Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CC(=O)OC(C)(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.5 g), tert-butyl bromoacetate (0.2 ml) and triethylamine (0.31 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. After filtration, the filtrate was concentrated to a syrup, which was subjected to a chromatography on a silica gel with a mixture of toluene and ethyl acetate (20:1) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(tert-butoxycarbonylmethyl)piperazine (0.52 g). This compound was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-carboxymethyl-2-(3,4-dimethylbenzyl)piperazine hydrochloride (0.33 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(CC(=O)O)no1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)no1
Yield: 69 %

Procedure:
Synthesized from (5-methyl-isoxazol-3-yl)-acetic acid (J. Med. Chem., 34(2), 518, 1991) and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 69%.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=1)#[CH:2].I[C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]2[O:34][CH2:35][CH2:36][O:37][C:28]=12>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.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>[CH2:22]([C:6]1([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:27]3[S:31][C:30]([CH:32]=[O:33])=[C:29]4[O:34][CH2:35][CH2:36][O:37][C:28]=34)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]3[O:34][CH2:35][CH2:36][O:37][C:28]=13)=[CH:15][CH:14]=2)[CH2:23][CH2:24][CH3:25]
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Reactant: O=Cc1sc(I)c2c1OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)c2cc(C#Cc3sc(C=O)c4c3OCCO4)ccc2-c2ccc(C#Cc3sc(C=O)c4c3OCCO4)cc21
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-dibutyl-9H-fluorene and 5-iodo-3,4-ethylenedioxythiophene-2-carboxaldehyde (Jessing, M.; Brandt, M.; Jensen, K. J.; Christensen, J. B.; Boas, U. J. Org. Chem. 2006, 71, 6734) (2.3 equiv) in toluene/Et3N (4/1) by blowing argon for 20 min. Then CuI (2×4 mol %) and Pd(PPh3)2Cl2 (2×4 mol %) were added, and deaeration was continued for 10 min. Thereafter the mixture was stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (heptane/CH2Cl2 50:50 then 40:60) to yield 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis(3,4-ethylenedioxy-2-thiophenecarboxaldehyde).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CCN(C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
A solution of crude tert-butyl 2-((2S,3S)-3-{[(benzyloxy)carbonyl]-amino}-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazinecarboxylate (906 mg, 1.8 mmol) in MeOH (15 mL) was added to 10% Pd/C (95 mg) and stirred in a hydrogen atmosphere (ambient pressure) for 4 h. The catalyst was filtered off over Celite and the filtrate was concentrated under reduced pressure to yield crude tert-butyl 2-((2S, 3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate. MS (ESI+) for C17H27F2N3O3 m/z 360.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[C:4]2[CH2:3]1.[N:21]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([N:19]=[N+:20]=[N-:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: O=N[O-]
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1Cc2c(C(=O)N=[N+]=[N-])ncn2-c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of 19 g (70 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide in 60 ml of water and 150 ml of glacial acetic acid is treated dropwise at 0° to 5° with a solution of 16.5 g of sodium nitrite in 30 ml of water. The white suspension is subsequently stirred in an ice-bath for 1 hour and cautiously poured into 150 g of sodium carbonate in 400 ml of water. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid azide which decomposes at 160°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>C(O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[N:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cnc(N2CCNCC2)nc1

Procedure:
To a solution of anhydrous piperazine (95 g; 1 mol) in ethanol (475 ml), there was added 2-chloropyrimidine (22.9 g; 0.2 mol), and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, a 5% aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The chloroform layer was washed thrice with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was distilled to give 1-(2-pyrimidinyl)piperazine. B.P., 131°-132° C./1.5 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH2:24])=[CH:21][C:15]=2[O:14]1.C(=O)(O)[O-].[Na+]>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][C:20]2[CH:19]=[CH:18][C:16]3[O:17][C:13]([F:25])([F:12])[O:14][C:15]=3[CH:21]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc2c(c1)OC(F)(F)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc3c(c2)OC(F)(F)O3)n1
Yield: 79 %

Procedure:
To a solution of 4,6-dichloro-2-methoxy-pyrimidine (0.606 g, 3.38 mmol, Intermediate (4)] and 2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethylamine hydrochloride (0.884 g, 3.72 mmol, Intermediate (62)]) in EtOH (11 mL) is added sodium bicarbonate (0.85 g, 10.14 mmol) and heated to reflux for 4 hours. The reaction mixture is filtered and filtrate is concentrated, residue solid is washed with small amount of EtOH to yield (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethyl]-amine [0.918 g, 79%, Intermediate (63)] as a solid. LC/MS: MS: 344 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7]([Cl:10])(=O)=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH3:1][C:2]1[S:6][C:5]([S:7][Cl:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Agent: O=S(=O)(O)O
Product: Cc1sc(SCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25.2 g (0.1 mcl) sample of 5-methyl-2-thienylsulfonyl chloride was added slowly to a solution of 100 cc concentrated sulfuric acid and 100 cc concentrated nitric acid. The resulting mixture was allowed to stir overnight at about 25° C. The reaction mixture was then added to ice water and filtered to give the 5-methyl-4-nitro-2-thienylsulfenyl chloride product.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: N#Cc1cccc(C=O)c1
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
The product of Example 268D (0.100 g, 0.27 mmol) was reacted with 3-formylbenzonitrile (0.362 g, 2.75 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.088 g, 69%).
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH3:12]>C(O)C>[CH2:11]([O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:12]
Reactant: CCBr
Reactant: Cc1ncccc1O
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1C

Procedure:
Sodium metal (46.2 g) was dissolved in absolute ethanol (1 l) with stirring under nitrogen. 3-Hydroxy-2-methylpyridine (200 g prepared as described in C.A. 48, P4597 h) was added. The mixture was stirred at ambient temperature for 30 minutes and then a solution of bromoethane (350 ml) in absolute ethanol (100 ml) was added. The mixture was boiled under reflux for 5 hours then cooled and filtered. The filtrate was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated off and the aqueous layer extracted with dichloromethane. The combined organic extracts were dried and evaporated. The residue was distilled to give 3-ethoxy-2-methylpyridine b.p. 80°-84° C. (20 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:23][CH:22]=1)(=[O:26])[CH3:25]
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc([C@@H]2CCCC[C@H]2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 42.5 %

Procedure:
To a mixture maintained at 0° C. of 4.0 g (12 mmoles) of trans-4-chloro-N-(2-phenylcyclohexyl)-benzenesulfonamide (prepared according to Das P. C. et al., Indian J. Chem. (1974), 12, 1139-40), 80 ml of anhydrous dichloromethane and 2.4 g (31 mmoles) of acetyl chloride, 5.3 g (40 mmoles) of aluminum chloride are added by fractions. After 4 hours at 0° C., the reaction mixture is thrown onto an ice-HCl mixture before being extracted with dichloromethane. The organic phase is washed with water to neutrality, dried over Na2SO4 and concentrated. The residue is purified by chromatography on a column of silica (eluant: hexane-ethyl acetate 4/1) to give 2 g of a colorless oil (yield: 42.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:17][C:18]([CH:19]1[CH:10]2[CH:11]1[C:12](=[O:13])[N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]2=[O:14])=[O:22])[CH3:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=CC(=O)N1c1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C2C(=O)N(c3ccc(Cl)cc3)C(=O)C12
Yield: 34.8 %

Procedure:
A solution of 19.4 g (93 mmol) of 1-(4-chloro-phenyl)-pyrrole-2,5-dione in 120 ml of xylene was treated with 19.4 ml (187 mmol) of ethyldiazoacetate and refluxed during 12 hrs. Evaporation of the solvent and chromatography on silica gel with toluene and then a gradient of toluene/AcOEt from 95:5 to 90:10 gave 9.5 g(35%) of the title compound. Off white solid. MS: 294 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: CC(C)(CN1CCOCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with morpholine to provide the title compound: MS m/z 255.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Cl)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-chloro-2-methylbenzoic acid methyl ester (5.62 g, 30.4 mmol), and N-bromosuccinimide (5.94 g, 33.4 mmol) in carbon tetrachloride (200 mL) was added benzoyl peroxide (800 mg, 3.30 mmol). The resulting suspension was immersed in an oil bath held at 85° C., and illuminated with a 300W halogen worklight. After stirring for 16 hours with heat and illumination the reaction mixture was allowed to cool to ambient temperature, filtered to remove the insoluble succinimide, and concentrated under reduced pressure to afford 2-bromomethyl-3-chlorobenzoic acid methyl ester as a yellow semi-solid. This crude material was carried on to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[O:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH:34]1([Mg]Br)[CH2:36][CH2:35]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([CH:34]3[CH2:36][CH2:35]3)[OH:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O)c1cccc(C(F)(F)F)c1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
103 mg (0.21 mmol) of 2-[3-(4-chlorophenyl)-4-(2-oxoethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 401 are dissolved in 1 ml of THF and treated at −78° C. with 1.1 ml (0.54 mmol) of cyclopropylmagnesium bromide (0.5 M solution in THF). This is stirred for 3 hrs at RT and then for a further 2 hrs at 50° C. For the workup, it is treated with saturated ammonium chloride solution and extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 12 mg (11% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2>>[NH:21]1[C:22]2[C:18](=[C:17]([NH:16][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2[nH]ccc12
Yield: 63.4 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.074 g) and 4-aminoindole hydrochloride (0.059 g) to give the title compound as a white solid (0.068 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)(=O)=O.[CH3:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl.CO>[I:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:26]2[CH2:27][CH2:28][C:23]([CH3:22])([OH:29])[CH2:24][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCOc1ccc(I)cc1
Reactant: CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC1(O)CCN(CCOc2ccc(I)cc2)CC1

Procedure:
The product was obtained analogously to Example 1.1g (3 hours at 70° C., potassium carbonate as base) from 4.79 g (14.0 mmol) of 2-(4-iodophenoxy)ethyl methanesulfonate and 1.94 g (16.8 mmol) of 4-methylpiperidin-4-ol. Yield: 3.40 g (67% of theoretical); C14H20INO2 (M=361.219); calc.: molpeak (M+H)+: 362; found: molpeak (M+H)+: 362; Rf value: 0.20 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:24]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:24]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
2.43 Grams of Z-Asn-Leu-Gln-NHNHBoc was suspended in 80 ml of methanol, a small amount of palladium black was added to the suspension, and the suspension was stirred for 18 hours under the condition of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure to remove the solvent, the residue obtained was dried under a reduced pressure in a desiccator to obtain the desired product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][O:37][C:38](=[O:50])[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH2:46][CH2:47][CH3:48])[C:40]=2[OH:49])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:30]1([CH2:36][O:37][C:38](=[O:50])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:41]([CH2:46][CH2:47][CH3:48])[C:40]=2[OH:49])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc(C(=O)OCc2ccccc2)c1O
Yield: 60.1 %

Procedure:
A mixture of 1.31 g (2.6 mmol) of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.74 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester and 0.54 g (3.9 mmol) of potassium carbonate in 35 mL of acetone was stirred at reflux for 39 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 1.03 g (60% yield) of 2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Br)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A suspension of 2-bromo-5-nitrobenzenamine (26.0 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (23.0 g) in chlorobenzene (150 ml) was heated to reflux under nitrogen and stirred for 15 hours before cooling to room temperature. The gummy mixture was diluted with dichloromethane (150 ml) and extracted with water (4×400 ml, acidified with 2N HCl). The combined aqueous extracts were basified with 2N sodium hydroxide (to pH 12) and extracted with dichloromethane (4×500 ml). The combined organic extracts were dried and concentrated in vacuo to give a brown oil which was purified by FCC eluting with System A (300:8:1 gradient to 200:8:1) to give the title compound as a brown solid (9.498 g) m.p. 100°-103° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][N:7](C(OCC)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][NH:7][CH2:6]1
Reactant: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)SCN2C3CNCC3CC21

Procedure:
6 g (22.2 mmol) of ethyl 9,9-dimethyl-10-thia-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate together with 12 g of Ba(OH)2 ×8H2O are refluxed overnight in 100 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction, and the filtrate is extracted ten times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCn1cc([N+](=O)[O-])cn1
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of 4-nitro-1H-pyrazole (1 equiv), 1-bromo-2-methoxyethane (1.05 equiv), potassium carbonate (1.5 equiv) and acetonitrile (0.44 M) was stirred and heated to 60° C. for 6 h. The resultant mixture was evaporated and the residue was purified by flash chromatography (2.5% MeOH in DCM) to afford the desired product as a yellow solid (76% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.25 (s, 1H), 8.08 (s, 1H), 4.34-4.31 (t, J=4.8 Hz, 2H), 3.77-3.74 (t, J=4.8 Hz, 2H), 3.37 (s, 3H).