Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NCC[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.CC1N=CSC=1C(Cl)=O>Cl.O1CCCC1>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: Cc1ncsc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a mixture of 1.18 g. (0.005 mole) of 4-(2-aminoethyl)-benzenesulfonamide hydrochloride [E. Miller et al., Journal of the American Chemical Society, Vol. 62, p. 2099 (1940)] and 1.4 ml. (0.010 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there was added 805 mg. (0.005 mole) of 4-methyl-5-thiazolecarboxylic acid chloride dissolved in 15 ml. of tetrahydrofuran. The addition caused a slight exothermic reaction to occur, after which the reaction mixture was allowed to stand at ambient temperatures for a period of approximately 16 hours with constant agitation being maintained throughout the entire step. At this point, the spent mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting cream-colored precipitate was then recovered by means of suction filtration, washed well with cold water and thereafter crystallized from acetonitrile (after treatment with activated carbon) to yield 1.8 g (73%) of pure 4-[2-methyl-5-thiazolecarboxamido)ethyl]benzenesulfonamide, m.p. 182°-183°C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: CCOC(=O)c1cn[nH]c1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]ncc1C(=O)NN
Temperature: 120 °C

Procedure:
In a 25 mL sealed tube, ethyl 5-methyl-1H-pyrazole-4-carboxylate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (1 mL, 5 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 5-methyl-1H-pyrazole-4-carbohydrazide (0.24 g) which was used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11]
Reactant: COC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C(C)=O

Procedure:
Methyl 2-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (117 mg, 31%) in the same manner as described in the above example 6 (1) from methyl 3-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.37 g, 1.31 mmol) and p-toluenesulfonic acid monohydrate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:23]=2)=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][N:45]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH:23]=2)=[CH:20][C:19]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:51])=[O:52])=[CH:46][N:45]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Reactant: Cc1ccc(-c2cc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-[3-(p-tolyl)isoxazol-5-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (426 mg, 0.7377 mmol) and 2-bromo-5-isopropylsulfonyl-pyridine (233.8 mg, 0.8852 mmol) in DMF (10 mL) was degassed and placed under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (30.51 mg, 0.07377 mmol) was added and the reaction again degassed. 2M aqueous Na2CO3 (1.106 mL, 2.213 mmol) was added and the reaction was stirred at 95° C. for 2 hours. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with water (×3) and brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a yellow solid (344 mg, 74% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.24 (d, J=6.8 Hz, 6H), 1.29 (s, 18H), 2.40 (s, 3H), 3.64 (sept, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 8.47 (dd, 1H), 8.58 (d, 1H), 9.12 (d, J=2.2 Hz, 1H), 9.17 (d, 1H) and 9.42 (d, J=2.2 Hz, 1H) ppm; MS (ES+) 635.2.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.C(N(CC)CC)C.[NH2:33][C@H:34]([C:58]([OH:60])=[O:59])[CH2:35][C:36](=[O:57])[NH:37][C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.S(=O)(=O)(O)[O-].[K+]>O1CCCC1.O.C(OCC)(=O)C>[NH:33]([C:9]([O:11][CH2:12][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])[C@H:34]([C:58]([OH:60])=[O:59])[CH2:35][C:36](=[O:57])[NH:37][C:38]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
3.4 g of 9-fluorenylmethyl N-succinimidyl carbonate (10 mmol) are added and, at the same time, 1.4 ml of triethylamine are added dropwise so that the pH is 8.3-8.7 to a vigorously stirred solution of 3.8 g of H-Asn(Trt)-OH.0.5 H2O (10 mmol) in 20 ml of tetrahydrofuran, 10 ml of water and 1.4 ml of triethylamine (10 mmol). After 20 minutes, the mixture is cooled in an ice bath and ethyl acetate and 25 ml of a one-molar aqueous potassium bisulfate solution are added. The organic phase is washed with water until free of sulfate, dried over sodium sulfate and concentrated under reduced pressure to about 50 g. The Fmoc-Asn(Trt)-OH can be crystallized by slow addition of diisopropyl ether, m.p. 210°-211° (with decomposition).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1.[CH3:17][C@@H:18]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[NH:19]1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:16][S:13]([C:4]1[CH:3]=[C:2]([N:19]2[C@H:18]([CH3:17])[CH2:22][CH2:21][S:20]2(=[O:24])=[O:23])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:15])=[O:14]
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1S(C)(=O)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Yield: 51.7 %

Procedure:
To a mixture of ethyl 4-bromo-2-methanesulfonylbenzoate (13.88 g), sodium iodide (13.54 g) and copper(I) iodide (4.30% g) were added toluene (46 mL) and N,N′-dimethylethylenediamine (4.86 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-iodo-2-methanesulfonylbenzoate (10.32 g). To a mixture of the obtained ethyl 4-iodo-2-methanesulfonylbenzoate (3.22 g), (R)-3-methylisothiazolidine 1,1-dioxide (1.23 g) described in Preparation Example 2, copper(I) iodide (4.30 g), N,N′-dimethylethylenediamine (0.92 mL) and potassium carbonate (2.52 g) was added toluene (9.2 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:23][C:24]([F:43])([F:42])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([NH2:41])=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[N:37][C:36]=23)=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([NH:41][C:33]2[C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:43])([F:23])[F:42])=[CH:31][CH:30]=3)=[C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]3[N:34]=2)=[O:11])[CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccnc1)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
3-Pyridylacetic acid hydrochloride (41.6 mg, 0.239 mmol) was suspended in dichloromethane (3.0 mL). Oxalyl chloride (24 μL, 0.28 mmol) and a drop of dimethylformamide were added and the mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated under vacuum. To this residue was added a solution of the product from Example 1C (59 mg, 0.2 mmol) in pyridine (2.0 mL). The mixture was stirred at ambient temperature for 1 hour and then at 40° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford 24 mg (29%) of the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.86 (d, J=5.8 Hz, 1H), 8.52-8.59 (m, 2H), 8.44-8.49 (m, 1H), 7.79-7.89 (m, 1H), 7.71-7.74 (m, 2H), 7.33-7.44 (m, 1H), 7.20-7.23 (m, 2H), 7.07 (dd, J=7.0, 4.1 Hz, 1H), 3.81 (s, 2H); MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:45][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 ethanol/acetonitrile in carbon dioxide).
Reaction SMILES: [BrH:1].C(C1CCCCN1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.Cl.C(C1CCCCN1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CC2CCCCN2CCCCCOc2ccccc2)cc1
Reactant: Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCCCCOc1ccccc1

Procedure:
2-Benzyl-1-(5-phenoxypentyl)piperidine hydrobromide. From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol), K2CO3 (652 mg, 4.72 mmol, ) and 1-bromo-5-phenoxypentane (860 mg, 3.54 mmol) in CH3CN (25 mL) there was obtained the free amine as a clear amber oil; (568 mg, 71%); 1H NMR (CDCl3), 1.15-1.90 (m, 12H), 2.29-2.89 (m, 6H), 3.08 (dd, J1=12.6 Hz, J2=3.3 Hz, 1H), 3.97 (t, J=6.3 Hz, 2H), 6.85-7.33 (m, 10H).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:47][C:48]1[CH:49]=[C:50]([NH:54][NH2:55])[CH:51]=[N:52][CH:53]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:50]3[CH:51]=[N:52][CH:53]=[C:48]([Cl:47])[CH:49]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cncc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(Cl)c2)n1

Procedure:
656 g (1.35 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 364 mg (2.02 mmol) of 5-chloropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 278 mg (45% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>O.CCOCC>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC(O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(NCC(O)CO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
1-Amino-2,3-propanediol (15.2 g, 167 mmol) and NaOH (8.1 g, 204 mmol) in water (70 ml) at -10° C. was treated dropwise with benzyl chloroformate (28.5 ml, 200 mmol) in ether (30 ml) over 20 min. The reaction was stirred at 0° for 30 min then at room temperature for 2 h. The mixture was acidified with 2M HCl and extracted with ethyl acetate which was washed with 0.5M H3PO4 and brine, then dried over Na2SO4 and evaporated. Recrystallization of the residue from benzene afforded 16.59 g (44%) of the desired product as a white powder. NMR (300 MHz, CD3OD, ppm): 3.12 (dd, 1H), 3.28 (dd, 1H), 3.50 (m, 2H), 3.68 (m, 1H), 5.08 (s, 2H), 7.35 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[S:48][C:47]([CH3:49])=[N:46][C:45]=1[CH3:50]>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[S:48][C:47]([CH3:49])=[N:46][C:45]=3[CH3:50])=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Cc1nc(C)c(Br)s1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3sc(C)nc3C)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 5-bromo-2,4-dimethyl-1,3-thiazole.
Reaction SMILES: [CH2:1]([C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:31][CH3:32])=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>O1CCCC1>[CH3:42][S:43]([O:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:19]([N:17]2[CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:34][CH:33]=4)=[C:10]([O:31][CH3:32])[CH:11]=3)[CH2:18]2)=[O:20])[CH:26]=1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCO)ccn4)C3)cc2OC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of {3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-(2-hydroxyethoxy)pyridin-2-yl]-methanone (8.49 g) prepared in Example 5 in THF (45 mL) were added triethylamine (2.8 mL) and methanesulfonyl chloride (1.5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. Diisopropyl ether was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (9.5 g, 97%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([OH:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].CCOCC>[OH:21][C:14]1[CH:13]=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccccc2)ccc1O
Reaction time: 6 h
Yield: 56.2 %

Procedure:
A solution of phenylboronic acid (1.34 g, 11.0 mmol) and methyl 5-bromo-2-hydroxybenzoate (2.42 g, 10.5 mmol) in acetone (25 ml) was treated with water (30 ml), followed by potassium carbonate (3.77 g, 27.3 mmol) and finally, palladium (II) acetate (0.16 g, 0.7 mmol). Upon addition of the palladium, the reaction mixture rapidly darkened. The reaction mixture was heated to reflux and stirred for 6 h. After cooling the dark mixture, ether (40 ml) was added, stirred vigorously and decanted. This extraction process was repeated an additional four times. The ethereal extracts were dried over sodium sulphate and evaporated in vacuo to give a yellow liquid. The crude product was dissolved in petrol and loaded onto a silica flash column. The column was eluted with petrol, followed by 5-10% ethyl acetate in petrol. The second product collected was evaporated in vacuo and then recrystallised from petrol to provide a white crystalline solid (1.35 g, 5.90 mmol, 56% yield). 1H NMR (200 MHz., d6-DMSO) δ 4.05 (3H, s); 7.20 (1H, m); 7.50-7.58 (3H, m); 7.74 (2H, m); 7.97 (1H, m); 8.13 (1H, m); 10.67 (1H, s, OH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1>C(O)(=O)C.O.[Zn]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2cn1
Yield: 39.8 %

Procedure:
Zinc powder (0.63 g) was added portionwise to a solution of 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.82 g) in a mixture of acetic acid (135 ml) and water (15 ml). On completion of the addition the mixture was heated under reflux for a period of 1 hour and was then filtered to remove any residual zinc. The solvent was removed by distillation under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenol (1.0 g) as an orange solid mp 140° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH3:22])[CH3:2].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:18])=[CH:20][CH:21]=2)[N:9]=[C:8]1[CH3:22])[CH3:2]
Reactant: CCCCCCN
Reactant: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(=O)O)cc2)N=C1C
Product: CCCCCCNC(=O)c1ccc(N2N=C(C)C(=CNc3ccccc3CC)C2=O)cc1

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid and hexylamine, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-N-hexylbenzamide is obtained, Mp 62.1° C.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:21]([CH3:22])([C@@H:2]12)[C@@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@H:13]([C@H:14]([OH:16])[CH3:15])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.O.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:21]([CH3:22])([C@@H:2]12)[C@@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@H:13]([C@H:14]([O:16][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH3:15])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3
Reactant: C1=COCCC1
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@@H](OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2.67 g (8.1 mmol) of (20R)-1α,2α-epoxy-20-hydroxy-pregna-4,6-dien-3-one in 120 ml of benzene is concentrated to 60 ml in a water-jet vacuum at 40° C., cooled to room temperature and to the suspension are added 1.6 ml of 3,4-dihydro-2H-pyran as well as 16 mg of anhydrous p-toluenesulphonic acid. The mixture is stirred at room temperature for 2.5 hours. The resulting solution is diluted with ether, washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There are obtained 3.3 g of crystalline (20R)-1α,2α-epoxy-20-[(tetrahydro-2H-pyran-2-yl)oxy]-pregna-4,6-dien-3-one. Recrystallisation from ether containing 0.1% triethylamine yields colourless prisms of melting point 139°-140° C.; [α]D25 =+233.6° (c=0.5 in chloroform), UV (ethanol): λmax 291 nm (ε=20940).