Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([NH:28][C:3](=[O:4])[CH2:2][F:1])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)CF
Product: O=C(CF)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 101 and making non-critical variations but starting with fluoroacetyl chloride (0.94 g), 1-benzyloxycarbonyl-4-[3-amino-2-pyridinyl]piperazine (PREPARATION 100,3.0 g), the title compound is obtained, NMR (300 MHZ, CDCl3) 8.83, 8.65, 8.14, 7.38-7.32, 7.12, 5.17, 4.96, 3.70 and 3.07 δ.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:28]=1[NH:29][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(F)cc(F)cc3F)cnc(OC)c2o1
Yield: 33.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 2,4,6-trifluoroaniline (0.18 g). Purification by column chromatography on silica with 30% ethyl acetate in hexane followed by trituration with ether gave the title compound (0.068 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(Cl)(=O)OCC.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N3CCSCC3)cc2)=C(C)C1=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (27 mg, 0.078 mmol) obtained in Example 1 and ethyl chlorocarbonate (15 mg, 0.139 mmol) in THF (10 ml) was added triethylamine (14 mg, 0.139 mmol) at −10° C. followed by stirring for 30 minutes, and then thiomorpholine (20 mg, 0.194 mmol) was added thereto followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, dried, and then the solvent was distilled off. The resulting residue was purified by a middle-pressure column chromatography using silica gel (hexane:ethyl acetate=1:1). The yellow powder thus obtained was crystallized from methylene chloride-diethylether to yield the title compound (26 mg, 0.061 mmol, yield 77%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:29]O>CO.C(OCC)(=O)C>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][N:29]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:12]=2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Yield: 74.6 %

Procedure:
The solution of 1-(4-Methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (1.00 g) and hydroxylamine hydrochloride (567 mg) in methanol (10 ml) was refluxed for 10 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml×2), brine (50 ml). The organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile (10 ml), collected by filtration, and dried under reduced pressure to give Methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (0.74 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[Cl:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])=[O:21]
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)CCl

Procedure:
This compound was prepared in the manner of Example 13, using 4.0 g (0.014 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1), 1.6 g (0.014 mole) of chloroacetyl chloride, and 1.2 g (0.015 mole) of pyridine, in 50 ml toluene. The product was a liquid, of which nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][F:18].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:16][CH2:17][F:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(OCCF)cc(C(C)(C)C)c1
Reaction time: 8 h

Procedure:
1-(3-tert-Butyl-5-hydroxyphenyl)ethanone (O3.106; 500 mg) was dissolved in DMF (10 ml), and 1-bromo-2-fluoroethane (195 μl) was added while stirring. Sodium hydride (80 mg) was added at RT. After stirring at RT for 3 h, the mixture was left to stand overnight and then further sodium hydride (20 mg) was added and the mixture was stirred for a further 2 h. Then water was added and the mixture was concentrated to dryness. The residue was taken up in EA and washed three times with water. The EA phase was dried over magnesium sulfate, filtered and concentrated. 600 mg of the title compound were obtained. LC-MS rt: 1.13 min [M+H]+: 239.1 (met. b)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Nc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1NC(C)C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a suspension of 4-bromo-2-(isopropylamino)benzoic acid (448 mg) and potassium carbonate (480 mg) in N,N-dimethylformamide (9 ml) was added methyl iodide (162 μl) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added water (20 ml) and extracted with mixed solvent (hexane/ethyl acetate=1/1). The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 4-bromo-2-(isopropylamino)benzoate (443 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.CNCC[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:35])=[O:40])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CNCCO
Product: O=C(Cn1c(C(=O)O)nc2ccc(C(=O)O)cc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 32 mg MS (ES+): m/e=556, chloro pattern.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[CH3:36][NH:37][CH2:38][CH:39]=[CH2:40].C(N(CC)CC)C.C(Cl)Cl>>[CH2:38]([N:37]([CH3:36])[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])[CH:39]=[CH2:40]
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: C=CCNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C)C[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), N-methylprop-2-en-1-amine (30 mg, 0.4 mmol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C=O.F[C:17](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.CCOCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[CH2:17])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CCc2cc(OC)ccc2C1=O

Procedure:
A mixture of 6-methoxytetralone (29.24 g, 165.9 mmol), paraformaldehyde (22.4 g, 746.6 mmol) and N-methylanilinium trifluoroactate (55 g, 248.9 mmol) in 250 mL THF was refluxed for 4 hours and allowed to come to room temperature. To this was added ether (250 mL) with stirring and the mixture was decanted to remove the gummy precipitate. The supernatant was washed with sat. NaHCO3, the oganic layer was dried (MgSO4) and concentrated. The residue was redissolved in ether, filtered through celite and concentrated to afford the title compound as a thick yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 1H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved with water (100 ml) and diethyl ether (300 ml). The organic layer was washed with water brine and dried over Na2SO4. After filtration, concentration of solvent afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CO)cc1F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C=O)cc1F
Reaction time: 1 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (as described in Example 1, Step C) (10 g, 0,066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)—DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine·SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane:EtOAc, 3:1).
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[C@H:22]([CH:23]=[CH:24][C@@H:25]([O:34]C2CCCCO2)[C@:26]([CH3:33])([O:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:41])[CH2:9]1.C([O-])(O)=O.[Na+]>C(O)=O.O.C1COCC1>[OH:7][C@H:8]1[C@H:22]([CH:23]=[CH:24][C@@H:25]([OH:34])[C@:26]([CH3:33])([O:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:41])[CH2:9]1
Reactant: CCCC[C@@](C)(OC)[C@@H](C=C[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OC)OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: CCCC[C@@](C)(OC)[C@H](O)C=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of the crude bis tetrahydropyranyl ether of Step C in formic acid, (16 ml), H2O (30 ml) and THF (35 ml) is stirred for 24 h at room temperature. The mixture is cooled in an ice-water bath, H2O (30 ml) is added, and solid NaHCO3 is added till a pH of 7 is reached. The aqueous layer is extracted with ether, the combined organic layers are washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Column chromatograph separation on silica gel, eluting with 2% MeOH in AcOEt, gives (8R,11R,12R,15R,16R)-11,15-dihydroxy-16-methyl-l6-methoxy-9-oxo-prost-13-en-1-oic acid, methyl ester which solidifies in the freezer (m.p. 44-45° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=1)=[N:10][N:9]([C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=O)[O:23]C(C)(C)C)[CH3:20])=[CH:15][C:14]=1[F:31])[CH:8]=2)[CH3:2].Cl.[C:33](OCC)(=O)C>C(OCC)(=O)C>[OH2:3].[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=1)=[N:10][N:9]([C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:23])[CH3:33])[CH3:20])=[CH:15][C:14]=1[F:31])[CH:8]=2)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1ccc2cn(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)nc2c1
Agent: Cl
Product: CCOc1ccc2cn(-c3ccc(OC[C@H](C)NC(C)=O)cc3F)nc2c1
Product: O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(1S)-2-[4-(6-ethoxy-2H-indazol-2-yl)-3-fluorophenoxy]-1-methylethyl}carbamate (6.53 g), 4M hydrogen chloride/ethyl acetate (20 mL) and ethyl acetate (40 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with acetic anhydride (20 mL) and pyridine (50 mL). The obtained mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF and ethyl acetate, and the mixture was washed three times with 1M hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and the solution was filtered through silica gel. The filtrate was concentrated, and the residue was recrystallized (ethanol/ethyl acetate) to give the title compound as colorless crystals (2.36 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.6 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (3.0 g, 15 mmol) and DIEA (2.4 g, 18.5 mmol) in n-BuOH (30 ml) was slowly added 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16.2 mmol) at 25° C. The resulting solution was stirred at 25° C. for 5 minutes and concentrated to dryness to give the title compound (3.1 g). NMR (CDCl3) 0.80 (m, 2H), 1.05 (m, 2H), 6.60 (s, 1H), 9.20 (s, 1H), 9.70 (br s, 1H), 10.40 (br s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:25](=[O:35])[NH:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:28]([O:27][NH:26][C:25]([C@@H:7]1[C@@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:6]1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of [3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid methyl ester (213 mg, 0.432 mmol) in THF (5 mL) was added water (3 mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambient temperature for 4 h, the reaction mixture was acidified with 1 N HCl to a pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) and the combined organic layers were washed with brine (5 mL), dried (NaSO4), and the volatiles were removed in-vacuo to afford 154 mg (87%) of [3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid as a sticky oil that was used without further purification in the following coupling reaction. MS (ESI): 480 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:13][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH3:3]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cnccn1)c1ccccc1

Procedure:
Following the method of Example 3, reaction of N,N-dimethyl-3-hydroxy-3-phenylpropylamine, sodium hydride and 2-chloropyrazine in DMSO gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3cc(F)c(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=2[C:43]([F:46])([F:45])[F:44])[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:42][C:39]5[CH:40]=[CH:41][C:36]([CH2:35][N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)=[O:25])=[CH:20][CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)ncn3-c2ccc(CC(=O)O)cc2)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)ncn3-c2ccc(CC(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using {4-[5-(4-methoxy-phenyl)-benzoimidazol-1-yl]-phenyl}-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 613.9 [M+H]+; single peak at tR=3.56 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+].Br[C:34]1[CH:35]=[C:36]2[C:42]([C:43]3[CH:44]=[C:45]4[C:49](=[CH:50][CH:51]=3)[NH:48][CH:47]=[CH:46]4)=[CH:41][N:40](S(C3C=CC(C)=CC=3)(=O)=O)[C:37]2=[N:38][CH:39]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:48]1[C:49]2[C:45](=[CH:44][C:43]([C:42]3[C:36]4[C:37](=[N:38][CH:39]=[C:34]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][N:24]6[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]6)=[CH:8][CH:7]=5)[CH:35]=4)[NH:40][CH:41]=3)=[CH:51][CH:50]=2)[CH:46]=[CH:47]1
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (100 mg, 0.337 mmol), N-acetylpiperazine (47 mg, 0.37 mmol) and K2CO3 (93 mg, 0.675 mmol) were combined in DMF (2.5 ml) and stirred overnight at room temperature. The reaction was quenched by the addition of water, extracted with DCM and dried. The residue was taken up in CH3CN (2 ml), Intermediate B (120 mg, 0.275 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.013 mmol) were added and the reaction was heated to 150° C. in a microwave reactor for 20 min. The mixture was partitioned between water and DCM, the organic phase dried, evaporated and purified by silica gel chromatography using 0-5% MeOH:DCM. 53 mg (46%) of the title compound were obtained. MS ESI (m/z): 450.4 (M+1)+, calc. 449.