Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH:14]=[O:15])[CH3:13])=[CH:3]1.O1CCCC1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[OH:15][CH2:14][C@@H:12]([C@@H:11]1[C@:16]2([CH3:24])[C@H:8]([C@H:7]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C:4](=[CH:3][C:2](=[O:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:13]
Reactant: C[C@@H](C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution of (20R)-3-oxopregn-4-ene-20carboxaldehyde (100 g, 305 mmol, commercially available from Upjohn) in 1500 ml ethanol and 250 ml tetrahydrofuran cooled to approximately 5° C. was added sodium borohydride (3.35 g, 89 mmol) portionwise to keep the temperature below 15° C. After 20 minutes, acetic acid (100 ml) was added and the mixture was concentrated to a slush on a rotary evaporator. The residue was then taken up in chloroform, successively washed with water and brine, then dried over sodium carbonate and concentrated to yield (20R)-20-hydroxymethyl-4-pregnen-3-one as a white solid (100 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@@:11]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH:12]=NC2C=CC=C3C=2C=NC(C)=N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.C([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:25])([C:26]([F:27])([F:29])[F:28])[CH:12]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])O
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: -30 °C

Procedure:
300 mg (0.92 mmol) of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 146 mg (0.92 mmol) of 5-amino-2-methylquinazoline are dissolved in 20 ml of toluene, and the solution is admixed with 0.29 ml (0.92 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 349 mg of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −30° C. 6 ml (6 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the reaction solution is allowed to warm to room temperature over 16 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-10%) and subsequent HPLC separation on a chiral stationary phase afford 70 mg of product (analytical HPLC: Rt=8.36 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 5%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>CC(O)C.O.Cl.C(OCC)C.[Fe]>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: COC(=O)Cc1ccc(F)c(N)c1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Methyl 4-fluoro-3-nitrophenylacetate (5.0 g, 0.023 mol) and iron powder (3 g, 0.053 mol) were suspended in a mixture of propan-2-ol (50 ml) and water (5 ml). Concentrated hydrochloric acid (5 drops) was added at room temperature and the mixture was heated at reflux with stirring for 2 hours. The reaction mixture was cooled, diluted with diethyl ether, filtered through diatomaceous earth and the resulting filtrate was evaporated in vacuo. The residue was further purified by chromatography on silica gel, eluting with diethyl ether to yield methyl 3-amino-4-fluorophenylacetate (3.5 g) as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[C:13]1=[O:40])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[C:13]1=[O:40]
Reactant: COC(=O)CCCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 20 (0.150 g, 0.274 mmol) was treated with trifluoroacetic acid (1.0 mL) in chloroform (10 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 9.0:1.0, to afford the product 25 (0.092 g, 75%) as a brown solid: mp 215-217° C. IR (KBr) 3075, 1729, 1687, 1673, 1572, 1532, 1433, 1202, 760, 722, 455 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 10.2 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.89 (dd, J=1.8, J=8.7 Hz, 1H), 7.74 (m, 3H), 7.54 (m, 2H), 7.47 (m, 1H), 4.53 (t, J=3.2 Hz, 2H), 3.59 (s, 3H), 2.96 (m, 2H), 2.38 (m, 4H), 2.13 (m, 2H), 1.87 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 190.1, 173.0, 171.0, 162.6, 154.4, 138.3, 136.6, 134.2, 134.0, 131.0, 127.1, 125.8, 123.5, 123.4, 122.6, 116.6, 107.4, 79.1, 51.3, 41.2, 38.6, 36.6, 35.2, 32.6, 27.3, 20.2; ESIMS m/z (relative intensity) 448 (MH+, 100); HRESIMS calcd for C25H25N3O5 448.1867 (MH+). found 448.1877 (MH+); HPLC purity: 100% (1% TFA in MeOH—H2O, 70:30).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16]1([CH:22]([N:24]2[CH:28]=[N:27][C:26]([NH2:29])=[N:25]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:29][C:26]3[N:27]=[CH:28][N:24]([CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:23])[N:25]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: CC(c1ccccc1)n1cnc(N)n1
Product: Cc1cn(-c2ccc(Nc3ncn(C(C)c4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(1-phenyl-ethyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=48%). MS ISP (m/e): 370.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N+:12]([O-])=O>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[NH2:12]
Reactant: COc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1ccc(N)cc1N

Procedure:
4-Methoxy-benzene-1,3-diamine (D-3) was synthesized following the general scheme above starting from 1-methoxy-2,4-dinitro-benzene. Yield (quant.). HPLC ret. time 0.31 min, 10-99% CH3CN, 5 min run.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:15][CH:14]=1)[CH:8]=[CH:7]2)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:17][CH:18]=1)[CH:8]=[CH:7]2
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-n2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-n2ccc3cc(N)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of HJC-1-79 (120 mg, 0.3 mmol) in 4 mL of MeOH was added 4 mL of saturated NH4Cl (aq.). Zinc dust (195 mg, 3.0 mmol) was added into the solution at 0° C. The reaction was stirred at 0° C. for 0.5 h. TLC indicated that the starting material was gone. The mixture was partitioned between EtOAc (50 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=1/1) to obtain HJC-1-86 (70 mg, 63%) as a pale brown oil. 1H NMR (600 MHz, CDCl3) δ 7.43 (d, 2H, J=8.4 Hz), 7.37 (d, 1H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.24 (d, 1H, J=8.4 Hz), 6.96 (s, 1H), 6.68 (d, 1H, J=8.4 Hz), 6.49 (s, 1H), 4.29 (t, 1H, J=6.6 Hz), 3.34-3.40 (m, 2H), 3.25-3.30 (m, 2H), 3.06-3.10 (m, 1H), 3.00-3.05 (m, 1H), 1.35 (d, 3H, J=6.6 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.28 (t, 3H, J=6.6 Hz). 13C NMR (150 MHz, CDCl3) δ 141.1, 140.2, 139.0, 130.8, 130.5, 128.5, 128.2, 124.2, 113.2, 111.2, 106.0, 102.7, 53.6, 50.5, 40.5, 19.2, 16.9, 16.6.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([O:32][CH3:33])[N:21]=3)[CH2:16][CH:15]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40]C=C)[CH3:36])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:40][CH2:39][CH2:38][CH2:37][N:35]([CH3:36])[C:34](=[O:43])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([O:32][CH3:33])[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(OC)n3)CC1C(=O)N2
Yield: 72.2 %

Procedure:
To a solution of the diolefin 13c (760 mg, 1.28 mmol) in DCE (700 ml) under argon (three times evaporated three times filled with argon) was added Hoveyda Grubbs catalyst 2nd generation (80 mg) and the mixture was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography with hexane ethyl acetate which gave the title compound (0.52 g, 70%), (M+H)+563.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:9][N:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH2:37][C:38]([F:41])([F:40])[F:39])C(=O)OC(C)(C)C)[CH:24]=4)[O:21][CH:22]=3)=[O:17])=[CH:13][N:12]([CH3:42])[N:11]=2)[C:7](=[O:43])[CH2:6]1)[CH3:3].C(OC(=O)C)C.Cl>CO>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:9][N:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:37][C:38]([F:39])([F:41])[F:40])[CH:24]=4)[O:21][CH:22]=3)=[O:17])=[CH:13][N:12]([CH3:42])[N:11]=2)[C:7](=[O:43])[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CC1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of tert-butyl (4-(4-((3-(4-((dimethylamino)methyl)-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (71 mg) in methanol (2.0 mL) was added 4M hydrogen chloride ethyl acetate solution (2.0 mL). The reaction mixture was stirred at room temperature for 16 hr, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, the suspension was basified with sodium methoxide, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (51 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:54](Cl)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[N:49]1([C:54]([O:39][C@H:36]2[CH2:37][CH2:38][C@@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OC(=O)N5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg) is dissolved in pyridine (1 mL), treated with pyrrolidine-1-carbonyl chloride (80 μL) and stirred for 12 hours at 70° C. Pyrrolidine-1-carbonyl chloride (160 μL) is added and the mixture is stirred for 48 hours at 100° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([N+:28]([O-:30])=[O:29])=[C:23](F)[C:22]=1[F:32]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:23]2[C:24]([N+:28]([O-:30])=[O:29])=[C:25]([F:27])[CH:26]=[C:21]([F:20])[C:22]=2[F:32])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (2.0 g, 10.5 mmol) in THF (80 mL) was dropwise added LHMDS solution (12.6 mL, 12.6 mmol, 1 M in THF) at −78° C. After stirring at −78° C. for 1 h, a solution of 1,2,3,5-tetrafluoro-4-nitro-benzene (2.05 g, 10.5 mmol) in THF (20 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h, and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was re-crystallized in hexane to yield (4-bromo-2-fluoro-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine as a yellow solid (1.6 g). 1H-NMR (400 MHz, CDCl3): δ 6.73-6.75 (1H, m), 6.86-6.87 (1H, m), 7.22 (1H, d, J=8.4), 7.30 (1H, dd, J=2.0 Hz, 10.8), 7.71 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ocnc2C(N)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ncoc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
5-(3-Methoxyphenyl)-4-oxazolecarboxamide (1.29 g, 5.9 mmol) was dissolved in dichloromethane (120 mL) and cooled to about 0° C. under N2. Boron tribromide solution (29 mL of 1 M in dichloromethane) was added dropwise and the solution stirred about 18 hours at room temperature. Methanol (10 mL) was added dropwise {caution: reacts vigorously}, and after being stirred 10 min the solution was concentrated onto SiO2 and chromatographed (elution with 20% methanol/ethyl acetate) to give the phenol 848 mg (70%), mp 202°-204° C.IR (KBr, cm-1) 3398, 3188, 3132, 1684, 1608, 1572, 1254, 1190, 866, 694, 618. 1H NMR (300 MHz, DMSO-d6)δ 6.82 to 6.85 (1H, m), 7.26 (1H, t, J=8.0 Hz) 7.56 to 7.69 (4H, m), 8.49 (1H, s), 9.66 (1H, s). 13C NMR 75 MHz, DMSO-d6) ppm 114.62, 116.95, 118.59, 128.08, 129.04, 129.52, 149.87, 151.10, 157.22, 162.80. m/e 205 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([S:32]([NH:35][C:40](=[O:41])[O:42][CH2:43][CH3:44])(=[O:34])=[O:33])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(N)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a mixture of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonamide (100 mg, 0.17 mmol) and ethyl chloroformate (0.022 mL, 0.21 mmol, 1.2 eq) in DCM was added Et3N (0.05 mL, 0.34 mmol, 2.0 eq). After stirring 3 h, the reaction mixture was diluted with EtOAc, washed with water and brine, and purified by chromatography (0 to 80% EtOAc/Hex, then 10% MeOH/DCM) to give 76 mg (68%) of ethyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonylcarbamate. MS (EI): 655 (MH+).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C(Cl)(Cl)Cl>[C:1]([Cl:26])(=[O:22])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Cl

Procedure:
To a solution of 605 mg of 5,8,11,14,17-eicosapentaenic acid 6 in 6 ml of dry chloroform was added 0.25 ml of oxalyl chloride under argon at room temperature. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the remaining oxalyl chloride by distillation under reduced pressure to give 5,8,11,14,17-eicosapentaenoyl chloride 7, which was then directly used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[C:15]([CH3:22])=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([N:31]3[CH2:32][CH2:33][CH:28]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:29][CH2:30]3)=[O:21])[C:15]([CH3:22])=[N:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COc1cc(-n2nc(C)c(C(=O)O)c2C)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: COc1cc(-n2nc(C)c(C(=O)N3CCC(N4CCCC4)CC3)c2C)cc(C(F)(F)F)c1
Yield: 63 %

Procedure:
In analogy to the procedure described in Example 18], 1-(3-methoxy-5-trifluoromethyl-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave, after purification on a flash isolute NH2-column (EtOAc), the title compound in 63% yield as light brown foam. MS: 451.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1C=C(O)[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:10].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:10].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2[C:1]3[CH:2]=[C:7]([OH:8])[C:6]([CH3:5])=[CH:29][C:28]=3[O:27][C:25](=[O:26])[C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(O)ccc1O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: Cc1cc2oc(=O)c3c(c2cc1O)CCN(Cc1ccccc1)C3
Yield: 28 %

Procedure:
Prepared by the procedure of Example 1 from 3-methyl-4-hydroxyphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. The crude product was converted to the hydrochloride salt. Yield 28%; mp 283°-289° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[S:4][CH:3]=1.[OH-].[Li+]>CO>[C:10]([C:8]1[NH:7][C:6]2[C:2]([Cl:1])=[CH:3][S:4][C:5]=2[CH:9]=1)([OH:12])=[O:11]
Reactant: COC(=O)c1cc2scc(Cl)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2scc(Cl)c2[nH]1
Yield: 99.9 %

Procedure:
3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 4; 0.61 g, 2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutralised using aqueous hydrochloric acid (2.0M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H, s); m/z 200.3.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][CH2:12][CH2:13][CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:13][CH2:12][NH:11][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CCNC(=O)Oc1ccccc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Phenyl chloroformate (0.132 mL, 1.05 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (300 mg, 1.05 mmol) and sodium bicarbonate (133 mg, 1.58 mmol) in dioxane (10 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl N-[1-(4-chlorophenyl)-3-(phenoxycarbonylamino)-propyl]carbamate (427 mg, 100%) as a gum.