Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:16]1[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=1)=[O:15])[CH:8]=[CH:7]2)[CH3:2].[CH:40]([Mg]Cl)([CH3:42])[CH3:41].[Cl-].[NH4+].O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)([OH:15])[CH:40]([CH3:42])[CH3:41])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-ethoxynaphthalen-2-yl)(1-trityl-1H-imidazol-4-yl)ketone (3.0 g) was dissolved in THF (45 ml). To the solution was added dropwise a solution of isopropylmagnesium chloride in THF (2 M, 4 ml) under ice cooling. The reaction mixture was stirred at room temperature for 30 min. To the mixture were added saturated aqueous solution of ammonium chloride (20 ml) and water (20 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the titled compound (1.72 g) as a colorless powder. Mother liquor was purified by silica gel chromatography (eluent, hexane-ethyl acetate=1:2) to give the titled compound (0.43 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:28]([O-])=O)[CH:24]=3)[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(OCC)(=O)C.C(Cl)Cl.CCCCCC.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:28])[CH:24]=3)[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Reaction time: 7 h
Yield: 89.8 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-isoindoline-1,3-dione (600 mg, 1.33 mmol) and Pd/C (100 mg, 10%) in ethyl acetate (40 mL) was shaken under hydrogen (50 psi) for 7 h in Parr type shaker. The mixture was filtered through a pad of celite, and the pad was washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo to give a solid. The solid was stirred in a mixture of methylene chloride (2 mL) and hexane (10 mL). The resulting suspension was filtered to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-aminoisoindoline-1,3-dione as a yellow solid (500 mg, 90% yield): mp, 224.5-227.0° C.; 1H NMR (DMSO-d6); δ 1.32 (t, J=6.8 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=7 Hz, 2H, CH2), 4.03-4.09 (m, 1H, CHH), 4.34 (dd, J=10.3, 14.2 HZ, 1H, CHH), 5.70 (dd, J=3.7, 10.2 Hz, 1H, NCH), 6.52 (br, s, 2H, NH2), 6.79-6.81 (m, 1H, Ar), 6.92 (br s, 3H, Ar), 7.06 (br s, 1H, Ar), 7.48 (d, J=8.2 Hz, 1H, Ar); 13C NMR (DMSO-d6) δ 14.64, 40.99, 46.99, 53.34, 55.46, 63.80, 106.99, 111.78, 112.31, 116.12, 116.80, 118.61, 125.12, 130.33, 134.11, 147.80, 148.74, 155.13, 167.39, 167.86; Anal Calcd for C20H22NO6S: 57.41; H, 5.30; N, 6.69. Found: C, 57.03; H, 5.40; N, 6.33.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)[N:18]=1.[Br:38]Br>CCCCCC.O1CCCC1>[Br:38][C:22]1[C:17]([F:16])=[N:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:20][N:21]=1
Reactant: CCCCCCCCOc1ccc(-c2cncc(F)n2)cc1
Reactant: BrBr
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
3.50 g (24.8 mmol) of 2,2,6,6-tetramethylpiperidine and 15.50 ml (24.80 mmol) of 1.6 M n-butyllithium solution in hexane are stirred at 0° C. for 0.5 hour in 80 ml of tetrahydrofuran, 250 ml of tetrahydrofuran are added, and the mixture is cooled to -78° C. 5.00 g (16.5 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyrazine in 150 ml of tetrahydrofuran and, after the mixture has been stirred for one hour, 0.85 ml of bromine are subsequently added dropwise at -78C. The reaction mixture is stirred overnight, during which it warms to room temperature, and is partitioned between ether and aqueous sodium chloride solution, the aqueous phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvent, and the residue is purified by chromatography (silica/hexane: ethyl acetate = 9:1). 4.68 g of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine are obtained. ##STR16## 1d
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].CNC>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([N:6]([CH3:7])[CH3:9])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1N
Agent: CNC
Product: CN(C)C(=O)c1cc(Br)ccc1N
Yield: 73 %

Procedure:
Prepared analogously to Compound 3D replacing diethylamine with dimethylamine to afford 1.47 g of the title compound (73%). 1H NMR (400 MHz, CD3OD) δ 7.24 (dd, J=2.4, 8.7 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 3.04 (br. s., 6H). MS (ESI): m/z 243.33 [M+H]+. UPLC: tR=0.88 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:30])[NH:13][C:14]2[CH:29]=[CH:28][C:17]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25](=[S:27])[NH2:26])[CH:20]=3)=[CH:16][CH:15]=2)[CH:6]=1)([CH3:4])([CH3:3])C.N[C:32]1N=CN=[C:34](C2C=CC=CC=2)[CH:33]=1>>[C:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:30])[NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](=[S:27])[NH2:26])[CH:20]=4)=[CH:28][CH:29]=3)[CH:6]=2)[CH:3]=[CH:34][CH:33]=[CH:32][CH:4]=1
Reactant: Nc1cc(-c2ccccc2)ncn1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(N)=S)c3)cc2)ncn1
Product: NC(=S)c1cc(Oc2ccc(NC(=O)Nc3cc(-c4ccccc4)ncn3)cc2)ccn1

Procedure:
The title compound was prepared in the same manner as described for 4-{-4-[3-(6-tert-butylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carbothioic acid amide, replacing 6-amino-4-tert-butylpyrimidine for 6-amino-4-phenylpyrimidine. 1H-NMR (DMSO-d6) δ 10.18 (broad s, 1H), 10.04 (broad s, 1H), 9.91 (broad s, 1H), 9.85 (broad s, 1H), 8.78 (d, J=1.2 Hz, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.15 (s, 1H), 8.06 to 8.02 (m, 2H), 7.94 (d, J=2.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.54 to 7.52 (m, 3H), 7.20 (d, J=8.7 Hz, 2H), 7.12 (dd, J=5.7, 3.0 Hz, 1H); LC-MS m/z 443 [M+H]+, RT=3.19 min.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10].N1C=CC=CC=1.[CH3:20][Si:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C(O)=O>CC#N.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:12][CH3:13])[C:9]([O:11][CH2:23][CH2:22][Si:21]([CH3:26])([CH3:25])[CH3:20])=[O:10]
Reactant: C[Si](C)(C)CCO
Reactant: CCC(C(=O)O)c1ccccc1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1I
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of the acid of Step 1 (103 g, 0.356 mol), pyridine (58 mL, 0.717 mol) and 2-(trimethylsilyl)ethanol (61.2 mL, 0.427 mol) in CH3CN (270 mL) was added a solution of dicyclohexylcarbodiimide (73.4 g, 0.356 mol) in CH3CN (100 mL). The reaction mixture was stirred at r.t. for 2 h, at which point 5M oxalic acid in DMF solution (11 mL) was added. After stirring for 30 min, the suspension was filtered and the filtrate was diluted with EtOAc, washed with water and dried over MgSO4. The crude product was distilled under reduced pressure to give 109 g of the title compound as a colorless oil (bp 120°-140° C./0.4 mm Hg).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[C:4]1=[O:33])[CH3:2].N>[Ni].CO>[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([CH:32]=[CH:31][CH:30]=1)[CH2:24][CH:5]1[N:6]=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=2[N:3]([CH2:1][CH3:2])[C:4]1=[O:33]
Reactant: CCN1C(=O)C(Cc2cccc(C#N)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCN1C(=O)C(Cc2cccc(CN)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 99.1 %

Procedure:
Leave under hydrogen pressure (Patm) for 12 hours, 40 mg of 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIcp), 0.4 ml of 30% ammonia, 4 ml of methanol, 1 spatula tip of Raney nickel. Filter on celite, rinse several times with methanol. Evaporate to dryness. Take up in 50 ml of dichloromethane, wash three times with 50 ml of 0.5 M NH3 and twice with water. Dry the organic phase on Na2SO4. Evaporate to dryness. Recrystallize in ether. Filter. One obtains 40 mg of the abovenamed product in the form of a white powder. Yield: 55%. M: 122–125° C. 1H-NMR (CDCl3, 200 MHz): d 1.10 (s, 3H, CH3), 1.30 (m, 2H exchangeable —NH2), 3.50–3.89 (m, 8H, 1H —CH2Ph+1H —NCH2+CH+CH2—NH2+OCH3), 3.98–4.11 (m, 4H, 1H —CH2Ph+OCH3), 4.37–4.47 (m, 1H —NCH2), 6.67 (s, 1H Ar), 6.84 (s,1H Ar), 7.20–7.64 (m, 9H Ar).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[F:14][C@H:15]1[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@H:16]1N1C=C(C)C(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.[OH-].[K+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:16]2[O:17][C@H:18]([CH2:21][OH:22])[C@@H:19]([OH:20])[C@@H:15]2[F:14])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: CCOc1nc(N)nc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Temperature: 37 °C
Reaction time: 8 h
Yield: 6.9 %

Procedure:
2-Amino-6-ethoxypurine (0.5 g, 2.8 mmoles) which may be prepared according to R. W. Balsiger and J. A. Montgomery J. Org. Chem., 25:1573, 1960) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (C. H. Tann et al., J. Org. Chem., 50:3647, 1985; 0.5 g; 1.9 mmoles) were suspended in 25 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (8,000 I.U) and purine nucleoside phosphorylase (11,100 I.U.) (T. A. Krenitsky, et al., Biochemistry, 20:3615, 1981 and U.S. Pat. No. 4.381,444) were added and the reaction stirred at 37° C. On day 24, 8,000 I.U. of thymidine phosphorylase and 5,500 I.U. of purine nucleoside phosphorylase were added. On day 49, the reaction was diluted to 250 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the reaction was adjusted to 7.0 with KOH and 12,000 I.U. of thymidine phosphorylase and 8,300 I.U. of purine nucleoside phosphorylase were added. On day 79, the solvent was removed under vacuum. The residue was dissolved in hot water and two volumes of acetonitrile added to precipitate the protein. After standing overnight the suspension was filtered. The filtrate was evaporated. The residue was dissolved in hot water and then allowed to cool to 25° C. The suspension was filtered and the filtrate applied to a 2.5×8 cm AG1X2-hydroxide (Bio-Rad) column. After washing the column with water and methanol/water (1/1) the product was eluted with methanol water (9/1). Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in chloroform/methanol/water (90/10/1) and applied to a 2.5×55 cm silica gel column. The column was eluted with chloroform/methanol/water (90/10/1). Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilisation yielded 0.041 g of title compound that analysed as 0.4 hydrate.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:14]([CH3:47])[C:15](=[O:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]1[CH2:43][C:42]2[CH:41]=[C:40]([OH:44])[CH:39]=[CH:38][C:37]=2[C@@H:36]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C@@H:31]([OH:45])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:10]([N:14]([CH3:47])[C:15](=[O:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]1[CH2:43][C:42]2[CH:41]=[C:40]([O:44][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:39]=[CH:38][C:37]=2[C@@H:36]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C@@H:31]([OH:45])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCN(C)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCN(C)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(OC(=O)c3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aqueous N-sodium hydroxide solution (0.15 ml.) and benzoyl chloride (0.023 ml.) were successively added at 0° C. to a stirred solution of N-n-butyl-N-methyl-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)undecanamide (Example 2; 0.06 g.) in acetone (1 ml.) and the mixture was stirred at 0° C. for 30 minutes and poured into saturated aqueous sodium bicarbonate solution (10 ml.). The mixture was extracted three times with diethyl ether (15 ml. each time) and the combined extracts were washed with water (3 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:2 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil N-n-butyl-N-methyl-11-(3-benzoyloxy-17β-hydroxyoestra-1,3,5(10)-trien-7α-yl)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>O>[CH3:16][O:17][CH2:18][O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1
Temperature: 30 °C
Yield: 79.1 %

Procedure:
Into a reactor, 40 g of p-bromophenol and 200 ml of DMF (dimethylformamide) were charged, to which 10 g of a 60% NaH (sodium hydride) were gradually added to give a solution. To the solution, 18 g of methoxymethyl chloride were added dropwise with stirring at a temperature of 30° C. or lower, and reacted overnight at room temperature to give a reaction solution. The reaction solution was poured into water, extracted with benzene, washed with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was distilled under reduced pressure to give 38.4 g (Y., 79.3%) of 4-bromopheny methoxymethyl ether. b.p.; 65°-67° C./0.6 mmHg GC; 99.4%
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.S(Cl)(Cl)=O.Cl.[NH2:40][OH:41].C(=O)([O-])O.[Na+]>ClCCl.O.CN(C)C=O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:40][OH:41])=[O:25])=[CH:22][CH:21]=1
Reactant: CC1=C(C)C(=O)C(C(CCCCCCOc2ccc(C(=O)O)cc2)c2ccccc2)=C(C)C1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC1=C(C)C(=O)C(C(CCCCCCOc2ccc(C(=O)NO)cc2)c2ccccc2)=C(C)C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 120.6 %

Procedure:
To a solution of 0.92 g (2.0 mmole) of 4-[7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptoxy]benzoic acid in dichloromethane (10 ml) were added 0.44 ml (2×3 mmole) of thionyl chloride and dimethylformamide (8 μl), and the mixture was stirred at 40° C. for 1 hour. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (10 ml), followed by ice-cooling. After 0.21 g (2×1.5 mmole) of hydroxylamine hydrochloride was added, a solution of 0.34 g (2×2 mmole) of sodium hydrogencarbonate in water (5 ml) was added to the reaction mixture, followed by stirring for 15 minutes under ice-cooling. The tetrahydrofuran was distilled off under reduced pressure, and ethyl acetate was added to the residue to conduct extraction. The ethyl acetate layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column to elute with ethyl acetate to give 4-[7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptoxy]benzohydroxamic acid (0.86 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[O:43]>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:42]([Cl:44])=[O:43])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reaction time: 0.5 h

Procedure:
To a solution of rac-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (710 mg, 1.43 mmol, example 2) and triethylamine (400 uL, 2.86 mmol) in 12 mL of dichloromethane at 0° C. was added 1.13 mL of 1.9 M phosgene in toluene solution (Fluka). After stirring for 30 min the mixture was taken up in dichloromethane and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel, eluting with hexane-ethyl acetate (4:1) provided 689 mg of rac-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl chloride as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl.O>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1onc(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.1 g, 36 mmol) in ethanol (50 mL) was added aqueous sodium hydroxide (4 N, 10 mL). After heating at reflux for 1 h the mixture was cooled to room temperature and acidified with HCl (4 N, 10 mL) and water (10 mL) at 0° C. Purification by filtration and drying afforded the title compound (8.3 g, 97%) which was obtained as a white solid. Mp: 171-173° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15]2)=[CH:12][CH:11]=[CH:10][C:9]=1[C:25]1[CH:33]=[CH:32][C:31]([C:34]([NH2:36])=[O:35])=[C:30]2[C:26]=1[C:27]1[CH2:40][NH:39][CH2:38][CH2:37][C:28]=1[NH:29]2>>[C:34]([C:31]1[C:30]2[NH:29][C:28]3[CH2:37][CH2:38][N:39]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:40][C:27]=3[C:26]=2[C:25]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15]3)[C:8]=2[CH3:7])=[CH:33][CH:32]=1)(=[O:35])[NH2:36]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Product: CCOC(=O)N1CCc2[nH]c3c(C(N)=O)ccc(-c4cccc(-n5cnc6ccccc6c5=O)c4C)c3c2C1
Yield: 59 %

Procedure:
Using the procedure of Example 43 but substituting ethyl chloroformate in place of acetic anhydride, 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (20 mg, 0.044 mmol) was converted into the desired product as a white solid (14.0 mg, 59% yield). LCMS (M+H)+ m/z 522.3. 1H NMR (400 MHz, methanol-d4) δ 8.16-8.56 (2 H, m), 7.87-7.98 (1 H, m), 7.76-7.87 (1 H, m), 7.61-7.73 (2 H, m), 7.42-7.59 (3 H, m), 6.89-7.06 (1 H, m), 3.42-4.22 (6 H, m), 2.79-3.01 (2 H, m), 1.86 (3 H, br. s.), 1.12-1.36 (3 H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:25])[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:12]3)=[C:6]([F:26])[C:5]([F:27])=[CH:4][C:3]=1[NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[C:7]([C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[N:12]3)=[O:25])=[C:6]([F:26])[C:5]([F:27])=[CH:4][C:3]=1[NH:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)c(C(O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
The solution of N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 1.3 mmol, 1.0 eq.) in DCM (10 mL) was added MnO2 (358 mg, 6.5 mmol, 5.0 eq.). The resulting mixture was stirred at 50° C. overnight, then cooled and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (PE/EA=1/2, v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg, 90%).
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)C1(Cl)CC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1
Yield: 80 %

Procedure:
Sodium borohydride (161 mg, 4.25 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of tert-butyl 1-chlorocyclopropane-1-carboxylate (hereinafter the compound will be referred to as “compound (4a)”) (500 mg, 2.83 mmol) at 10C. Cobalt chloride hexahydrate (3.3 mg, 0.014 mmol) was added to the resultant solution. After completion of addition, the resultant mixture was stirred at 40° C. for 21 hours. After completion of reaction, the whole reaction mixture was diluted with an HPLC mobile phase to 50 mL, to thereby yield a solution containing 320.3 mg (yield: 80%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).