Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(=O)C>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([CH3:24])([CH3:25])[CH:22]=[C:21]([F:35])[CH2:20][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:27][CH:28]=1)[CH3:34]
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)(C)C=C(F)Cc2cccc(Oc3ccccc3)c2)cc1
Yield: 45.1 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.31 g), tetrahydrofuran (2 ml) and magnesium (24 mg), and 4-(4-ethoxyphenyl)-2-fluoro-methylpent-2-enyl acetate (Example 14) (70 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (44 mg, 45%/).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.Br.[Br:25][CH2:26][CH2:27][NH2:28]>C(N(CC)CC)C>[Br:25][CH2:26][CH2:27][NH:28][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCBr
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
272.1 g (976 mmol) of triphenylchloromethane, 800 ml of dichloromethane and 200 g (976 mmol) of 2-bromoethanamine hydrobromide are introduced into a 2-1 round bottom flask placed under nitrogen. The mixture is stirred and 300 ml of triethylamine are added dropwise and stirring is continued for 48 h. The triethylamine hydrochloride which precipitates is separated off, water is added to the filtrate, the organic phase is separated off and is washed with water and dried over sodium sulphate, and the solvent is evaporated off. An oil is obtained, which is purified by chromatography on a column of silica gel. After recrystallisation from a mixture of dichloromethane and cyclohexane 273.17 g of white solid are obtained. Melting point: 108°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([OH:22])=[C:17]([F:23])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([OH:22])=[C:17]([F:23])[CH:16]=1)[C:7](=[O:12])[CH:6]=2
Reactant: Oc1c(F)cc(CBr)cc1F
Reactant: Oc1cc2ccc(Br)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc2ccc(Br)cc2cn1Cc1cc(F)c(O)c(F)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-isoquinoline (1.30 g, 5.80 mmol) using 4-bromomethyl-2,6-difluorophenol (1.68 g, 7.54 mmol) and cesium carbonate (2.46 g, 7.54 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). The solid is collected by filtration, washed with water, ethyl acetate, and allowed to air dry under house vacuum. Drying will afford the desired product. Step (2): 2-(3,5-difluoro-4-hydroxybenzyl)-7-[3-(4H-[1,2,3]triazol-4-yl)prop-1-ynyl]-2H-isoquinolin-3-one
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 L glass parr vessel was charged with of 7-(benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (59.34 g, 0.151 mol), platinum on carbon (5%, 6.6 g) and acetonitrile (600 mL) to provide a black mixture. The vessel was placed on a shaker and pressurized with hydrogen gas (−50 psi, 3.4×105 Pa). After shaking for 18 hours at ambient temperature, the mixture was filtered through CELITE filter agent, and the filter cake washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 7-(benzyloxy)-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:12]=2[N:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49]>>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:18]=2)=[O:21])[CH:52]=[CH:51][CH:50]=1)#[N:49]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: N#Cc1cccc(NC(=O)c2ccc3[nH]c(Nc4c(Cl)cccc4Cl)nc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid (32 mg, 0.1 mmol) in DMF TEA (50 μL, 0.36 mmol) and TBTU (32.1 mg, 0.1 mmol) were added, followed by 3-amino-benzonitrile (11.8 mg, 0.1 mmol). After shaking overnight at room temperature, the solvent was removed i.vac. and the residue purified by preparative reverse phase chromatography (gradient H2O/AcCN=90:10 to 35:65; both solvents containing 0.1% TFA).
Reaction SMILES: O(C([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=2)[CH:7]=1)(C)C)O.CC(C)=[O:22]>S(=O)(=O)(O)O>[OH:22][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=2)[CH:7]=1
Reactant: COC(=O)c1ccc2cc(C(C)(C)OO)ccc2c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1

Procedure:
In the case where 1.0 g of the present compound, methyl 2-(2-hydroperoxy-2-propyl)naphthalene-6-carboxylate are heated in 10.0 g of acetone for 30 min at a temperature between 50° and 70° C. in the presence of 0.02 g of sulfuric acid as a catalyst, methyl 2-hydroxynaphthalene-6-carboxylate is formed nearly quantitatively. The thus formed compound is hydrolyzed nearly quantitatively into 2-hydroxynaphthalene-6-carboxylic acid (acid-6) by heating the thus formed compound for 30 min at a temperature between 20° and 50° C. in an aqueous about 1N alkali solution.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 153 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.403 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-fluoropyridin-2-amine (366 mg) in THF (dry) (15 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 15 hr and at 50° C. for 1 hr. The mixture was quenched with water at 0° C. carefully and water was added to form precipitates. The precipitate was crystallized from THF-MeOH/IPE to give the title compound (170 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH3:16])=[N:18][N:19]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(F)cc3)nn12

Procedure:
A mixture of 6.25 g. of 3-chloro-6-(p-fluorophenyl)pyridazine (prepared as in Example 8), 4.65 g. of acetylhydrazine and 50 ml. of butyl alcohol is refluxed until a clear solution results. The reaction mixture is cooled, filtered, and the solid precipitate washed with hexane and with water. The solid is recrystallized from 50 ml. of ethyl alcohol to give the product of the example as crystals, m.p. 227°-229° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J9) (306 mg. 1.0 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (246 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (333 mg).
Reaction SMILES: [CH3:1]CCCCC.C([Li])(C)(C)C.[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=O)=[CH:19]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=[CH2:1])=[CH:19]2
Reactant: COc1cc2cc(C=O)ccc2c(OC)c1OC
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (2.8 g) was suspended in dry THF (10 mL) under an argon atmosphere, and a 1.7 M hexane solution (3.3 mL) of tert-butyllithium was added to the suspension at −20° C. After stirring the mixture at room temperature for 1 hour, the reaction mixture was cooled again to −20° C., a solution of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.26 g) in dry THF (30 mL) was added dropwise thereto, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:33]([O:32][C:31]([N:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:24]2[O:19][CH2:20][CH2:21][O:22][C:23]=2[CH:28]=1)[CH:38]1[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]2=[O:1])[CH2:40][CH2:39]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To 24 mL of dichloromethane suspension containing 0.8 g of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 1.1 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.24 mL of acetic acid was added, at room temperature and stirred at room temperature for 1 hour. To the reaction mixture, 1.0 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate], to give 1.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate as a slight yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1.N1CCCCC1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1
Reactant: BrCC1CO1
Reactant: O=C1C=C(c2ccccc2O)CC1
Solvent: C1CCNCC1
Product: O=C1C=C(c2ccccc2OCC2CO2)CC1

Procedure:
2.0 g 3-(2-hydroxyphenyl)-2-cyclopenten-1-one are stirred with 30 ml epibromohydrin and catalytic amounts of piperidine for 1 hour at 100° C. After concentration, the mixture of epoxy- and bromohydrin is separated by high-pressure liquid chromatography. In this manner, 2 g 3-[2-(2,3-epoxypropoxy)phenyl]-2-cyclopenten-1-one are obtained as an oil which is then dissolved in 20 ml t-butanol. 2 ml of t-butylamine were added and the mixture is stirred at room temperature for 48 hours.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].CN1CCOCC1.[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][N:33]=1>C(Cl)Cl>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=3)[CH:10]=[CH:11][C:12]=2[Cl:18])=[CH:34][N:33]=1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc(N)nc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1ncc(NC(=O)c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2Cl)cn1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of intermediate 1 (Example 2) (380 mg, 1.11 mmol) in DCM was charged with CDMT (233 mg, 1.33 mmol), and NMM (0.3 mL, 2.73 mmol). After 1 hr of stirring, 2,5-diaminopyrimidine (121 mg, 1.10 mmol) was added and the solution was allowed to stir for 48 h. The mixture was concentrated and purified by HPLC to afford the title compound as a white solid (350 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([NH:22][O:23]C(=O)NC2C=CC=CC=2)[CH2:10][N:9]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>C(O)C>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:23][NH:22][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccccc1)ONC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Solvent: CCO
Product: O=C(Nc1ccc(Cl)c(Cl)c1)ONC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1

Procedure:
1 g of 5-(2-chlorophenyl)-2-hydroxyamino-7-nitro-3H-1,4-benzodiazepine of Example 18 is reacted with 0.56 g of 3,4-dichlorophenyl isocyanate and worked up as in Example 18. Yield: 1.1 g, melting point: 190° to 192° C. decomposition (from ethanol).
Reaction SMILES: [CH2:1](/[C:3](/[C:10](=[O:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2].O.[BH4-].[Na+].Cl>CO>[CH2:1](/[C:3](/[CH:10]([OH:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2]
Reactant: CC/C(C(C)=O)=C(/CC)C(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC/C(C(N)=O)=C(/CC)C(C)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
26 (diethyl (2E)-4-oxopent-2-enamide) (5.92 g, 35 mmol) is dissolved in MeOH (14 ml) and H2O (56 ml) and cooled to 0° C. To the resulting solution is added NaBH4 (0.50 g, 13.1 mmol) in portions over 5 minutes. After 15 minutes of additional stirring at 0° C., the reaction mixture is acidified with 2 M HCl (30 ml) and extracted with AcOEt (1 l and 2×0.75 l). The organic phases are washed with H2O (100 ml), saturated NaHCO3 (100 ml) and brine (100 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. 27 (rac-Diethyl (2E)-4-hydroxypent-2-enamide) (5.66 g, 94%) is obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2snc(Cl)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (20 mg, 0.04 mmol, 1.00 equiv, 90%), TFA (0.5 mL), CH2Cl2 (2 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The crude product (2 mL) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, Sum, 19*100 mm; mobile phase, Water of 0.05% TFA and CH3CN (40% CH3CN up to 100% in 6 min, hold 100% in 2 min, down to 40% in 0.1 min, hold 40% in 1.9 min); Detector, UV 220&254 nm. This resulted in 10 mg (59%) of 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoic acid as a brown solid. 1H NMR (400 MHz, CD3OD) δ 7.49 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 5.10 (s, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.75 (q, J=7.2, 15.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H18ClF2NO3S, 438.1 (M+H). found 438.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:13]/[C:12]([C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[OH:1])=[O:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C(F)(F)F)ccc1O
Product: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Temperature: 110 °C

Procedure:
1-[2-Hydroxy-5-(trifluoromethyl)phenyl]ethanone, (Preparation 860, 7.0 g, 0.0343 mol) was taken in dimethylformamide dimethylacetal (18.2 mL, 0.137 mol) at room temperature and then heated at 110° C. for 30 min. The reaction mixture was concentrated in vacuo and the crude product was crystallised from 2-propanol to give the title compound as bright yellow solid (6.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(O)(=O)C.Br>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccncc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.6 %

Procedure:
To a stirred solution of 4-acetylpyridine (10 mL, 90 mmol) in glacial acetic acid (40 mL) and 48% hydrobromic acid (15 mL), bromine (4.65 mL, 90 mmol) in glacial acetic acid (10 mL) was added dropwise. After addition, the solution was stirred at room temperature overnight. The white precipitate was filtered off and washed with absolute ethanol, thus obtaining the title compound (22.2 g, 90%) as a white solid containing traces of dibromoderivative, that was used as such in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:39](=[O:40])[C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added N-t-butyloxycarbonyl-L-phenylalanine (382 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (315 mg, 39%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NC1CCCC1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 83.1 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]+.