Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]OS(C)(=O)=O)=[CH:19][N:18]=2)=[O:16])=[CH:11][S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].C(OCC)(=O)C.O>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:19][N:18]=2)=[O:16])=[CH:11][S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNCc1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
N-(4-t-Butoxycarbonylaminothiophen-3-yl)-5-methanesulfonyloxymethylpyridine-2-carboxylic acid amide (Reference Compound No. 4-1, 0.36 g, 0.83 mmol) and N,N-dimethylethylenediamine (0.46 mL, 4.2 mmol) were dissolved in anhydrous dichloromethane (5.0 mL)-anhydrous acetonitrile (5.0 mL), and then the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (0.10 L) and water (0.10 L) were added to the reaction solution, and then the mixture was partitioned. The organic layer was washed with brine (0.10 L), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 98 mg of the title reference compound as a brown amorphous product. (Yield 28%)
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:33])=[C:9]([C:24]([N:26]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:27])=[O:25])[C:10]([I:23])=[C:11]([C:21]=1[I:22])[C:12]([N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:15])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.[O:38]1[CH2:40][CH:39]1[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]1[CH2:47][O:46]1.Cl>C(#N)C.O.O.CO>[OH:38][CH:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]([OH:46])[CH2:47][N:6]([C:7]1[C:21]([I:22])=[C:11]([C:12]([N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:15])=[O:13])[C:10]([I:23])=[C:9]([C:8]=1[I:33])[C:24]([N:26]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:27])=[O:25])[C:3](=[O:1])[CH3:4])[CH2:40][N:6]([C:7]1[C:21]([I:22])=[C:11]([C:12]([N:14]([CH3:15])[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:13])[C:10]([I:23])=[C:9]([C:8]=1[I:33])[C:24]([N:26]([CH3:27])[CH2:28][CH:29]([OH:32])[CH2:30][OH:31])=[O:25])[C:3](=[O:5])[CH3:4]
Reactant: C(CCC1CO1)CC1CO1
Reactant: [OH-]
Reactant: CC(=O)Nc1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CCCCC(O)CN(C(C)=O)c1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I)c1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of water/methanol (4.9 ml, 2.5 ml) and potassium hydroxide (0.47 g, 8.4 mmol) at 40° C. was added 5-acetylamino-N,N′-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-N,N′-dimethyl isophthalamide (5.0 g, 6.5 mmol). To the clear solution was then added boric acid (0.28 g, 4.5 mmol). The mixture was cooled to room temperature and pH adjusted to 12.6. 2-(4-oxiran-2-ylbutyl)oxirane (0.315 g, 2.22 mmol) was added. The pH of the solution was adjusted to the interval 12.6-13. The reaction was left over weekend. To the solution was added HCl (18%) to pH 4. Salts were removed by treatment with ion exchanger AMB200C and IRA67. The solution was filtered from the resin and evaporated. An aliquot of the crude material was purified by preparative HPLC (column Phenomenex Luna C18(2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 10-18% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm), the product was obtained in 393 mg after lyophilisation. Analysis by LC-MS (column Agilent Zorbax SB-Aq 3.5 μm 3.0×100 mm, solvents: A=water/0.1% formic acid and B=acetonitrile/0.1% formic acid; gradient 0-30% B over 20 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave one broad peak centred at 14.77 minutes with m/z 1692.6 (MH+) corresponding to the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Nc2c(C(=O)O)cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.5 g of 4-ethoxyaniline in 250 ml acetonitrile was added over a 1.5 hour period to a solution of 20 g of 2,6-dichloro-3,5-dinitrobenzoic acid and 11 g of N,N-diisopropylethylamine in 400 ml of acetonitrile and stirred at room temperature for five hours. After the solvent was removed in vacuo, the residue was dissolved in 500 ml of chloroform and extracted with several portions of 5% ammonium hydroxide. The aqueous extracts were washed with chloroform and acidified with dilute acid. The resulting solid was collected by filtration and was washed with water to provide 2-chloro=6-[(4-ethoxyphenyl)amino]-3,5-dinitrobenzoic acid, mp 202°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15][CH2:30][CH3:31])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To a solution of 2-(5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)aniline (Example 62) (50 mg, 0.12 mmol, 1 eq) in THF (2 mL) was added acetaldehyde (0.028 mL, 0.49 mmol, 4 eq). After 15 min, sodium cyanoborohydride (61 mg, 0.98 mmol, 8 eq) and acetic acid (0.1 mL) were added and the solution stirred 3 days. Water and NaHCO3 were added, extracted with DCM, dried over MgSO4 and concentrated. Purification by column chromatography (8 g) eluting with 15 to 30% EtOAc/hex gave the title compound (28.3 mg, 50%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16](Cl)=[N:15][N:14]3[CH:20]=2)=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:4])=[O:3].[H][H]>[Pd]>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][N:14]3[CH:20]=2)=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: COc1cc(S(N)(=O)=O)ccc1-c1cn2nc(Cl)ccc2n1
Agent: [Pd]
Product: COc1cc(S(N)(=O)=O)ccc1-c1cn2ncccc2n1

Procedure:
Prepared from 2-(4-aminosulphonyl-2-methoxyphenyl)-6-chloro-imidazo[1,2-b]pyridazine and hydrogen in the presence of Pd/C analogously to Example 54.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:36][NH2:37].[CH2:38](O)[CH3:39]>>[CH3:4][C:16]1[CH:15]=[C:17]([CH:18]=[CH:38][CH:39]=1)[CH:22]=[N:36][NH:37][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1
Reactant: CCO
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(N5CCOCC5)cc4)cc3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-7-morpholin-4-yl-2-(4-morpholin-4-yl-phenyl)-pyrazolo[1,5-a]-pyrimidine (36.3 mg, 0.0908 mM) and then potassium carbonate (13.8 mg, 0.0999 mM) and hydrazine monohydrate (44.0 μL, 0.908 mM) were added to the suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (10.7 μL, 0.0908 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to give the title compound (23.8 mg, overall yield of these two steps: 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:14][CH2:13]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](OCCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester and 1,5-dibromopentane were reacted to yield trans-[4-(5-Bromo-pentyloxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester as yellow oil, MS: 433 (MH+, 1Br, 1Cl).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Cl)=[CH:13][N:12]=1)=[O:10].CC1(C)C(C)(C)OB([C:26]2[O:30][C:29]([Si](C(C)C)(C(C)C)C(C)C)=[N:28][CH:27]=2)O1>CN(C)C=O>[O:30]1[C:26]([C:14]2[N:15]=[CH:16][C:11]([C:9]([OH:8])=[O:10])=[N:12][CH:13]=2)=[CH:27][N:28]=[CH:29]1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-c2cnco2)cn1
Temperature: 80 °C

Procedure:
Aqueous Na2CO3 solution (2 M, 14.5 mL) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium dichloromethane complex (950 mg) are added to a mixture of 5-chloropyrazine-2-carboxylic acid methyl ester (2.00 g) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(isopropyl)silyl]-oxazole (4.70 g) in N,N-dimethylformamide (20 mL) under an argon atmosphere. The reaction mixture is stirred over night at 80° C. After cooling to room temperature, the solvents are evaporated, the residue is mixed water and acidified with 4 N hydrochloric acid (12 mL). A precipitate is formed upon addition of ethyl acetate, which is filtered off, washed with ethyl acetate and methanol, and dried. LC (method 7): tR=0.46 min; Mass spectrum (ESI−): m/z=190 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@@H:3]([NH:22][C:23](=[O:29])OC(C)(C)C)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:20][C:15]3=[N:16][C:17]([CH3:19])=[CH:18][N:14]3[C:13]2=[O:21])[CH2:8][CH2:7]1)=[O:5].[ClH:32].[CH2:33](O)[CH3:34]>>[Cl:32][C:34]1[CH:33]=[CH:10][C:9]([NH:12][C:23]([NH:22][C@@H:3]([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:20][C:15]4=[N:16][C:17]([CH3:19])=[CH:18][N:14]4[C:13]3=[O:21])[CH2:8][CH2:7]2)=[O:5])[C:2]([CH3:1])([CH3:30])[CH3:31])=[O:29])=[CH:8][CH:7]=1
Reactant: Cc1cn2c(n1)CN(C1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2=O
Reactant: Cl
Reactant: CCO
Product: Cc1cn2c(n1)CN(C1CCN(C(=O)[C@H](NC(=O)Nc3ccc(Cl)cc3)C(C)(C)C)CC1)C2=O
Yield: 53 %

Procedure:
To tert-butyl(1R)-2,2-dimethyl-1-((4-(2-methyl-5-oxo-5H-imidazo[1,5-a]imidazol-6(7H)-yl)-1-piperidinyl)carbonyl)propylcarbamate (0.17 g) obtained in Example 89c) was added a 40% solution of hydrogen chloride in ethanol (10 ml), and mixed for 1 hour. The reaction solution was concentrated under reduced pressure. The residue and triethylamine (0.16 ml) were dissolved in acetonitrile (15 ml) and a solution of 4-chlorophenyl isocyanate (72 mg) in acetonitrile (15 ml) was added dropwise thereto. The reaction mixture was mixed for 15 hours, then the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1). The product was recrystallized from diethyl ether to obtain the title compound as colorless powder (0.17 g, 53%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[C:20]12([CH2:30][NH2:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:20]12([CH2:30][NH:31][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH3:1])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ncccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-methylnicotinic acid (2.06 g, 15 mmol) in 40 mL of DMF is added sequentially diisopropylethylamine (5.2 mL, 30 mmol), 1-adamantan-1-ylmethanamine (2.5 g, 15 mmol), and benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 8 g, 18 mmol). The resulting mixture is stirred at rt for 17 h. The mixture is then poured into ice water (150 mL), and the precipitated solid is collected by vacuum filtration and dried in vacuo to afford the title compound as an off-white solid. Mass spec. (285.19, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[F:38][C:39]([F:51])([F:50])[C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:46]([C:43]3[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:50])[F:51])=[CH:45][CH:44]=3)(=[O:48])=[O:47])[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C[C@@H](c1ccc(OCc2cccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of the aniline (27.3) (0.050 g, 0.100 mmol) in DCM (1 mL), was added TEA (28.2 μL, 0.200 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (73.8 mg, 0.300 mmol). A catalytic amount (<5.0 mg) of DMAP was then added to drive the reaction to completion. The reaction mixture was stirred for two hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 10 to 45% EtOAc:hexanes) to give 32.1 (17.0 mg). MS ESI (pos.) m/e: 706.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27]C(Cl)=O.[CH2:31]([N:33]1[C:45]2[CH:44]=[CH:43][C:42]([NH2:46])=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[CH2:27][O:26][CH3:25])[C@H:12]([C:22]([NH:46][C:42]2[CH:43]=[CH:44][C:45]3[N:33]([CH2:31][CH3:32])[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: COCC(=O)Cl
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOCc4ccccc4)CN3C(=O)COC)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=499.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[CH2:10][N:11]1[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)=[N:12]1.N1C=NN=N1.C(N(C(C)C)[P:48]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(C)C.[OH:68]O>C(Cl)Cl>[P:48]([O:38][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[CH2:10][N:11]1[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])=[CH:22][CH:23]=2)=[N:12]1)([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([O:57][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:68]
Reactant: OO
Reactant: OC(Cn1cncn1)(Cn1cnc(/C=C/c2ccc(OCC(F)(F)C(F)F)cc2)n1)c1ccc(F)cc1F
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(OCc1ccccc1)(OCc1ccccc1)OC(Cn1cncn1)(Cn1cnc(/C=C/c2ccc(OCC(F)(F)C(F)F)cc2)n1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2-(2,4-Difluorophenyl)-1-{3-[(E)-4-(2,2,3,3-tetrafluoropropoxy)styryl]-1H-1,2,4-triazol-1-yl}-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (the racemate of Example 19, EP 0472392, 475 mg, 0.88 mmol), 1H-tetrazole (185 mg, 2.64 mmol) and dibenzyl diisopropylphosphoramidite (607 mg, 1.76 mmol) in methylene chloride (5 ml) was stirred at room temperature under a nitrogen atmosphere for 20 hours. The mixture was then cooled to 0° C., and hydrogen peroxide (1.0 ml, 30% solution in water) was added dropwise maintaining the temperature below 20° C. The resulting mixture was stirred at 20° C. for 30 minutes before separating the organic layer, which was washed with water, dried (MgSO4) and the solvent evaporated. The resulting pale yellow oil was purified by column chromatography (silica gel, eluting with ethyl acetate/hexane) to give the subtitle compound as a viscous syrup (595 mg, 84%).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Sc1ncnc2ccccc12
Product: CN(C)c1ccccc1CSc1ncnc2ccccc12
Yield: 24 %

Procedure:
The title compound(1.31 g) was prepared from 4-mercaptoquinazoline(3.0 g) and 2-dimethylamino benzyl chloride(6.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[C:4]([C:15](=[O:18])[CH2:16][CH3:17])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)c1c(OC)cc(OC)cc1C(=O)O

Procedure:
This compound is synthesized by reacting methyl 3,5-dimethoxybenzoate with propionyl chloride via the Friedel-Crafts reaction, followed by saponification of the ester obtained, according to the method described in 2.1. It is used in crude form in the following reaction.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 85.2 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (70.3 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][O:11][C:12]=2[CH2:13][Br:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A stirred solution of the above Compound 17a (404 mg, 1.28 mmol), N-bromosuccinimide (239 mg, 1.35 mmol) and AIBN (11 mg, 0.064 mmol) in CCl4 (3 mL) was heated to reflux and placed under a 300 W lamp for 18 h. The solution was diluted with CH2Cl2 (15 mL), extracted with H2O (3×10 mL), brine (40 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 15-20% EtOAc-hexanes) provided the title compound (287 mg, 0.728 mmol, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si]([N:37]=[C:38]=[O:39])(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:38]([NH2:37])=[O:39])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:23])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2-{4-[l-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine obtained by Example 53 (300 mg) and triethylamine (0.57 ml) in dichloromethane (10 ml) was added dropwise trimethylsilyl isocyanate (0.555 ml) at room temperature.