Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:10][C:9]1([CH3:14])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccccc1O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccccc2O1
Temperature: 25 °C
Yield: 37840.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 10.0 grams (0.091 mole) of catechol in 100 mL of toluene and 100 mL of acetone was stirred and 0.01 gram (catalyst) of para-toluenesulfonic acid was added in one portion. Upon completion of additon the reaction mixture was warmed to reflux where it was maintained during a 48 hour period. After this time the reaction mixture was cooled to ambient temperature, then it was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])CCCC1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.O>[OH:6][C:7]1[CH:8]=[C:9]([N:15]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid (10.0 g, 23.9 mmol) was dissolved in DCM and 22.3 g (167 mmol) of AlCl3 was added. The dark brown solution stirred at room temperature overnight under N2. The reaction mixture was diluted with 100 mL of DCM and 100 mL of H2O and the pH of the aqueous phase adjusted to 5.5. The aqueous phase was extracted with 500 mL of EtOAc and the combined organic fractions were concentrated to dryness giving the desired compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:11].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20].Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([CH2:18][CH:12]([C:10]#[N:11])[C:13]([O:15][CH3:16])=[O:14])=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Diisopropylethyl amine (15.5 g, 0.12 mol) is added to dry tetrahydrofuran (60 mL) followed by a solution of methyl cyanoacetate (5.4 g, 0.055 mol) in tetrahydrofuran (10 mL). Finally, a solution of α-bromo-p-chloroacetophenone (11.0 g, 0.05 mol) in tetrahydrofuran (50 mL) is added. After three hours at room temperature, TLC (75/25 hexanes/ethyl acetate) indicates very little starting material. The reaction mixture is then heated at 50° C. for fifteen minutes, cooled and filtered. The filtrate is concentrated in vacuo to obtain an oil which solidifies when treated with dilute hydrochloric acid. The supernatant is decanted and the residue is taken up in ethyl acetate and dried. Work-up leaves a brown waxy solid (8.0 g, 64% crude yield) which on recrystallization from methanol gives the title compound as a white solid (4.3 g, mp 75°-79° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][C:63](O)=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:63](=[O:64])[CH2:62][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][N:56]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)Nc1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Nc1cc(-c2ccc3nc(NC(=O)Cc4ccccn4)sc3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (121.8 mg, 0.382 mmol) and HATU (215.9 mg, 0.568 mmol) were suspended in DCM (2.9 ml) and diisopropylethylamine (0.21 ml, 1.2 mmol) and 2-pyridylacetic acid hydrochloride (94.3 mg, 0.543 mmol) were added. The reaction was stirred under nitrogen at room temperature overnight, concentrated and purified on a silica gel column (20:1 DCM/MeOH). Fractions with product were collected, concentrated, and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes). Fractions with product were collected, concentrated, and dried under high vacuum in a water bath (˜50° C.), then at room temperature overnight to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)-2-(pyridin-2-yl)acetamide (57.5 mg, 34% yield). MS (ESI pos. ion) m/z: 438. Calculated exact mass for C22H20ClN5OS 437.
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][NH:9][CH:10]=[CH:11][CH:12]=1>C(Cl)(Cl)Cl.P(Br)(Br)Br>[BrH:1].[Br:1][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][NH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCOC1=CC=CNC=C1
Agent: Br
Agent: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: BrCCOC1=CC=CNC=C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of (C) (8 g) in dry chloroform, phosphorous tribromide (8 ml) was added. The mixture was stirred for 24 hours at room temperature. The solvent was stripped in vacuo, and the residue was triturated with five 50 ml portions of dry ether, and finally dried in vacuo to give (D) as a viscous oil.
Reaction SMILES: [Br:1][CH2:2][CH:3]([S:6]([C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:8])=[O:7])[CH2:4]Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:9]([S:6]([C:3](=[CH2:4])[CH2:2][Br:1])(=[O:7])=[O:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(=O)(=O)C(CBr)CBr
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C(CBr)S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of 16.78 g (0.052 mol) of 1,3-dibromo-2-(t-butylsulfonyl) propane and 14 mL (0.12 mol) of 2,6-lutidine in 55 mL of CH2Cl2 was refluxed for 75 minutes. The solution was allowed to cool to room temperature and extracted with three 80-mL portions of 5% HCl followed by 80 mL of water. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. to give 11.46 g (91%) of the allyl bromide as a white solid, mp 40.5°-42.0° C., which was used without further purification; IR (KBr) 2980 cm-1,1480, 1395, 1230, 1100, 970, 730, 640; 1H NMR (CDCl3) δ1.40 (s, 9H, t-butyl), 4.30 (s, 2H CH2Br), 6.50 (s, 2H, vinyl).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[Br:14]Br>CO>[Br:14][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:26]([CH3:28])[CH3:27])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:26]([CH3:27])[CH3:28])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CN(C)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 91 step E from 6-chloro-4-(3-chloro-phenyl)-2-dimethylamino-quinoline-3-carboxylic acid tert-butyl ester (70 mg, 0.17 mmol) and 4N HCl in dioxane. Off white solid (41 mg, 68%). LC-MS (ESI): 361 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1Br.[Cu](C#N)[C:23]#[N:24].N>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:23]#[N:24]
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(Br)c2)cc1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Temperature: 140 °C

Procedure:
15 g (4-(2-hydroxyethyloxy)-3-bromo-4′-cyanoazobenzene are dissolved in 25 ml hot DMF. 4.3 g copper cyanide are then added and the reaction mixture is stirred at 140° C. for 5–6 hours. This solution is added to approx. 500 ml of a 13% aqueous ammonia solution and the precipitate is filtered off. The precipitate is dissolved in hot dioxane. The solution is filtered off from the undissolved residue, the dioxane is evaporated off on a rotary evaporator and the product is purified by chromatography on silica gel in toluene/THF (½) and recrystallized once from ethanol. The yield of 4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene is 4.5 g. M.p.=138° C.; max=356 nm (DMF).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[C:18](OCC)(=[O:24])[C:19](OCC)=[O:20]>>[N:11]1([C:4]2[CH:5]=[C:6]3[C:7](=[CH:8][C:3]=2[C:2]([F:1])([F:16])[F:17])[NH:9][C:19](=[O:20])[C:18](=[O:24])[NH:10]3)[CH:12]=[CH:13][CH:14]=[CH:15]1
Reactant: Nc1cc(-n2cccc2)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared by the method of Example 1f from 0.8 g (3.3 mmol) of N-(2-trifluoromethyl-4,5-diaminophenyl)pyrrole and 32 g (221 mmol) of diethyl oxalate.
Reaction SMILES: C[C@H]1CC[C@H]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:15]([O:25][CH3:26])[CH:14]=2)[C:9]([NH2:11])=[O:10])CC1>[C].[Pd].CO>[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:11][C:9](=[O:10])[CH2:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])=[C:15]([O:25][CH3:26])[CH:14]=2)[CH2:15][CH2:14]1
Reactant: COc1cc(C=C(C(N)=O)[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C

Procedure:
Using 2 g of N-(trans-4-methylcyclohexyl-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (Example 139), 0.1 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 1.89 g of N-(trans-4-methylcyclohexyl)-3-[4-(2-dimethylaminoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([C:14]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=3[C:21]([F:24])([F:23])[F:22])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+]>CO>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([F:24])([F:22])[F:23])=[C:14]([CH2:12][C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:19]=1
Reactant: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)-acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride.diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30]([N:32]1[CH2:35][C:34]2([CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:37]3[CH2:38][CH2:39][C:34]4([CH2:35][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:33]4)[CH2:36]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.3 g, 1 eq.) dissolved in ethylacetate (20 mL) and cooled to −70° C. where tert-butyl-2,6-diazaspiro[3.4]octane-2-carboxylate (0.22 g, 1.2 eq.), T3P (50% in EtOAc) (0.61 mL, 1.2 eq.), followed by DIPEA (0.6 mL, 4 eq) were added. The clear reaction mixture was stirred at −60° C. for 1 h, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-4% Methanol in DCM) to yield (Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (0.2 g; 43% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[N+:15](=[CH2:17])=[N-:16]>C(OCC)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:17]=[N+:15]=[N-:16])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: Cc1ccc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O

Procedure:
12 g of 4-methyl-3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the substance precipitating as fair yellow precipitate was filtered off. Melting point: 176° C. (decomposition).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:19]#[C:20][CH2:21][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.C(O)C>[Pd].C(OCC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14]1
Reactant: CC1(C)CC(c2ccc(C#CCN3CCCCCC3)cc2Cl)CC(C)(C)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CC(c2ccc(CCCN3CCCCCC3)cc2Cl)CC(C)(C)C1
Yield: 59 %

Procedure:
3.6 g of the compound of EXAMPLE 1 are hydrogenated in the presence of 0.36 g of 10% palladium on charcoal and 50 ml of ethanol. The reaction mixture is filtered, and the filtrate is evaporated off under reduced pressure. The oily residue obtained is taken up in diethyl ether and hydrochloric acid is bubbled through. The precipitate obtained is filtered off and dried; yield=59%; m.p.=215° C. (HCl).
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:10][CH:9]=1)=[O:3].[O-]O.S(=O)(O)[O-:33].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][S:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:10][CH:9]=1)(=[O:33])=[O:3]
Reactant: O=S([O-])O
Reactant: CS(=O)CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Agent: [Na+]
Agent: [O-]O
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCCS(C)(=O)=O)s3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound of Step D (192 mg, 0.43 mmol) was dissolved in 5 ml TFA and 3 ml DCM. At room temperature 22 mg (0.64 mmol) hydroperoxide 30% were added. This mixture was stirred at room temperature for 4 hours. Afterwards 10 ml 10% sodium bisulfite solution was added and stirring continued for 15 minutes. The solution was basified with 40% NaOH and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 75 mg (37%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=[O:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23].[I:24](C1C=CC=C(CC([O-])=O)C=1CC([O-])=O)=O>C1C=CC=CC=1>[F:23][C:3]1[C:2]2[C:11](=[N:12][O:13][N:1]=2)[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:24])=[CH:18][C:17]=1[CH3:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Solvent: c1ccccc1
Product: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nonc2c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (from Step d, Example 1) and iodosobenzenediacetate (1.76 equiv.) in benzene is stirred at ambient temperature for 5 hours. The mixture is concentrated in vacuo and the residue purified by column chromatography to give the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@@H](C)CS3(=O)=O)cc2F)CC1
Yield: 34.4 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (180 mg) described in Preparation Example 7 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (371 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 4, the title compound (144 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-nitro-pyridine (1.74 g) and 1,1,1-trifluoro-propan-2-ol (1.097 g) in DMF (15 ml) under an argon atmosphere was added under ice cooling NaH (0.528 g, 55% suspension in oil). The mixture was stirred for 3 h at RT then partitioned between diethyl ether and water, the layers were separated dried over Na2SO4 and the solvent was evaporated off to give (rac)-5-nitro-2-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine as brown oil (2.28 g) that was used in the next step without further purification.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[C:23]([C:27]1[CH:50]=[CH:49][C:30]([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[C:43]([F:45])[C:42]([O:46]C)=[CH:41][C:40]=3[F:48])[CH2:35][CH2:34]2)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:50]=[CH:49][C:30]([C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:39]3[CH:44]=[C:43]([F:45])[C:42]([OH:46])=[CH:41][C:40]=3[F:48])[CH2:37][CH2:38]2)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc(F)c(N2CCN(C(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CC(C)(C)c1ccc(C(=O)N2CCN(c3cc(F)c(O)cc3F)CC2)cc1
Yield: 67.6 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-(4-tert-butylbenzoyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (433 mg), to provide crude 1-(4-tert-butylbenzoyl)-4-(2,5-difluoro-4-hydroxyphenyl)piperazine (282 mg).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:17]([C:25]([NH:27][C@H:28]([C:33](O)=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23].[NH2:53][C@H:54]([C:58]([NH:60][C@H:61]([C:69]([NH:71][C@H:72]([C:77]([O:79][CH2:80][C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)=[O:78])[C@H:73]([CH2:75][CH3:76])[CH3:74])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:68])[NH2:67])=[O:59])[CH:55]([CH3:57])[CH3:56].C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[NH:16]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:53][C@H:54]([C:58]([NH:60][C@H:61]([C:69]([NH:71][C@H:72]([C:77]([O:79][CH2:80][C:81]1[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=1)=[O:78])[C@H:73]([CH2:75][CH3:76])[CH3:74])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:67])[NH2:68])=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)C(C)C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)CC)C(C)C

Procedure:
3.3 g of DCC are added, at 0° C., to a stirred solution of 7.4 g (15 mmol) of Fmoc-Arg-Ile-OH, 7.15 g of H-Val-Arg-Ile-OBzl and 2.44 g of HOObt in 150 ml of dimethylformamide. The working-up is carried out in analogy to Example 2b. The dried residue is triturated with ethyl acetate, filtered off with suction and dried.