Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3]
Reactant: CCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC(=O)C(C)(C)C
Yield: 89.2 %

Procedure:
2,2-Dimethyl-heptan-3-ol (0.23 mol) was dissolved in 350 mL of CH2Cl2 in a 500 mL round bottom flask with a magnetic stirbox. The flask was partially cooled with ice. 76.6 g (0.355 mol) of pyridinium chlorochromate was added, while vigorously stirring. The reaction turned black and warmed up slightly. The reaction mixture was stirred at room temperature for 24 hours. The solution was decanted away from the black sludge, which was rinsed with hexane. The organic extracts were combined and chromatographed directly on silica gel. (Note: only silica has been found to trap and remove the reduced non-reacted chromium compounds). The product, 2,2-dimethyl-heptan-3-one, eluted with CH2Cl2/hexane and in a subsequent 10% ethyl acetate/hexane fraction to yield 29.19 g of product at 88% yield. 1H NMR (CDCl3, 500 MHz) δ (ppm): 2.48 (t, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 1.13 (s, 9H), 0.90 (m, 3H).
Reaction SMILES: [OH:1][C@H:2]([C@@H:7]([OH:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].OS(O)(=O)=O>CCOC(C)=O>[CH3:6][O:5][C:3]([C@H:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][C:18]([CH2:19][CH3:20])([CH2:17][CH3:16])[O:1]1)=[O:4]
Reactant: CCC(=O)CC
Reactant: COC(=O)[C@H](O)[C@@H](O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCC1(CC)O[C@@H](Cc2ccccc2)[C@H](C(=O)OC)O1
Reaction time: 20 h
Yield: 45.3 %

Procedure:
To a stirred solution of (2R,3S)-methyl 2,3-dihydroxy-4-phenylbutanoate (Preparation example 260, 2.0 g, 9.51 mmol) in 3-pentanone (5 mL, 47.55 mmol) was added a catalytic amount of H2SO4 (0.051 mL, 0.951 mmol) at room temperature. The mixture was stirred for 20 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (1.2 g, 50˜75%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([O:19]C)=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([OH:19])[C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c2[nH]c(-c3ccc(Cl)cc3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12

Procedure:
A 1.0 g portion of 2-(4-chlorophenyl)-4,7-dimethoxy-1H-benzimidazole, 1.40 g of aluminum chloride and 50 ml of toluene was heated at reflux for 2 hours, then cooled and poured into cold 3N hydrochloric acid. The resulting solid was collected and recrystallized from ethanol, giving 680 mg of the desired product, mp>300° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]1[O:12][C@@H:11]1[CH2:13]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[C:1]1([O:7][CH2:13][C@@H:11]2[O:12][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(OC[C@H]2CO2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of phenol (336 mg) in anhydrous N,N-dimethylformamide (16 mL) was added sodium hydride (60% in mineral oil, 190 mg). The mixture was stirred for 1 h and (2S)-(+)-glycidyl 3-nitrobenzene sulfonate (1.0 g) in N,N-dimethylformamide (5 mL) was added. The mixture was heated to 60° C. and stirred for 30 min. The reaction was allowed to cool to room temperature, water (100 mL) was added and the mixture was extracted with 2:1 hexane:ethyl acetate (2 times 40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to supply the crude product. Purification by silica gel chromatography (eluting with 10:1 hexane: ethyl acetate) afforded the title compound (474 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:37]>O1CCOCC1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:37])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:34])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoic acid (39 mg, 0.08 mmol) in 0.8 mL dioxane was added to NbCl5 (64 mg, 0.238 mmol), followed by 0.95 mL NH3 (0.5M in dioxane). The temperature was slowly raised to 50° C. and stirred for 2 days. The solvents were evaporated and the residue dissolved in CH2Cl2, followed by filtration of the precipitate. The residue was dissolved in CH2Cl2 and washed with brine. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford analytically pure product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:16][CH2:17][NH2:18]>CC(O)C>[NH:15]1[CH:11]=[C:12]([CH2:16][CH2:17][NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:13]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCc1cnc[nH]1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]cn2)nc1

Procedure:
2.22 g (14 mmol) of 2-chloro-5-nitropyridine and an equimolar equivalent of histamine base (1.56 g) in 10 ml of 2-propanol are brought to reflux for 48 h. The reaction mixture is concentrated to dryness and the solid residue is taken up in water, heated to boiling, cooled and filtered. The filtrate is concentrated to dryness and chromatographed on a column of silica gel which is eluted with a mixture of chloroform and methanol (5, 10 and 20%). The combined pure fractions are evaporated to dryness and the solid residue is crystallized from absolute ethanol to provide the product. M.p.: 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(F)c2)c1
Yield: 63.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:15][N:16](C(OCC3C=CC=CC=3)=O)[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:33][N:34](C(OCC1C=CC=CC=1)=O)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:15][NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:33][NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc2c(OC)c(CN(C(=O)OCc3ccccc3)C3CCCCC3)ccc2c1CN(C(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(OC)c(CNC3CCCCC3)ccc2c1CNC1CCCCC1

Procedure:
A solution of 1,6-dimethoxy-2,5-bis-[N-(cyclohexyl)benzyloxycarbonylaminomethyl)-naphthalene (250 mg) in methanol (10 ml) was hydrogenated at atmospheric pressure in the presence of 5% palladium-on-charcol (50 mg) for 2 hours at room temperature. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to afford the product as a yellow syrup; yield 60 mg (37%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O>[CH2:13]([O:20][C:21]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To the solution of azetidine-3-carboxylic acid (1 g, 10 mmol) of tetrahydrofuran/water (50 ml:50 ml) was added NaHCO3 (2.05 g, 25 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and adjusted to pH=2, extracted with ethyl acetate. The residue was dried in vacuum. 2.4 g of crude 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid was obtained.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:13]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)#[N:12]
Reactant: O=C(O)c1ccncc1F
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(CNc2cnccc2C(=O)O)cc1
Temperature: 166 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol), 4-(aminomethyl)-benzonitrile hydrochloride (240 mg, 1.42 mmol), and DIEA (250 μL, 1.42 mmol) were combined in DMA (2 mL) and the reaction mixture was stirred at 166° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified by silica gel chromatography (10-20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a pale yellow precipitate, which was collected by filtration and dried under vacuum to give 32 mg (18%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11N3O2, 254; found 254.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(NC3CCN(Cc4ccccc4)C3)ccc2[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(NC3CCNC3)ccc2[nH]1
Yield: 54.9 %

Procedure:
A solution of 2.8 g (7 mmol) 5-(1-benzyl-pyrrolidin-3-ylamino)-1H-indole-2-carboxylic acid ethyl ester in 180 ml ethanol and 20 ml acetic acid was hydrogenated over Pd/C for 24 h at room temperature. After filtration and evaporation the residue was taken up in 200 ml 10% NaHCO3 aq. and extracted with 150 ml dichloromethane (DCM). The aqueous phase was washed 7 times with 80 ml DCM each and the combined organic phases were dried over Na2SO4. After filtration and evaporation to dryness the residue was purified over Isolute® SPE (solid phase extraction) eluting with a gradient formed from DCM/2N NH3 in methanol to yield 1.05 g (74%) of the title compound and light brown crystals. MS (m/e): 274.3 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-6 in 300 ml of dimethylformamide were heated at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C:2]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1c(Cl)cc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 3-chloro-3-oxopropanoate (317 mg, 249 μl, 2.25 mmol, Eq: 1.2) was added dropwise to a yellow solution of (2-amino-3,5-dichloro-phenyl)-phenyl-methanone (500 mg, 1.88 mmol, Eq: 1.00) in DCM (5 ml) at 0° C. The yellow solution was then allowed to warm slowly to RT. After completion of the reaction the mixture was washed with sat. NaHCO3 solution and brine, dried with Na2SO4 and evaporated. The remaining light brown residue (603 mg) was used in the next reaction step without further purification. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[C:26]([CH3:36])=[C:25]1[CH3:37])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:19][C@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])[C:25]([CH3:37])=[C:26]3[CH3:36])=[O:34])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]([CH3:22])[N:10]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][C:3]=1[C:9]1[C:13]([C:14]([F:16])([F:17])[F:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]([CH3:22])[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C

Procedure:
21 g (58 mmol) of 3-(2,4-dichlorophenyl)-1-methyl-4,5-di-(trifluoromethyl)-1H-pyrazole were added, at (-30)° C., to 250 ml of concentrated nitric acid, whereupon the mixture was stirred for 1 hour at (-10)° C. The solution was subsequently stirred into 1.2 l of ice-water. The product was then extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]1[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:7][N:8]1[C:12]([NH:13][C:15](=[O:17])[CH3:16])=[CH:11][C:10]([CH3:14])=[N:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)n(C)n1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Pyridine (7.1 mL, 90 mmol) was added to a solution of 2,5-dimethyl-2H-pyrazol-3-ylamine (10 g, 90 mmol) in acetic anhydride (46 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum to yield the title compound as a brownish liquid (13.7 g, yield: 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:12]>N1CCCCC1.C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:29]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Yield: 55.5 %

Procedure:
A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28]
Reactant: COc1ccc(Cl)cc1C(=O)CN
Reactant: COC(=O)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0362 g, 41.92 mmol), 4-(dimethylamino)pryidine (1.0525 g, 8.62 mmol) and adipic acid monomethyl ester (6.71 g, 41.90 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(5-chloro-2-methoxy-phenyl)-ethanone hydrochloride (10.99 g, 46.55 mmol) and triethylamine (9.42 g, 93.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 21 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 9.39 g of the crude titled product: mass spectrum: m/z=342.1 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[C:1]1([CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
5 g (42.7 mmol) of phenylacetonitrile are added dropwise to a suspension of 2 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes at 0° C., 5.32 ml (42.7 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at ambient temperature and then treated with ice and extracted with ethyl ether. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated under pressure. An orangey-yellow oil is obtained and purified by fractionated distillation under reduced pressure (70-75° C. under 1×10−1 mbar). 5.14 g in the form of an orangey oil are obtained with a yield of 64%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48][CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([N:46]4[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48][CH2:47]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Reactant: O=S1(=O)CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was coupled with thiomorpholine 1,1-dioxide (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H48Cl2N5O5S [(M+H)+] 768.2748, observed 768.2748.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: FC(F)(F)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1
Solvent: CO
Product: FC(F)(F)c1cnc(N2CCNCC2)nc1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
To a solution of 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine (0.63 g) in methanol was added Palladium-C (Degussa EL101N; 5%) and the reaction mixture was heated at 60° C. under hydrogen atmosphere. The reaction mixture was then allowed to cool down to room temperature, the catalyst was filtered of and solvent was removed in vacuo to yield the title compound as a colorless solid (0.41 g). MS (m/e): 233.1 (M+H+).