Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:17][OH:18])[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH:24]1([N:27]2[CH:32]=[C:31]([CH:33]=[CH2:34])[CH:30]=[CH:29][C:28]2=[O:35])[CH2:26][CH2:25]1.[Cl:36][O-].[Na+]>C(Cl)Cl.O>[Cl:36][C:29]1[C:28](=[O:35])[N:27]([CH:24]2[CH2:26][CH2:25]2)[CH:32]=[C:31]([CH:33]2[O:18][N:17]=[C:16]([C:14]3[N:13]=[C:12]([CH3:19])[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:20]=[CH:21][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=4)=[O:9])[CH:15]=3)[CH2:34]2)[CH:30]=1
Reactant: COc1cc(CNC(=O)c2cc(C=NO)nc(C)n2)ccc1F
Reactant: [O-]Cl
Reactant: C=Cc1ccc(=O)n(C2CC2)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4cc(Cl)c(=O)n(C5CC5)c4)C3)nc(C)n2)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (4.0 g, 12.57 mmol, Preparation #9) and 1-cyclopropyl-5-vinylpyridin-2(1H)-one (2.026, 12.57 mmol, Preparation #F.1.33) in DCM (60 mL) was added 9% aqueous sodium hypochlorite solution (60 mL, 12.57 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. The reaction mixture was allowed to stir for another 15-30 min, reaction mixture was diluted with water (100 mL) and the product extracted with DCM (100 mL). The combined organic layers were dried over sodiumsulphate and evaporated to dryness. The resulting crude material contained two products, and these were separated by silica gel column chromatography eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to obtain the first eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, 1H NMR (400 MHz, DMSO): δ 9.518-9.486 (m, 1H), 8.177 (s, 1H), 7.889-7.883 (d, J=2.4 Hz, 1H), 7.753-7.747 (d, J=2.4 Hz, 1H), 7.186-7.120 (m, 2H), 6.907-6.871 (m, 1H), 5.757-5.672 (m, 1H), 4.492-4.476 (d, J=6.4, Hz, 2H), 3.820 (s, 3H), 3.784-3.740 (m, 1H), 3.502-3.371 (m, 2H), 2.762 (s, 3H), 1.091-0.902 (m, 4H); MS m/z: 512.2 (M+H)+. and the second eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.28 g (4.67%) as a brown color solid. 1HNMR (400 MHz, DMSO): δ 9.515-9.485 (m, 1H), 8.179 (s, 1H), 7.680-7.675 (d, J=2 Hz, 1H), 7.489-7.459 (dd, J=9.6 Hz, 1H), 7.180-7.119 (m, 2H), 6.900-6.874 (m, 1H), 6.448-6.390 (dd, J=13.6 Hz, 1H), 5.757-5.661 (m, 1H), 4.489-4.474 (d, J=6 Hz, 2H), 3.817 (s, 3H), 3.805-3.732 (m, 1H), 3.472-3.342 (m, 2H), 2.759 (s, 3H), 1.073-0.863 (m, 4H); MS m/z: 478.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([NH2:12])=[O:11].C(O)=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: O=Cc1ccc(O)cc1
Solvent: O
Solvent: O=CO
Product: O=CNCc1ccc(O)cc1
Temperature: 189 °C
Yield: 77.4 %

Procedure:
4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03 mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL round bottom flask equipped with a thermometer, a reflux condenser, a magnetic stirrer and a heating mantle. The reaction mixture was heated to 189° C. The heating was immediately turned off; the reaction flask was quickly raised from the heating mantle and allowed to cool to room temperature. The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])[CH3:9])=[CH:4][CH:3]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:27]2=[O:29])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (2.2 g, 5.5 mmol) in CH2Cl2 (50 mL) was added triphosgene (3.2 g, 11 mmol) and Et3N (1.7 g, 16.5 mmol) at 0° C. The mixture was stirred at room temperature overnight, and put at room temperature for 3 days, the volatile was evaporated. The resulting mixture was washed with 1 N aq HCl and extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated to give the crude final product, which was purified by chromatography to afford two isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:31])[N:14]([CH2:27][CH2:28][O:29]C)[C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1.BrB(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:31])[N:14]([CH2:27][CH2:28][OH:29])[C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:25])([F:26])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCn1c(=O)c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)n(CCO)c2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 800 mg (1.83 mmol) N-[(3-fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 4) in DCM (30 ml) was added 0.26 ml (2.7 mmol) tribromoborane at −78° C. The reaction mixture was stirred at 0° C. for 2 h. Then the reaction mixture was cooled to −78° C. and quenched with a sat. NaHCO3 sol. The reaction mixture was diluted with DCM (20 ml) and washed with a sat. NaHCO3 sol. (20 ml), brine (20 ml), and water (20 ml), dried over Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 750 mg (1.77 mmol, 97%) N-[(3-Fluorophenyl)-methyl]-1-(2-hydroxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 38) were obtained. MS: m/z 423.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:1])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Solvent: CN(C)C=O
Product: O=C1C2=C(c3ccccc3)N(Cc3ccccc3)C(=O)C2=C(c2ccccc2)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5.6 Parts of potassium t-butylate are added to a suspension of 5.8 parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole in 70 parts of dimethylformamide at 20° C. and the mixture is stirred at 20° C. for 1 hours. 7.6 parts of benzyl chloride are then added to the mixture and the mixture is kept at 65° C. for 2 hours. After cooling to 20° C., the reaction product is filtered off and washed with a little dimethylformamide and then with acetone and hot water. After drying, 4.5 parts of 1,4-diketo-2,5-dibenzyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole (formula XVII) are obtained and, if necessary, can be crystallised from dimethylformamide. Yellow-orange crystals of melting point 290°-292° C. are formed. ##STR21##
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]2[NH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O.[NH3:17].Cl>>[CH:1]1([CH:4]=[CH:5][C:6]2[NH:7][C:8]([CH:13]([C:12]([OH:16])=[O:15])[NH2:17])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C(=C/C1CC1)\c1ccc[nH]1
Reactant: N
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: NC(C(=O)O)c1ccc(C=CC2CC2)[nH]1

Procedure:
cis-/trans-2-(2-Cyclopropylvinyl)pyrrole (3.0 g., 0.023 mole) was added to a stirred solution of glyoxylic acid hydrate (2.1 g., 0.023 mole) in 0.880 (sp. gr.) ammonia solution (15 ml.) and the reaction mixture heated at 60° for 2.5 hours, then allowed to cool. The pH was adjusted to 5-6 with concentrated hydrochloric acid, and the mixture was then filtered. The resulting solid was washed with water, acetone and diethyl ether, and dried under vacuum to provide DL-2-[5-(2-cyclopropylvinyl)-2-pyrrolyl]glycine as a pink solid (1.2 g.), M.P. 275°.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([CH3:34])[N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:32]3[C:27]([CH3:26])=[N:28][C:29]([CH3:34])=[CH:30][CH:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(I)c(C)n1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c(C)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 105 mg (0.26 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 134 mg (0.58 mmol) of 2,6-dimethyl-5-iodo-pyridine in 1 mL THF with 0.30 mL 2M isopropylmagnesium chloride. Yield: 19 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 1.2 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C@@H:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1.C1(=O)CCCCC1.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C@@H:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O=C1CCCCC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 90 °C
Yield: 85.8 %

Procedure:
From a solution of 17-(3-Pyridyl)-5α-androst-16-en-3α-ol (1.05 g, 3.0 mmol) in dry toluene (60 ml) and cyclohexanone (10 ml) was distilled off part of the solvent (20 ml) to eliminate moisture. After allowing to cool to 90° C., aluminium isopropoxide (1.02 g, 5.0 mmol) was added and the mixture heated under reflux for 90 min. then allowed to cool. The mixture was diluted with diethyl ether (250 ml), washed with aqueous trisodium citrate (15% w/v; 2×30 ml), dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-methanol (40:1), afforded the title compound (0.90 g, 86%) which crystallised from toluene, m.p. 190°-192° C. IR νmax 1713 cm-1 ; 1H-NMR (CDCl3) inter alia δ1.04 (3H,s,19-CH3), 1.07 (3H,s,18-CH3), 5.98 (1H,M,16-H), 7.22 (1H,m,Py 5-H), 7.64 (1H,m,Py 4-H), 8.46 (1H,m,Py 6-H), 8.61 (1H,m,Py 2-H); MS m/z 349 (M+). Anal. Calcd: C,82.47; H,8.94; N,4.01. Found: C,82.00; H,8.94; N,3.84%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1.[Li][CH2:12][CH2:13][CH2:14]C.C(I)(C)C>C1COCC1.CCCCCC>[CH:13]([CH:8]1[C:3]([O:2][CH3:1])=[CH:4][CH2:5][CH:6]=[C:7]1[O:9][CH3:10])([CH3:14])[CH3:12]
Reactant: COC1=CCC=C(OC)C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)I
Product: COC1=CCC=C(OC)C1C(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 1,5-dimethoxy-cyclohexa-1,4diene (7 g, 50 mmol) in dry THF (140 mL) was added dropwise nBuLi solution (2.5 M, 30 mL) in hexane at −20° C. The orange colored reaction mixture was stirred for 0.5 hours at −20° C., then isopropyl iodide (17 g, 100 mmol) was added dropwise. The reaction mixture was stirred for 1 hour, while the temperature was raised to 0° C. Excess nBuLi was destroyed cautiously with methanol. Cold water (140 mL) was added to the reaction mixtures, then the product was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a light yellow liquid (8.5 g, 93.4%). 1H NMR CDCl3): δ 0.90 (d, 6H, 2×CH3), 2.1 (m, 1H, CH), 2.76 (m, 3H, CH2 and CH), 3.53 (s, 6H, 2×OCH3), 4.73 (t, 2H, olefinic).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1cccc(CC#N)c1C
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C

Procedure:
The title compound was prepared according to Example 1, starting from 2,3-dimethylphenylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 330-333° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 97.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10 mg, 0.0315 mmol) obtained in Example 1, (3), and benzenesulfonyl chloride (8.3 mg, 0.0473 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (14 mg, yield 97%) as slightly brown amorphous.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[CH:10]([CH2:12][C:13]([O:15]CC)=[O:14])[O:9][B:8]([OH:18])[C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][CH2:2][C:3]1[C:11]2[CH:10]([CH2:12][C:13]([OH:15])=[O:14])[O:9][B:8]([OH:18])[C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(CN)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CN)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
The mixture of ethyl 2-(4-(aminomethyl)-1-hydroxy-6-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (20 mg), LiOH (24 mg, 1 mmol) in THF/MeOH/H2O (1.5 ml/1.5 ml/1.5 ml) was stirred at room temperature for 2 hrs. The solvent was removed in reduced pressure to dryness. The crude product was purified by Prep-HPLC to give desired product 5 mg as white powder (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.22 (brs, 3H), 7.19 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 5.60 (dd, J=9.4, 2.2 Hz, 1H), 4.04 (q, J=4.5 Hz, 2H), 3.78 (s, 3H), 2.99 (dd, J=15.8, 2.4 Hz, 1H), and 2.11 (dd, J=9.4, 15.8 Hz, 1H). MS (ESI) m/z=252 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[N:24]1[C:31]([Cl:32])=[N:30][C:28](Cl)=[N:27][C:25]=1[Cl:26]>ClCCl>[CH2:1]([O:8][C:28]1[N:30]=[C:31]([Cl:32])[N:24]=[C:25]([Cl:26])[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCc1ccccc1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Solvent: O
Product: Clc1nc(Cl)nc(OCc2ccccc2)n1
Yield: 46 %

Procedure:
First, a synthesis method of the hydroxy group-protecting agent 3 will be explained. An activated molecular sieve 4A, 54.1 μL (0.525 m mol) of benzyl alcohol, 118.9 mg (0.600 m mol) of 1,10-phenanthroline hydrate, 1.00 mL of dichloromethane, 92.2 mg (0,500 m mol) of cyanuric chloride were added to a test tube, and reacted at 0 degree under a nitrogen atmosphere for 5 hours. After the reaction, a precipitate was filtered, and 20 mL of ethyl acetate was added to the filtrate, which was washed with 10 mL of an aqueous solution of saturated sodium hydrogen carbonate, 5 mL of water, 10 mL of 1 N hydrochloric acid, 5 mL of water and 10 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which ethyl acetate was distilled away, and the residue was isolated and purified by silica-gel chromatography to obtain 58.9 mg of 6-benzyloxy-2,4-dichloro-1,3,5-triazine (yield: 46%).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:8][C:9](=[O:13])/[CH:10]=[CH:11]/[I:12])[CH2:7][CH2:6][CH2:5][CH2:4]1>C1C=CC=CC=1>[CH:3]1([CH2:8][CH:9]([OH:13])/[CH:10]=[CH:11]/[I:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(/C=C/I)CC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: OC(/C=C/I)CC1CCCC1

Procedure:
To a solution of 7.1 g. of sodium borohydride in 60 ml. of absolute alcohol, stirred in an ice bath under nitrogen atmosphere, is added dropwise, over a period of about 2 hours, a solution containing 7 g. of 4-cyclopentyl-1-iodo-1-trans-buten-3-one (Example 33) in 160 ml. of absolute alcohol. The temperature is maintained at 5°-10° C. The solution is poured into 850 ml. of iced water and the resulting mixture is extracted three times with ether. The combined extracts are washed with dilute sodium bisulfite solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 81 g. of yellow oil. Column chromatography on a column of 1 kg. of silica gel using benzene gives 75 g. (88%) of oily product.
Reaction SMILES: N1(CCO)CCNCC1.BrC1SC(C=O)=CC=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:39][C:40]#[N:41]>>[CH3:34][O:35][C:36]1[CH:37]=[C:38](/[C:39](=[CH:32]/[C:30]2[S:31][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][OH:18])[CH2:26][CH2:25]3)=[CH:28][CH:29]=2)/[C:40]#[N:41])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(N2CCN(CCO)CC2)s1
Agent: O=Cc1ccc(Br)s1
Agent: OCCN1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCN(CCO)CC3)s2)cc1OC
Yield: 48.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-piperazineethanol (7.81 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiophene-2-carbaldehyde (yield: 3.22 g, 67%). The produced 5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiophene-2-carbaldehyde (1.85 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.37 g) through Method A (production step 2), to thereby yield the target product (yield: 1.51 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl.CO>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
1.11 g (5.85 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy to Example 2j first with 0.63 ml (8.77 mmol) of thionyl chloride and subsequently with 1 g (2.34 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.65, FD-MS: M+ =599.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])([CH3:26])[CH3:25]>>[OH:23][C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:37])([F:38])([F:39])[F:40])[CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:25])[CH3:26]
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 52.9 mg (0.17 mmol) of the compound of Example 19A were reacted and worked up analogously to the procedure of Example 19. This gave 49 mg (49% of theory) of the title compound.
Reaction SMILES: [OH:1][P:2]=[O:3].[OH:4][PH2:5]=[O:6].[OH2:7].[OH2:8].O.O.[N+]([O-])([O-])=O.[Ca+2:15].[N+]([O-])([O-])=O>>[P:2]([O-:8])([O-:7])([O-:1])=[O:3].[Ca+2:15].[P:5]([O-:8])([O-:7])([O-:4])=[O:6].[Ca+2:15].[Ca+2:15]
Reactant: O=[PH2]O
Reactant: O=PO
Reactant: O
Agent: *CC*
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
An aqueous solution of 8.51 g 50 wt % hypophosphorus acid, H3PO2 (Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt % [PO4]−3 was combined with 8.00 g distilled water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO3)2.4H2O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4) equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in this mixture was 3/2 and the equivalent solids level [as Ca3(PO4)2] was 25.4 wt %. Endothermic dissolution of the calcium nitrate tetrahydrate proceeded under ambient temperature conditions, eventually forming a homogeneous solution. Warming of this solution above 25° C. initiated a reaction in which the solution vigorously bubbled while evolving red-brown acrid fumes characteristic of NOx(g). The sample turned into a white, pasty mass which foamed and pulsed with periodic expulsion of NOx(g). After approximately two minutes, the reaction was essentially complete, leaving a white, pasty mass which was warm to the touch. After cooling to room temperature, the solid (A) was stored in a polyethylene vial.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:17]([Cl:16])=[O:19])[CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled 0° C. To the resulting mixture was added triphosgene (0.127 g, 0.429 mmol) and the mixture was stirred for 2 h at an ambient temperature.