Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[C:15](=[O:16])[CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=31)[NH:5][CH2:4][CH2:3]2.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:17]1([CH2:20][N:5]2[CH2:4][CH2:3][C:2]3([CH3:1])[C:15](=[O:16])[CH:6]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=23)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: CC12CCNC(Cc3ccc(O)cc31)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCN(CC3CC3)C(Cc3ccc(O)cc31)C2=O

Procedure:
A mixture of 1,2,3,4,5,6-hexahydro-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (part A, 0.220 g.), cyclopropylmethyl bromide (0.200 g.), sodium bicarbonate (0.084 g.) and N,N-dimethylformamide (5 ml.) was stirred in a nitrogen atmosphere under reflux (for 2 hr.), then stripped of N,N-dimethylformamide. A solution of the residue in dilute hydrochloric acid (5%) was extracted with ether, neutralized and extracted with ether again. Desiccation and concentration of the latter ether extracts afforded 1,2,3,4,5,6-hexahydro-3-cyclopropylmethyl-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (I: Q = CH2CHCH2CH2, R = CH3, X = HO, Y + Z = O) as a yellow oil, from which with methanesulfonic acid was obtained the methanesulfonate salt as another oil, from which with 1,5-naphthalenedisulfonic acid was obtained the crystalline 1,5-naphthalenedisulfonate tetrahydrate salt (220 mg., m.p. 287°-288° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH3:12].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([Cl:8])=[C:6]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=2)=[O:18])[CH:7]=1
Reactant: COc1cc(Cl)ccc1Br
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 1-bromo-4-chloro-2-methoxybenzene (5.1 g, 23 mmol) and 4-ethylbenzoyl chloride (4.1 g, 24 mmol) in 15 mL of anhydrous dichloromethane (DCM) was added aluminum trichloride (3.2 g, 24 mmol). The mixture was stirred at room temperature for 1 hour, followed by heating at reflux for 18 hours. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and evaporated. Recrystallization from petroleum ether gave the intermediate (5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone 21 (5.6 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>O1CCCC1.[Ru].C>[C:4]([CH:3]1[CH2:7][CH:8]([CH3:11])[CH2:9][CH2:10][CH:2]1[NH2:1])([OH:6])=[O:5]
Reactant: [H][H]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: [Ru]
Solvent: C1CCOC1
Product: CC1CCC(N)C(C(=O)O)C1
Reaction time: 14 h

Procedure:
50 g (0.33 mol) of 2-amino-5-methyl-benzoic acid, dissolved in 100 ml of tetrahydrofuran, are hydrogenated for 14 hours at 200° C. and 200 bar hydrogen in the presence of 5 g of ruthenium/charcoal. After cooling and evaporation, 30 g o f 2-carboxy-4-methyl-cyclohexan-1-yl -amine are obtained as a pale oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]=1[CH3:18])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]=1[CH2:18][Br:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1CBr
Yield: 99.7 %

Procedure:
4,5-Dichloro-2-methyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester (14.3 g, 48.9 mmol), N-bromosuccinimide (8.93 g, 50.2 mmol), and benzoyl peroxide (1.18 g, 4.89 mmol) were suspended in 123 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated to afford 18.1 g of the crude 4,5-dichloro-2-bromomethyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a brown oil.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1cn(CCCCO)c2ccccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCO)c2ccccc12

Procedure:
Beginning with 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide and 1-(4-hydroxybutyl)indole-3-glyoxylic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:10])[CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C1(C)C=CC=CC=1>[O:23]=[C:19]([CH3:18])[CH2:20][C:21]([O:10][CH:8]([CH3:9])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: CC(O)CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(C)CN1CCOCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.0 g (34.4 mmol) 1-(4-Morpholinyl)-2-propanol and 35 mg (0.34 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 3.76 g (44.77 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the water phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][NH:19][C@@H:20]([CH3:30])[C@H:21]([OH:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[O:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][NH:19][C@@H:20]([CH3:30])[C@H:21]([OH:29])[C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[O:5][C:6]([CH3:12])([CH3:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NCCc1ccc(OC(C)(C)C(=O)O)cc1Cl)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 2-[3-Chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-phenoxy]-2-methylpropionate (2.39 g) in ethanol (20 ml) was added 2N aqueous sodium hydroxide solution (8.2 ml), and the mixture was stirred for 13 hours at room temperature. To the stirred reaction mixture was added 2N hydrochloric acid (8.2 ml) under ice-cooling. After the reaction mixture was concentrated under reduced pressure, azeotropic concentration with ethanol was undergone. The residue was washed with water (180 ml) and dried under reduced pressure to give 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionic acid (2.02 g).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[OH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@@H:30]([OH:29])[CH2:31]3)[CH2:26][CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: O[C@@H]1CCNC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@@H](O)C2)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-3-hydroxyl-pyrrolidine in direct analogy to the general procedure used in example 129. MS: 463.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:35]2[CH2:36][CH2:37][N:32]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:33][CH2:34]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Temperature: 110 °C
Yield: 56.2 %

Procedure:
2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (2.6 g, 13 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (5.8 mL, 34 mmol), 1-(2-thiophenylsulfonyl)piperazine hydrochloride (3.0 g, 11 mmol, Example 29, step 1), and acetonitrile (22 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 110° C. for 19 h. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (50 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated, hexanes (100 mL) was added to the residue and the slurry was filtered to give 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (2.5 g) as a light tan solid. The material was used in the next step without purification
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[C:26](OC)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CO>[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[CH2:26][OH:27])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1cc2cnc(SC)nc2n1C1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc2cc(CO)n(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
DIBAL-H (1.0 M in toluene) (33.8 mL, 33.8 mmol) was added dropwise to a solution of compound 227 (4.93 g, 16.9 mmol) in dichloromethane (85 mL) at −78° C. The reaction was stirred for 20 minutes, then warmed to 0° C. and quenched with 400 mL of 0.5 M Rochelle's salt saturated with NaCl. The mixture was stirred for 3 h then extracted with ethyl acetate (4×250 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to provide 4.36 g of crude. The crude material was taken up in dichloromethane and methanol, plated onto silica gel, and flashed through a plug of silica using 30% ethyl acetate in hexanes, then switching to 10% methanol in DCM to provide compound 228 (3.37 g, 75.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1 H) 6.29 (s, 1 H) 4.83-4.95 (m, J=17.30, 8.59, 8.59 Hz, 1 H) 4.79 (d, J=5.87 Hz, 2 H) 2.62 (s, 3 H) 2.47-2.58 (m, 2 H) 1.97-2.15 (m, 5 H) 1.67-1.81 (m, 2 H) ppm.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]CC)=[O:36])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(C(=O)O)cc2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.ClCCl>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:26]=[CH:25][C:24]([N:11]2[C@@H:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[NH2:21])[CH2:13][CH2:14][C@@H:10]2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1cccc([C@H]2CC[C@H](c3cccc([N+](=O)[O-])c3)N2c2ccc(C(F)(F)F)cc2)c1
Solvent: CO
Solvent: ClCCl
Product: Nc1cccc([C@H]2CC[C@H](c3cccc(N)c3)N2c2ccc(C(F)(F)F)cc2)c1

Procedure:
The product from Example 205B was processed using the method described in Example 55E. The title compound was isolated by flash chromatography (silica gel, methanol/dichloromethane). MS (ESI) m/z 398 (M+H)+, 396 (M−H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(C2CC2)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-1H-pyrazole-5-amine (250 mg, 2.0 mmol), 4-(2-chloroethyl)morpholine HCl salt (372 mg, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) in dry DMF (10 mL) was stirred at room temperature overnight. After being diluted with ethyl acetate (50 mL), the reaction mixture was filtered through a pad of Celite and rinsed with ethyl acetate (2×15 mL). The combined filtrates were concentrated in vacuo and purified by ISCO (CH2Cl2-MeOH—NH4OH: 100:0:0 to 90:10:1) on silica gel to afford the desired amino-pyrazole.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C[O-].[Na+].C[CH2:22][O:23]C(C)=O>CS(C)=O.CO>[CH3:22][O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1,3-dinitro-5-trifluoromethyl-benzene (5.43 g, 20.1 mmol) was dissolved in 10 mL anhydrous DMSO. Sodium methoxide (5.85 mL of a 25% w/w solution in methanol) was added by syringe. The yellow solution immediately turned pink-orange, with heat evolved. The reaction was left stirring overnight at room temperature, then EtOAc (300 mL) was added and the mixture was washed once with dilute HCl aqueous solution, thrice with water and once with brine. The organic solution was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified through a short plug of silica gel and 4.65 g of 2-methoxy-1,3-dinitro-5-trifluoromethylbenzene was isolated as a yellow solid.
Reaction SMILES: [NH2:1][C:2](=[N:12][N+:13]([O-:15])=[O:14])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26](Cl)=[O:27]>>[NH2:1][C:2](=[N:12][N+:13]([O-:15])=[O:14])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH:8][C:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)=[O:27]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)O
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Yield: 64 %

Procedure:
Prepared analogously to Example 4a) from (R)-N5 -[amino(nitroimino)methyl]-ornithine and 2-naphthoylchloride in a yield of 64% of theory. Colourless crystals which were used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:7][CH2:6]1)=[O:4].C1C[O:25][CH2:24]C1>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:25])[CH2:9][CH2:10]1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 1,1-carbonyldiimidazole (17 g, 103.5 mmol) in THF (200 mL), trans-4-[(2-Amino-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (15 g, 51.72 mmol) was added and the reaction was heated to reflux temperature for 16 hours. The mixture was allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was washed with 100 mL of H2O and the precipitate was filtered. The tiled compound (15.9 g, yield 97%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:52])([F:51])[F:50])[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:50])([F:51])[F:52])=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccccc2C(F)(F)F)cc1-c1ccnnc1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 71 %

Procedure:
Prepared according to Preparation 22 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 291 mg, 0.63 mmol) and 3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-ol (Preparation 9, 200 mg, 0.63 mmol) to afford the title compound as a solid (339 mg, 71%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4].[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:29]1([CH2:2][C:3]([NH:5][C:6]2[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1
Reactant: COCC(C)(C)OC(=O)c1c(NC(=O)CBr)nc(N(C)C)n1-c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)(C)OC(=O)c1c(NC(=O)Cn2cnc3ccccc32)nc(N(C)C)n1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
2-Methoxy-1,1-dimethylethyl 4-[(bromoacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate (35 mg, 1 eq), synthesized in an analogous manner/method as described for example 90), benzimidazole (2.5 eq) and K2CO3 (22 mg, 2 eq) were dissolved in DMF (5 mL). The reaction was stirred for 1 h at 75° C. The solvent was evaporated off and to the residue was added K2CO3(aq) (1 M, 50 mL) and extracted with ether. The organic phases were pooled, dried (MgSO4.H2O), filtered and evaporated. Eventually the crude material was purified by preparatory HPLC, which gave the desired pure product. Yield: 41%. 1H-NMR d (CDCl3): 1.29 (s, 6H), 2.68 (s, 6H), 3.27 (s, 2H), 3.31 (s, 3H), 5.3-5.9 (s, 2H), 7.24-7.32 (m, 4H), 7.41 (m, 4H), 7.80 (d, 1H), 8.02 (s, 1H), 9.50 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (181 mg, 0.57 mmol) [Prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.87 mmol) in Dichloromethane (4.23 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (295 mg, 0.632 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (240 mg, 0.37 mmol, 64.8% yield) as a white foam: LCMS (ES) m/e 645, 647 (M, M+2)+.