Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[ClH:14].Cl.[CH2:16]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:14].[CH2:16]([N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:4])[CH2:27][CH2:26]1)[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=C(CCl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1

Procedure:
A mixture of 2-chloro-1-(4-nitrophenyl)ethanone (3.2 mmol), N-phenacyl piperazine dihydrochloride (3 mmol), and K2CO3 (9 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-11), 0.71 g (61%), mp 204-205° C., M+ 367.
Reaction SMILES: CCCCC[C@H](O)/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19]CC(O)=O)[C:12](=[O:13])[CH:11]=[CH:10]1.C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[C:14]1([C:9]2[CH:8]=[CH:7][C:12]([OH:13])=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example 1 but using 0.561 g. of PGA2, 0.302 ml. of triethylamine, 0.286 ml. of isobutylchloroformate, and 0.570 g. of p-phenylphenol, there is obtained a crude oily residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3) saturated with water. The residue obtained by concentration of selected fractions, 0.381 g., an oil, is the title compound, having Rf 0.5 (TLC on silica gel in ethyl acetate-hexane (2:3).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:18])=[C:8]3[C:13](=[C:14]([OH:15])[C:4]2=[CH:3][CH:2]=1)[C:12](O)=[CH:11][CH:10]=[C:9]3O.[CH3:19][NH:20][CH2:21][CH2:22][NH2:23]>>[CH3:19][NH:20][CH2:21][CH2:22][NH:23][C:12]1[C:13]2[C:14](=[O:15])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:18])[C:8]=2[C:9]([NH:23][CH2:22][CH2:21][NH:20][CH3:19])=[CH:10][CH:11]=1
Reactant: CNCCN
Reactant: Oc1ccc(O)c2c(O)c3ccccc3c(O)c12
Product: CNCCNc1ccc(NCCNC)c2c1C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2.4 g. of leuco-quinizarin and 25 g. of de-aerated N-methylethylenediamine is heated at 50° C. with stirring under nitrogen for one hour. Heating at 50° C. is continued as air is bubbled into the mixture for 40 minutes. The mixture is evaporated to dryness, then re-evaporated twice from 25 ml. portions of ethanol. Crystallization of the residue from ethanol-ether at -70° C. gives 2.32 g. of crude solid which is recrystallized twice from carbon tetrachloride giving 1.92 g. of the desired product as dark blue crystals, mp. 131°-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]

Procedure:
The 3-hydroxy-4-nitrobenzoic acid starting material is acetylated using, for instance, acetic anhydride and pyridine at reflux temperatures for 1-4 hours to afford 3-acetoxy-4-nitrobenzoic acid. This compound is then dissolved in a non-polar, aprotic solvent, such as benzene or toluene, and refluxed with thionyl chloride for a period of about 2-6 hours to form the desired 3-acetoxy-4-nitrobenzoyl chloride.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N=Cc2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)NNc1ccc(NCc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzalaminophenyl)hydrazine (5.1 g, 0.02 mole) and platinum oxide (catalytic amount) were suspended in ethanol (200 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a white crystalline powder. Yield 4.7 g (92%), m.p. 118°-120° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41]1([P:47](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([P:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])[O:32][C:30]([CH3:31])=[C:16]([N:13]2[C:12](=[O:33])[CH:11]3[CH:14]2[S:15][C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]3)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OP(=O)(c1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 ml) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by diphenylphosphinyl chloride (2.73 g.) dropwise over 5 minutes. After stirring for 3 hours at 20° C., the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1% hydrochloric acid and then water, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silica) RF 0.54 (ethyl acetate). NMRδCDCl3 2.5 (s, 3H), 3.63 and 4.40 (ABq, 2H, J=14 Hz), 5.13 (s, 2H), 5.68 (d, 1H, J=4 Hz), 5.85 (d, 1H, J=4 Hz) and 6.5-8.03 (m, 20H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>>[C:25]([C:27]1[CH:32]=[C:31]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:30]=[CH:29][CH:28]=1)#[N:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 21 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-cyanophenylboronic acid (available from Combi-Blocks Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (19 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 13.30 (br s, 1H), 8.48 (s, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.85-7.92 (m, 2H), 7.71-7.81 (m, 2H), 7.57-7.69 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[S:16][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:30][CH2:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])(=O)=O>CC#N.C(OCC)C>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 7-hydroxychromane-3-carboxylate (250 mg, 1 mmol) in CH3CN (10 ml), K2CO3 (414 mg) and 3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propyl methanesulfonate (325 mg) were added and the reaction mixture was heated under reflux for overnight. The reaction mixture was cooled to room temperature and diluted with 30 mL of diethyl ether. The diluted solution was passed through a pad of silica and the silica was washed with more ether. The ether solution was evaporated to dryness and purified using silica chromatography. The product was isolated as a white sold (397 mg, 88%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[O:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:20]2[CH2:21][CH2:22][CH:18]([O:17][C:16]3[CH:23]=[CH:24][CH:25]=[C:14]([F:13])[CH:15]=3)[CH2:19]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cccc(OC2CCNC2)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(F)c2)C1
Yield: 60.9 %

Procedure:
The title compound (D95) (250 mg) was prepared according to the experimental procedure described in Description 62 starting from methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and 3-(3-fluorophenoxy)pyrrolidine (D60) (253 mg, 1.39 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[Cl-].O[NH3+:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:13]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: [NH3+]O
Agent: [Cl-]
Product: N#Cc1ccc(O)c(Cl)c1

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxyl ammonium chloride, using the same method as that described for preparation 70. The title compound was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as a white solid in 76% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH:23]([CH3:24])[CH3:25])[C:20]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 100 °C
Yield: 97.7 %

Procedure:
A mixture of 890 mg (2.52 mmole) of (3S, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-isopropyldihydrofuran-2(3H)-one (prepared as described in Preparation 1) and 2.5 ml (25.3 mmole) of butylamine was heated at 100° C. for 4 hours. At the end of this time, an excess of the butylamine was removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure column chromatography through silica gel (using a 20:1 by volume mixture of methylene chloride and methanol as the eluent), followed by recrystallization from diisopropyl ether, to afford 1.05 g (yield 98%) of the title compound as white crystals, melting at 115°-118° C. [α]D20 =-34.9° (c=1, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1cc(-c2ccc(N)cc2)no1
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 53 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (S)-methyl 1-(3-(4-aminophenyl)isoxazole-5-carbonyl)pyrrolidine-2-carboxylate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 53% of the title compound. MS (ES+): m/z 453 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ: 9.35 (s, 1H), 8.65 (s, 1H), 8.15 (m, 1H), 7.92 (d, 2H), 7.66 (s, 1H), 7.6 (d, 2H), 7.26 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 3.92 (t, 1H), 3.67 (s, 3H), 3.65 (m, 1H), 2.29 (m, 1H), 1.97 (m, 2H), 1.24 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH:17]([C:20]1[N:24]2[N:25]=[CH:26][C:27]3[C:32]([C:23]2=[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]=1/[CH:39]=[CH:40]/[CH:41]=[O:42])=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[OH:42][CH:41](/[CH:40]=[CH:39]/[C:21]1[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[N:25][N:24]2[C:20]=1[CH:17]([CH3:19])[CH3:18])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1c(/C=C/C=O)c(-c2ccccc2)c2c3ccccc3cnn12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A stirred suspension of sodium hydride (80% dispersion in oil, 112 mg; 3.7 mmol) in dry tetrahydrofuran (15 ml) was treated with ethyl acetoacetate (0.43 g) under an atmosphere of argon, maintaining the temperature at -10° C. The mixture was stirred for 30 minutes and then it was treated with a solution of butyl lithium in hexane (2.5M; 1.38 ml), still maintaining the temperature at -10° C. The mixture was stirred for a further period of 20 minutes and then it was treated dropwise with a solution of (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propenal (0.56 g) in tetrahydrofuran (5 ml) at -10° C., and the resulting mixture was stirred at -10° C. for 1 hour. The reaction mixture was then quenched at -10° C. by treatment with saturated aqueous ammonium chloride solution (15 ml). The mixture was allowed to warm to the ambient temperature and then it was partitioned between water (20 ml) and diethyl ether (50 ml). The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml). The combined organic layers were dried over magnesium sulphate, evaporated and subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v), to give ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-3-oxohept-6-enoate (0.33 g) in the form of an orange oil. [NMR (in a mixture of CDCl3 and D2O): 1.27 (3H, t, J=7 Hz), 1.54 (6H, d, J=7 Hz), 2.52-2.62 (2H, m), 3.44 (2H, s), 3.78 (1H, septet, J=7 Hz), 4.21 (2H, q, J= 7 Hz), 4.50-4.62 (1H, m), 5.3 (1H, dd, J=16 Hz, 7 Hz), 6.65 (1H, dd, J=16 Hz, 1 Hz), 7.22-7.62 (9H, m), 8.24 (1H, s)].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[OH-].[Na+].[OH-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.O>[CH2:13]([O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: NC1CCCCC1OCc1ccccc1

Procedure:
0.2 mol of trans-2-aminocyclohexanol are dissolved in 600 ml of xylene isomer mixture and heated to reflux. 0.2 mol of a 50% sodium hydroxide or potassium hydroxide solution in water is added dropwise to this solution over 15 minutes. In the course of this, the water which has been introduced and which forms is distilled off immediately. After the addition has ended, the water present in the reaction solution is distilled off further until a transition temperature of 140-141° C. is attained. Thereafter, 0.2 mol of benzyl chloride is added dropwise over 30 minutes and the solution is stirred further under reflux for two hours. After aqueous workup, the desired 2-benzyloxycyclohexylamine is obtained in 62% (GC area%) yield in the case of sodium hydroxide, and in 69% (GC area%) yield in the case of potassium hydroxide.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:19])(=[O:18])[CH2:16][CH3:17]>>[ClH:19].[C:9]1([N:6]2[CH:7]=[CH:8][C:3](=[N:2][C:15](=[O:18])[CH2:16][CH3:17])[CH:4]=[N:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: CCC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 41 %

Procedure:
5.0 g (24.1 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of propionyl chloride were refluxed for 20 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was recrystallized from ethanol/methyl tert.-butyl ether. 2.6 g (41% of theory) of 1,4-dihydro-1-phenyl-4-(propionylimino)-pyridazine hydrochloride were isolated as slightly yellowish crystals of melting point 214°-215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[O:11][C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[O:8])[S:5][CH:6]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:3]=[C:4]([C:7]([NH:9][C:10]4[O:11][C:12]([C:15]5[O:16][CH:17]=[CH:18][CH:19]=5)=[N:13][N:14]=4)=[O:8])[S:5][CH:6]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cs1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3csc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 4-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-thiophenecarboxamide prepared in Reference Example 12 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[OH:37])[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[OH:37])[CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCNc1ccc(-c2ccc(C(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of methyl 4′-[[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) was added 1N aqueous sodium hydroxide solution (1.05 ml) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and to the residue were added ethyl acetate (40 ml) and water (20 ml). The pH value was adjusted to 5.70 by addition of 0.1N hydrochloric acid and the separated organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (123 mg) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[Li]CCCC.[I:20]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OC)(C)(C)C.C1CCCCC1.O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([I:20])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 33 g of freshly distilled N-(5-fluoro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.168 mol) in 500 mL tert-butylmethylether at −78° C. was added dropwise 323 mL of a ca. 1.3 M solution of sec BuLi (0.42 mol) in cyclohexane at a rate that the temperature did not exceed −60° C. (liquid nitrogen cooling; ca 5 min). The mixture was stirred at −78° C. for 30 min. To the resulting light yellow suspension was added dropwise a solution of 107 g iodine (0.420 mol) in 150 mL tetrahydrofuran at a rate that the temperature did not exceed −65° C. (liquid nitrogen cooling; ca 5 min). The mixture was then stirred at −78° C. for 2 h. To the resulting suspension was added a 10% sodium thiosulfate solution in water (800 mL) and the phases were separated. The organic phase was washed with a 10% solution of sodium thiosulfate in water, 10% citric acid solution in water, 10% sodium bicarbonate solution in water and brine, dried over magnesium sulfate and concentrated under aspirator vacuum whereby crystallisation occurred. The solid was collect by filtration and washed with cyclohexane and air-dried to constant weight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1)=[CH2:6])[CH3:2].[C:25]([OH:28])(=[S:27])[CH3:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1)[CH2:6][S:27][C:25](=[O:28])[CH3:26])[CH3:2]
Reactant: C=C(C(=O)OCC)c1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CC(O)=S
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CSC(C)=O)c1ccc(NC(=O)OCc2ccccc2)cc1

Procedure:
A solution of 2-(4-(benzyloxycarbonylamino)phenyl)prop-2-enoic acid ethyl ester (2.2 g, 7.55 mmol) and thioacetic acid (5 mL) in 10 mL of chloroform was heated for 18 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography through silica gel (5/1 hexanes/ethyl acetate) to afford 2-(4-(benzyloxycarbonylamino)phenyl)-3-(acetylthio)propanoic acid ethyl ester, 0.22 g (8%) as an oil.