Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1>>[Br:1][CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: CC(=O)C(C)(C)CSc1ccc(Cl)cc1
Reactant: BrBr
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Yield: 98.7 %

Procedure:
64 g (0.4 mol) of bromine were slowly added to 97 g (0.4 mol) of 1-(4-chlorophenylmercapto)-2,2-dimethyl-butan-3-one at room temperature. The reaction mixture was worked up in a manner corresponding to that in Example 1. 127 g (99% of theory) of 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a viscous oil. ##STR823##
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([CH:12]([OH:26])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([CH:12]([OH:26])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(NC(=O)C(O)c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)C(=O)Nc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 22e, by reacting 0.7 g (1.54 mmol) of methyl 4-[2-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthyl)-2-hydroxyacetylamino]benzoate with 0.25 g (6 mmol) of lithium hydroxide hydrate, a solid is obtained (0.68 g; yield=91%; m.p.=145° C.).
Reaction SMILES: [C:1]([Cl:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cu][C:9]#[N:10].C#N.Cl>[Cu]>[C:1]([Cl:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:1]([C:9]#[N:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#C[Cu]
Agent: [Cu]
Agent: C#N
Agent: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)C#N
Yield: 98 %

Procedure:
A mixture of 120.6 grams (1.0 mole) of pivaloyl chloride, 9.0 grams (0.1 mole) of copper (I) cyanide, 6.4 grams (0.1 gram atom) of pulverized copper and 150 ml of 2-methylglutaric acid dinitrile were treated in the course of 6 hours with 29.7 grams (1.1 moles) of hydrogen cyanide. The mixture in the meanwhile was held under nitrogen at a temperature of 90° to 110° C. Hereby there escaped hydrogen chloride and hydrogen cyanide; the hydrogen cyanide was condensed and returned. From the reaction mixture by fractional distillation under reduced pressure there were obtained 10 grams of pivaloyl chloride and 96 grams of 98% pivaloyl cyanide. The yield of pivaloyl cyanide amounted to 85% based on the pivaloyl cyanide employed. For further batches in each case there was used the residue remaining in the distillation of the previous reaction mixture. To these there were added first 120.6 grams (1.0 mole) of pivaloyl chloride and then in the course of 6 hours 29.7 grams (1.1 moles) of hydrogen cyanide. For the rest the process was as previously described. The yields of pivaloyl cyanide amounted to 86 to 88% based on the pivaloyl chloride employed.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](Cl)=[S:19])=[CH:13][CH:12]=1.C(OCC)C>O>[O:17]([C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:18]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:19]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: S=C(Oc1ccccc1)SCc1ccccc1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Benzyl mercaptan (1.24 g, 10 mmol) was added to an aqueous (20 mL) solution of NaOH (0.8 g, 20 mmol) at room temperature and stirred for 15 minutes. Phenyl thionochloroformate (2.07 g, 12 mmol) was next added dropwise to this solution at the same temperature and stirred for a further 2 hours. Diethyl ether (20 mL) and water (50 mL) was added and the organic layer separated. The aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic fractions were dried with Na2SO4, filtered, the solvent removed and the crude product chromatographed (using silica gel, 2% ethyl acetate in petroleum spirits) to afford the title compound (1.95 g, 75%) as a yellow oil. 1H-nmr (CDCl3) δ 4.43 (2H), 7.10-7.50 (10H). 13C-nmr (CDCl3) δ 41.7, 122.1, 126.7, 127.8, 128.8, 129.3, 129.6, 135.1, 154.0, 213.0.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH3:19]
Reactant: CCI
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cscc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is reacted with 2.8 g. of 50% sodium hydride in mineral oil in 175 ml. of dimethylformamide. After 2 hours 11.5 g. of ethyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is poured into ice-water. After 3 hours the brown crystals are collected, washed with water and then ether and dried. The solid is heated to boiling in 75 ml. of methanol, filtered and the filtrate is treated with charcoal, reheated to the boil and filtered through diatomaceous earth. To the filtrate is added, portionwise with swirling, 100 ml. of water. The mixture is cooled in a chill room and the solid is collected, washed with ether and dried giving the desired product, mp. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][CH:19]=O)[CH:10]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([CH2:18][CH2:19][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[CH:10]=1
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CC=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of 2-(2′,5′,6-trichloro-4-methoxybiphenyl-3-yl)acetaldehyde (300 mg, 0.92 mmol) in DCM (20 mL) at room temperature, tert-butyl piperazine-1-carboxylate (205 mg, 1.1 mmol) was added followed by drops of AcOH. The reaction mixture was stirred at room temperature for 1 h, and then NaBH(OAc)3 (1.95 g, 9.2 mmol) was added. The resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-33% ethyl acetate/petroleum ether) to afford the desired product (350 mg, 77% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:49]([O-])=[O:50].[Na+]>>[CH2:1]([N:8]([N:49]=[O:50])[C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C(NCc1ccccc1)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a ice-cold solution of 3.10 g (5.85 mMol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 19.1 ml (333 mmol) acetic acid and 40.14 ml (708 mmol) acetic anhydride were added in portions over 20 min. 2.02 g (29.25 mmol) sodium nitrite. The reaction mixture was stirred overnight at room temperature and evaporated. The residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 by adding solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Yellow foam (85%). MS (Turbo Spray): m/z=559.2 [M+H].
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:8]4[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:3][CH2:4]4)[C:15]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 45.9 %

Procedure:
4-chloro-3-nitro-pyridine (1 g, 6.307 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.145 g, 6.938 mmol) and PdCl2(PPh3)2 (221.4 mg, 0.3154 mmol) in DME (20.00 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (9.460 mL of 2 M, 18.92 mmol) was added followed by further degassing and the reaction heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column, eluting with 0 to 70% EtOAc/Petroleum Ether, dry loaded) to give tert-butyl 3′-nitro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate as a pale yellow solid (884 mg, 46% Yield). MS (ES Na+) 328.1.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:36])[CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:59]([O:63][C:64](=[O:72])[NH:65][CH2:66][C:67]([CH3:71])([CH3:70])[CH2:68][NH2:69])([CH3:62])([CH3:61])[CH3:60].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:1][CH2:2][C:3](=[CH2:36])[CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:69][CH2:68][C:67]([CH3:71])([CH3:70])[CH2:66][NH:65][C:64](=[O:72])[O:63][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:30])=[CH:32][CH:33]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (1.1 g) and TBTU (0.74 g) in NMP (10 mL) was added tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (0.51 g) and DIPEA (1.47 mL). After stirring at room temperature for 2 hours, the mixture was diluted with 100 mL of water and extracted with EtOAc (2×150 mL). The organic layer were combined, washed with brine (100 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel column to give tert-butyl 3-(4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamate (1 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.C([NH2:25])=O>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[N:25]=[C:11]([OH:12])[C:10]3[C:9](=[C:17]([CH3:18])[C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: COc1ccc(C(=O)O)c(NC(=O)c2ccc(F)cc2)c1C
Product: COc1ccc2c(O)nc(-c3ccc(F)cc3)nc2c1C
Yield: 83 %

Procedure:
2-(4-Fluoro-benzoylamino)-4-methoxy-3-methyl-benzoic acid (29) (830 mg, 2.7 mmol) was heated to 150° C. in formamide (20 ml) for 4 h. The excess formamide was removed by distillation. Water was added and the precipitated product was filtered of to give pure title compound (642 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH2:6].[N:19]1[CH:24]=[C:23]([C:25]([NH:27][C:28]2([C:31](O)=[O:32])[CH2:30][CH2:29]2)=[O:26])[CH:22]=[N:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH:6][C:31]([C:28]1([NH:27][C:25]([C:23]2[CH:22]=[N:21][CH:20]=[N:19][CH:24]=2)=[O:26])[CH2:30][CH2:29]1)=[O:32]
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: COc1ccc(Oc2ccc(CN)cc2F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.7 mg (0.1 mmol) of 3-fluoro-4-(4-methoxy-phenoxy)-benzylamine were dissolved in 1 ml DMF. 20.7 mg (0.1 mmol) of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (prepared in 1b) were also dissolved in DMF and 35.3 mg (0.11 mmol) and 21 μl triethylamine (0.15 mmol) were added. Shaken overnight at ambient temperature and purified by reversed-phase chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(-c2ccc(F)cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
A mixture of 0.9 g (4.8 mmol) of 4-(4-fluorophenyl)pyridine-1-oxide and 10 mL of phosphoryl chloride is heated at reflux overnight.
Reaction SMILES: [OH-].[K+].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][CH:5]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([CH3:15])[O:12][N:11]=3)=[CH:6][CH:5]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)no1
Temperature: 90 °C

Procedure:
A well stirred mixture of 0.015 mmol of bis(tri-t-butylphosphine)palladium, 0.01 mmol of cetyltrimethylammonium bromide, 2 mmol of powdered potassium hydroxide, 2 mmol of 3-(4-bromo-phenyl)-5-methyl-[1,2,4]oxadiazole and 2.1 mmol of N-BOC-piperazine in 1 ml of toluene was heated under Ar to 90° C. for 17 hours. The resulting reaction mixture was diluted with water, extracted with ethyl acetate and the product purified by column chromatography (SiO2; cyclohexane/ethyl acetate 7:3) to yield the title compound as a yellowish solid. MS (m/e): 345.3 (MH+, 100%)
Reaction SMILES: C(OC([NH:8][CH:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[NH2:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[NH2:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[C:17]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccncc1)C(=O)O
Product: NC(Cc1ccncc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-(tert-butoxycarbonyl)-3-(pyridin-4-yl)-D,L-alanine [J. Gen. Chem. USSR, 40, 2488 (1970)]and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there were obtained (S or R)-α-amino-N-[(1S,2R,3 S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-4-yl)propionamide, MS: 267 (M+H)+, and (R or S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-4-yl)propionamide, MS: 267 (M+H)+, each as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:31][CH2:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13](=[O:14])[NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[N:12]=2)=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(C)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Aminophenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.30 g) obtained in Example 21 was dissolved in pyridine (20 ml) and acetoxyacetyl chloride (0.1 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using, as a mobile phase, chloroform/ethyl acetate=20:1. Theresidue was recrystallized from ethyl acetate to give 4-[5-(4-methylphenyl)-4-(2-thiazolylcarbamoyl)imidazol-2-yl]phenylcarbamoylmethyl acetate (0.13 g), melting point 250° C. or above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cccn4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-pyrazole as described in Example 49 and isolated as white solid (0.075 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.55-8.58 (m, 1H), 7.91 (d, J=4 Hz, 1H) 7.65-7.73 (m, 4H), 7.29-7.31 (m, 1H), 7.34 (d, J=8 Hz, 2H), 7.40 (d, J=4 Hz, 1H), 6.86 (d, J=2 Hz, 1H), 6.47 (d, J=2 Hz, 1H), 6.09-6.14 (m, 1H), 5.37 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=456.2; Rt=1.19 min; HRMS (M+H)+=456.16.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[OH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2>N1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(CCCO)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCCCN(C)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Yield: 97 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at −18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100% yield). p-Toluoyl chloride (4.26 g, 27.56 mmol) was added dropwise over 10 min to an ice-cooled solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (7.8 g, 25.05 mmol) in pyridine (100 ml). The resultant mixture NA as stirred for 2 h at 0° C., concentrated in vacuo and redissolved in ethyl acetate. The solution was washed with 10% citric acid and brine, then separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 30% ethyl acetate/hexane to give (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (97% yield). A solution of (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (0.91 g, 2.12 mmol) and triethylamine (5.0 ml) in DMF (5 ml) was stirred for 1 h at +80° C. The resultant mixture was cooled to room temperature and compound 1 (2.01 g, 1.74 mmol) was added. The reaction was diluted with DMF (5), stirred for 2 days, and then diluted with ether (100 ml). The precipitated solid was isolated by filtration, washed with ether and vacuum dried to afford compound 2b (89% yield) as a pale solid, which was sufficiently pure to be used in the next step without additional purification.