 0.88) were heated at reflux in ethanol (15 ml) for 6 hours. The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with petroleum ether (60°-80° )/ether mixtures. Recrystallisation from ether/petroleum ether (60°-80° ) gave the title compound (1.1 g) as yellow crystals mp 139°-41°.
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)#N.C(N(CC)CC)C>CO>[C:25]1([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH3:3])=[O:31])=[N:7][CH:8]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat at reflux 4 gm. (0.01 mole) of cyanomethyl-5-(triphenylmethyl)picolinate and 2 ml. triethylamine in 50 ml.methanol for 4 hr. Remove methanol under reduced pressure. Triturate solid residue with water and recrystallize from ethylacetate - isopropyl ether, to obtain the product of this example, m.p. 160°-164°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[NH2:10]N.[CH2:12]([OH:14])[CH3:13]>[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:13][C:12]([NH2:10])=[O:14])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NN
Agent: [Ni]
Product: NC(=O)Cc1ccc(N)cc1

Procedure:
To a suspension of Nitrobenzene (NB-2-A13, NB-2-A14 or NB-3-A16; 1.61 mmol) and Raney Ni (50 mg) in refluxing ethanol (10 mL) was added drop-wise anhydrous hydrazine (0.5 mL). After the addition was complete, the mixture was refluxed for an additional 20 minutes and then filtered through a pad of Celite. The Celite bed was washed with ethanol (100 mL) and the combined solution was evaporated under reduced pressure to provide pure 2-(4-aminophenyl)-acetamide (2-NB-2-A13, 2-NB-2-A14 or 2-NB-3-A16).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:10].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:10][C:9]([C@@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:28])=[O:1])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:25]
Reactant: CC(C)=O
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of (3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one (50 mg) in acetone (3 ml) was added to a solution of 2N Jones reagent (0.284 ml) in acetone (3 ml) at ambient temperature over a period of 30 minutes and the mixture was stirred for 30 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was evaporated off. The residue was dissolved in chloroform and washed with water. The aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in chloroform (5 ml) and the solution was extracted with 0.1N aqueous solution of sodium bicarbonate (2 ml), 0.05N aqueous solution of sodium bicarbonate (2 ml) and water. The aqueous extracts were combined, acidified with 1N hydrochloric acid and extracted three times with chloroform. The combined chloroform extracts were washed with brine, dried over magnesium sulfate and evaporated to give {(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-4-oxoazetidin-2-yl}acetic acid (56 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[CH3:13][N:14]([CH3:25])[C:15]([C:17]1[C:18]([Cl:24])=[C:19](F)[CH:20]=[CH:21][CH:22]=1)=[O:16]>>[ClH:24].[CH3:13][N:14]([CH3:25])[C:15]([C:17]1[C:18]([Cl:24])=[C:19]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:20]=[CH:21][CH:22]=1)=[O:16]
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: CN(C)C(=O)c1cccc(F)c1Cl
Product: CN1CCC(Oc2cccc(C(=O)N(C)C)c2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-dimethylcarbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]O.C1(C)C=CC(S(OCCC2SC=CC=2)(=O)=O)=CC=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[ClH:27].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: NCc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Product: Cl
Product: Clc1ccccc1CNCCc1cccs1

Procedure:
Another synthetic route involved preparation of a 2-(2-thienyl)ethanol, its conversion to 2-(2-thienyl)ethyl paratoluene sulfonate and benzylation with o-chlorobenzylamine to give N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine hydrochloride, which is cyclized to give ticlopidine free base, as described by Braye in U.S. Pat. No. 4,127,580.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][CH2:2]1.CS([Cl:25])(=O)=O.C(N(CC)CC)C.O>ClCCl>[Cl:25][CH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)Cc1nc2cc(CO)ccc2n1CC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)Cc1nc2cc(CCl)ccc2n1CC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]methanol (Step D, 200 mg, 0.73 mmol) in dichloromethane (3 mL) were added methanesulfonyl chloride (114 μL, 1.5 mmol) and triethylamine (226 μL, 1.6 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (2 mL) was added and the mixture was extracted with ethyl acetate (10 mM×2). The organic extracts were dried over sodium sulfate and concentrated to afford the title compound as pale red oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[C:10]([C:13](OCC)=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:10]([C:13]([OH:14])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[N:18]3[CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[N:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCC1=O
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 5-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}pyridine-2-carboxylate and ethyl 3-chloro-3-oxopropionate in a manner similar to that described in Example 1, Steps 10-11 and was obtained as a white solid: 1H NMR (CDCl3) δ 8.50 (1H, d, J=1.4 Hz), 8.11 (1H, s), 7.26 (2H, m), 7.00 (2H, ddd, J˜9, 9, 2 Hz), 4.52 (2H, q, J=7 Hz), 4.33 (2H, br t, J˜7 Hz), 4.14 (2H, s), 3.52-3.44 (4H, m), 2.35 (2H, t, J=8 Hz), 2.00 (2H, m), 1.48 (3H, t, J=7 Hz); HRMS calcd for C24H24FN3O5+H+: 454.1778. Found: 454.1787.
Reaction SMILES: C[C:2]1([CH3:15])[C@H:6]2[CH2:7][CH2:8][C@:3]1([CH2:10]S(O)(=O)=O)[C:4](=[O:9])[CH2:5]2.[NH:16]1[CH2:20][CH2:19][C@@:18]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22](=[O:29])[O:21]2)[CH2:17]1.F[P-](F)(F)(F)(F)F.[N:37]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:41]2C=CC=CC=2N=N1.CN1CCOCC1>>[N:37]1[CH:5]=[CH:6][C:2]([C:3]2([C:4]([N:16]3[CH2:20][CH2:19][C@@:18]4([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[C:22](=[O:29])[O:21]4)[CH2:17]3)=[O:9])[CH2:8][CH2:7][CH2:10]2)=[CH:15][CH:41]=1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Reactant: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccncc4)CCC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide, monohydrate (0.013 g, 0.00031 mol) was added to a solution of ethyl 1-pyridin-4-ylcyclobutanecarboxylate (32 mg, 0.00016 mol) in tetrahydrofuran (1.6 ml., 0.020 mol) and water (0.3 mL, 0.02 mol). The mixture was stirred at room temperature until the reaction was complete. The mixture was acidified (to pH=5) with 4 M HCl (75 μl) and concentrated to afford the carboxylic acid. Then [(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid—(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (0.033 g, 0.000078 mol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.041 g, 0.000078 mol) were added to the above crude product of the carboxylic acid, followed by 4-methylmorpholine (6.0 μL, 0.00055 mol). The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by prep-LCMS. LC/MS: 349.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl>C1COCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:21]([C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: CC(C)[Mg]Cl
Reactant: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixed solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (149 mg) in THF (5 ml) and N-methylpyrrolidone (0.5 ml) were added under nitrogen atmosphere iron(III) acetylacetonate (26 mg) and isopropylmagnesium chloride (2M THF solution, 1 ml), and the resulting mixture was stirred at room temperature for two and a half hours. The reaction solutions were added to 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-isopropyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (53 mg).
Reaction SMILES: C([CH:3]1[N:6]([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[CH:4]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=O.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH:39]1C=CC=CC=1>>[CH2:30]([O:37][N:38]=[C:3]1[N:6]([CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[C:4]1([CH3:39])[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1C=O
Reactant: NOCc1ccccc1
Reactant: c1ccccc1
Product: COC(=O)C(c1ccccc1)N1C(=O)C(C)(N2C(=O)c3ccccc3C2=O)C1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 2-(4-formyl-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate (390 mg.) and O-benzyl hydroxylamine (170 mg.) were dissolved in dried benzene (10 ml), and the solution was stirred at ambient temperature for 4 hours and then heated at 50° to 60° C. for an hour. The reaction mixture was washed with 1% hydrochloric acid (10 ml.), water and an aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue (560 mg.), which was subjected to column chromatography on silica gel (15 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solution was removed by distillation from the solution under reduced pressure to give methyl 2-(4-benzyloxyimino-methyl-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate (530 mg.).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:6])=[O:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:25]([NH:26][C:27]1[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=1)=[O:24])(=[O:15])=[O:14])(=[O:6])=[O:5]
Reactant: CN(C)NS(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)NN(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
To a solution of 0.14 g of the product of Example 1 and 0.15 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 2 mL of dry acetonitrile was added 0.1 mL of 1,5-diazabicyclo[5.4.0]undec-5-ene. The solution was stirred for 15 minutes at room temperature, diluted with 2 mL of water and acidified with 5% hydrochloric acid to a pH of 4. The precipitated product was collected by filtration, washed thoroughly with water, washed with 1-chlorbutane, and dried in vacuo at 40° C. to afford 0.02 g of the subject compound, m.p. 127°-128° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: BrCc1ccc(Oc2ccccc2)nc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(Oc2ccccc2)nc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(bromomethyl)-2-phenoxypyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 419.25 g/mol.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:24][C:25]1[CH:31]=[C:30]([CH3:32])[C:28]([NH2:29])=[CH:27][CH:26]=1.[C:33](OCC)(=[O:35])C>>[Br:24][C:25]1[CH:31]=[C:30]([CH3:32])[C:28]([NH:29][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:27]([O:35][CH3:33])[CH:26]=1
Reactant: CCOC(C)=O
Reactant: CC(C)N(c1ccc(C#N)cc1)c1cccc2nc(Cl)n(C)c12
Reactant: Cc1cc(Br)ccc1N
Product: COc1cc(Br)cc(C)c1Nc1nc2cccc(N(c3ccc(C#N)cc3)C(C)C)c2n1C
Temperature: 120 °C
Reaction time: 72 h
Yield: 9.5 %

Procedure:
A mixture of 4-[(2-chloro-1-methyl-1H-benzimidazol-7-yl)(isopropyl)amino]benzonitrile (50 mg, 0.154 mmol) and 4-bromo-6-methylaniline (100 mg, 0.46 mmol) was stirred at 120° C. for 3 days. The mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a solution of 33% ethyl acetate/hexane. The desired fractions were concentrated in vacuo, and the residual solids were washed with diethyl ether-hexane to give 7.4 mg (9.5%) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C1(N[C:13]([C:15]2[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:14])C=CC=CC=1.O>ClC1C=CC=CC=1>[Cl:29][C:25]1[CH:26]=[CH:27][C:28]2[C:13](=[O:14])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[CH2:21][CH2:22][C:23]=2[CH:24]=1
Reactant: O=C(Nc1ccccc1)c1ncccc1CCc1cccc(Cl)c1
Solvent: Clc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C1c2ccc(Cl)cc2CCc2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of trifluroromethanesulfonic acid (63.2 ml; 0.71 mol) and phosphorus oxychloride (66.4 ml; 0.71 mol) in chlorobenzene (400 ml) was stirred for ½hour at room temperature. A solution of N-phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridine carboxamide 4 (120 g; 0.36 mol) in chlorobenzene (240 ml) was added. The mixture was heated at 110° C. for 18 hours followed by cooling to 50° C. Water (400 ml) was added and the biphasic mixture heated to 80° C. for ½ hour. The mixture was cooled to room temperature, stirred vigorously for 10 minutes, then allowed to stand for 10 minutes. The product was removed by filtration and partitioned between water (300 ml) and toluene (500 ml). The pH of the aqueous phase was adjusted to 10 with 10M NaOH solution. 100 ml of the organic phase was removed by distillation under reduced pressure. Charcoal (5.5 g) was added and the mixture filtered through a pad of celite. The solution was concentrated under vacuum to 300 ml and 150 ml of hexane was added. The mixture was cooled to 0-10° C. for 1 hour with stirring prior to filtration. The product was washed with 100 ml of chilled toluene and then air-dried for several hours. Yield 44.1 g (50.8%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[O:25]1[CH2:29][C:28](=O)[N:27]=[C-:26]1.[H-].[Na+].CN(C=[O:37])C>>[O:37]=[C:26]1[N:27]([CH2:2][C:3]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=2[O:5][C:6]2[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH2:28][CH2:29][O:25]1
Reactant: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CBr)c1
Reactant: CN(C)C=O
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-[3-(2-bromomethyl-4-trifluoromethyl-phenoxy)-phenyl]-propionic acid (0.042 g, 0.10 mmol) and 2-oxazolidone (0.018 g, 0.21 mmol) in DMF was added sodium hydride (60% in mineral oil; 0.008 g, 0.21 mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was acidified and purified by preparative HPLC to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH3:9][C:10]([N+:17]#[C-:18])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH:19]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>Cl(O)(=O)(=O)=O>[CH3:8][C:4]1[N:3]2[C:18]([NH:17][C:10]([CH3:16])([CH3:9])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:33]([C:30]3[C:29]4[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:19][C:32]=5[CH:31]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Cc1cccc(N)n1
Reactant: O=Cc1cc2ccccc2c2ccccc12
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cccc2nc(-c3cc4ccccc4c4ccccc34)c(NC(C)(C)CC(C)(C)C)n12

Procedure:
Compound (36) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-6-methylpyridine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of phenanthrene-9-carbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[F:26][C:27]1[C:28]([CH3:36])=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH:30]=O.[C:37](OCC)(=O)CC(C)=O.C(OC)(=O)CC(C)=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:30]([C:29]2[CH:32]=[CH:33][C:34]([F:35])=[C:27]([F:26])[C:28]=2[CH3:36])[C:5]=1[C:3]([O:2][CH2:1][CH3:37])=[O:4]
Reactant: Cc1c(C=O)ccc(F)c1F
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: COC(=O)CC(C)=O
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)c(F)c1C

Procedure:
Compound C-7 was prepared in analogy to compound C by using 3,4-difluoro-2-methylbenzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate.