Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[S:23][C:24]([F:28])=[C:25](F)[CH:26]=5)=[CH:16][C:15]4=[O:29])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:30]C1C=C(COC2C=CN(C3C=CC4N=C(C5CC5)N(C)C=4C=3)C(=O)C=2)SC=1>>[Br:30][C:25]1[CH:26]=[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:29])[CH:16]=2)[S:23][C:24]=1[F:28]
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)cs4)cc3=O)cc21
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(F)c(F)s4)cc3=O)cc21
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)c(F)s4)cc3=O)cc21

Procedure:
A mixture of the title compound, 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one and 4-((4-bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one obtained in step D in example 219 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The solution was neutralized with saturated Na2CO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through a plug of silica gel, and concentrated in vacuo. The residual solid was recrystallized from EtOH to give the title compound (10.0 mg) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)=[O:46]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 73.4 %

Procedure:
A solution of 45 mg (0.1 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 12 mg (0.12 mmol) of triethylamine and 12 mg (0.1 mmol) of pivaloyl chloride in 5 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction solution was diluted with 10 ml of methylene chloride, then washed with 5 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 4:1 mixture of hexane, and ethyl acetate as the eluent. There were obtained 39 mg (73% of theory) of tert-butyl (3RS,4RS)-4-[4-(2,2-dimethyl-propionyloxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 549 (M+NH4)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH:21]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3]CC1C=CC=CC=1)=[O:2].C([NH:39][C@@H:40]([C:52]([OH:54])=O)[CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[C:1]([N:11]([C@@H:12]([CH:21]([C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:52](=[O:54])[C@H:40]([NH2:39])[CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])([O:3][C:15]([CH3:20])([CH3:16])[CH3:14])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2[nH]1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2[nH]1

Procedure:
N-Cbz-(1R)-1-[(RS)-(2-Benzimidazolyl)hydroxymethyl]-3-phenylpropylamine (581 mg) is deprotected in trifluoroacetic acid, and the residue is coupled to N,N′-bis-Boc-D-ornithine to afford the title compound (110 mg): mass spectrum (ES+) m/e 596.3 (M+1); 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.46 (m, 9H), 1.42 (s, 9H), 1.58 (m, 4H), 2.02 (m, 2H), 2.63 (m, 2H), 2.82 (m, 2H), 3.18 (m, 1H), 4.16 (m, 1H), 4.49 (m, 1H), 5.17 (m, 1H), 5.42 (m, 1H), 7.03-7.23 (m, 8H), and 7.57 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH3:48])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:45](=[O:46])[C:42]3[C:41]([CH3:48])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=3)[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A round-bottomed flask was charged with N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (rac-4l, 0.233 g, 0.589 mmol), DCM (8 mL), N,N-diisopropylethylamine (0.133 mL, 0.766 mmol), 5-chloro-3-methylpicolinic acid (intermediate 6) 0.131 g, 0.766 mmol) and finally with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.347 mL, 0.589 mmol). The reaction mixture was stirred at room temperature for 15 min. The Reaction mixture was poured into aqueous saturated NaHCO3 (50 mL) and then extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over Na2SO4 and loaded onto silica gel. Purification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane) gave the title compound (50 mg). MS m/z=549.1 [M+H]+. Calculated for C26H21ClF4N4O3: 548.9
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([O-:21])=[O:20])=[N:17][CH:18]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[CH3:28][CH2:29][CH:30](O)[CH2:31][CH3:32]>S(=O)(=O)(O)O>[C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH:30]([CH2:31][CH3:32])[CH2:29][CH3:28])=[O:20])=[N:17][CH:18]=2)=[O:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc(C(=O)[O-])nc1
Reactant: CCC(O)CC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCC(CC)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccccc2)cn1
Temperature: 90 °C

Procedure:
5 drops of concentrated sulfuric acid were added to 0.9 g (2.94 mmol) of 5-[((phenylsulfonyl)amino)carbonyl]-pyridine-2-carboxylate in 30 ml of 3-pentanol, while stirring, and the mixture was heated at 90° C. for 6 hours. The excess 3-pentanol was distilled off in vacuo and the residue was treated with ethyl acetate. The crystalline crude product was combined with the product obtained from the mother liquor by purification by column chromatography (melting point 186° to 187° C.), treated with hot ethyl acetate, cooled, filtered off with suction and washed with ethyl acetate. This gave 0.55 g of the colorless title compound, melting point 182° to 183° C.
Reaction SMILES: C(NCC)C.[NH:6](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:7]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10]>CN(C)C=O>[NH2:6][C@@H:7]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
12.05 ml of diethylamine are added to a solution of 8.04 g (11.5 mmol) of Fmoc-D-Leu-Arg-D-Val-OBzl in 60 ml of dimethylformamide. The mixture is left to stand at room temperature for 15 minutes, and is concentrated. The residue is partitioned between n-pentanol and NaHCO3 solution. The pentanol phase is concentrated, and the residue is triturated with diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]2)=[O:14])=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.O>C(O)C>[NH2:1][C:2]1[N:7]2[C:8]([Cl:27])=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CCCCN1CCC(CNC(=O)c2ccc(N)n3cc(CC)nc23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCO
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3c(Cl)c(CC)nc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 5-amino-N-[(1-butylpiperidin-4-yl)methyl]-2-ethylimidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 10, Step 4, 170 mg, 0.48 mmol) in ethanol (4 mL) was added N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature. After stirring at room temperature for 1 h, water (50 mL) was added to the mixture. The aqueous layer was extracted with dichloromethane (60 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in diethyl ether and the insoluble solid was collected by filtration to give 71 mg (38%) of the title compound as a gray solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[CH:1]([NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: c1csc(OCC2CO2)n1
Solvent: CCO
Product: CC(C)NCC(O)COc1nccs1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 0.6 g. of isopropyl amine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-isopropylamino-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.
Reaction SMILES: C1C=CC=CC=1.NCCCCCCC#N.[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=O)[C:26](OCC)=[O:27])#[N:17]>N1C=CC=CC=1>[OH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:16][NH2:17]
Reactant: CCOC(=O)C(=O)NCCCCCCC#N
Agent: N#CCCCCCCN
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: NCCCCCCCNCCO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The intermediate N-(2-hydroxyethyl)-1,7-heptanediamine was prepared in two steps as follows: To a stirred and ice-cooled solution containing 650 ml. of benzene and 43.5 g. of pyridine was added dropwise over a period of 30 minutes 75 g. of ethyl oxalyl chloride followed by dropwise addition over a period of 30 minutes 63 g. of 7-amino-heptanonitrile. The reaction mixture was stirred in the ice bath for 3 minutes, next stirred at room temperature for 45 minutes and then allowed to stand overnight at room temperature. The white solid was filtered off and rinsed with fresh benzene. The combined benzene filtrates were washed successively with two 250 ml. portions of 5% aqueous glycine solution containing 25 ml. of 10% aqueous potassium hydroxide solution, a 250 ml. portion of 0.6N hydrochloric acid and two 250 ml. portions of water. The benzene solution was then dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 102.7 g. ethyl N-(6-cyanohexyl)oxamate. A 23.1 g. portion was fractionally distilled at high vacuum for analysis, thereby yielding 14.7 g. of ethyl N-(6-cyanohexyl)oxamate, b.p. 170°-174° C. at 0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:21][C:22]1[C:23](=[O:32])[N:24]([CH3:31])[CH:25]=[CH:26][C:27]=1[C:28](Cl)=[O:29].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:28]([C:27]3[CH:26]=[CH:25][N:24]([CH3:31])[C:23](=[O:32])[C:22]=3[OH:21])=[O:29])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C(=O)Cl)ccn(C)c1=O
Reactant: N[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(C(=O)N[C@@H]2CC[C@H](c3ccc(Cl)c(Cl)c3)c3ccccc32)c(O)c1=O
Reaction time: 2 h

Procedure:
To a solution of cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (10 mg, 0.034 mmol) (Intermediate 16) and 3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 12A) (6.90 mg, 0.034 mmol) in DCM (1 mL) was added Et3N (0.014 mL, 0.10 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was quenched with H2O and DCM. The DCM portion was dried over Na2SO4, filtered and the solvent removed under reduced pressure to give Example 8A which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([Sn](C)(C)C)[CH3:3].[C:8]([O:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[O:20][C:21]3[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:25]=[CH:24][C:22]=3[CH:23]=2)[O:15][C:14](=[O:36])[C:13]=1[CH3:37])(=[O:10])[CH3:9]>C1(C)C=CC=CC=1.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:8]([O:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[O:20][C:21]3[CH:27]=[C:26]([N:2]([CH3:3])[CH3:1])[CH:25]=[CH:24][C:22]=3[CH:23]=2)[O:15][C:14](=[O:36])[C:13]=1[CH3:37])(=[O:10])[CH3:9]
Reactant: CN(C)[Sn](C)(C)C
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3o2)oc(=O)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C)c(-c2cc3ccc(N(C)C)cc3o2)oc(=O)c1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium (3 mg) and dimethylaminotrimethyltin (34 mg) were added to a solution of 4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy) benzofuran-2-yl)-2H-pyran-2-one (45 mg) in toluene (5 ml), and the mixture was stirred at 50° C. overnight. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(6-dimethylaminobenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:31][Mg]Br>C1COCC1.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:31])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:28])([F:30])[F:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 1-(6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-pyridin-3-yl)-ethanone (50 mg, 0.12 mmol) in dry THF (2 mL) was added methylmagnesium bromide (3 M, 44 μL, 0.13 mmol) under nitrogen at room temperature and the resulting mixture stirred for 18 h. The mixture was then diluted with HCl (0.1 N) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:3 to 0:100) afforded the title compound (50.3 mg, 97%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)[nH]1
Yield: 83 %

Procedure:
4-[2-(4-Chlorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-chlorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 83%. 1H (CDCl3, 400 MHz): δ 9.65 (NH, broad s), 7.28 (3H, m), 7.2 (2H, d), 4.35 (2H, q), 4.04 (2H, s), 2.57 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.7, 161.5, 141.0, 133.5, 132.6, 130.9, 130.7, 128.9, 128.6, 121.4, 120.5, 116.9, 61.0, 46.1, 14.4, 14.0 ppm. LC/MS: 100%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:31]([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)n1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1-isopropylpyrazole-4-boronic acid pinacol ester (153 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (217 mg, 68%) in an orange oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>C(C1C=CC=CC=1)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:18][O:19][CH3:20])[CH:9]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Product: COCOc1ccc(C=O)cc1OC
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To 14.0 g of vaniline and 51.0 g of potassium carbonate was added 280 ml of acetophenone, and chloromethyl methyl ether was further added and the mixture was refluxed for 1 hour. The reaction liquid was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The reaction mixture was dissolved in ether, washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to the column chromatography [230-400 mesh Kieselgel; eluting solvent=hexane/ethyl acetate (2/1)] to obtain 9.6 g (yield=53.1%) of 3-methoxy-4methoxymethoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:27]([CH3:44])[NH:26][C:25]=1[CH:45]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:45]\[C:25]1[NH:26][C:27]([CH3:44])=[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol), 3,5-dimethyl-4-[3-oxo-3-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-propyl]-1H-pyrrole-2-carbaldehyde (1.7 eq.) and piperidine (1.5 eq.) in ethanol (2 mL) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:13]3[N:14]([CH3:18])[C:15](=O)[NH:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:15]1[N:14]([CH3:18])[C:13]2[C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C)n1-c1cccc2[nH]c(=O)n(C)c12
Product: Cc1ccc(C)n1-c1cccc2nc(Cl)n(C)c12
Temperature: 85 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of 239 mg (0.991 mmol) of 7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of phosphorus oxychloride was stirred at 85° C. for 4 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was diluted with ice and neutralized by aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-20% ethylacetate/n-hexane gradient mixture to give 185 mg (72%) of the title compound.