Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][CH2:37][C:38]([OH:41])([CH3:40])[CH3:39])=[CH:30][C:29]=2[CH3:42])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][CH2:37][C:38]([OH:41])([CH3:39])[CH3:40])=[CH:30][C:29]=2[CH3:42])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCC(C)(C)O)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 M aqueous NaOH solution (420 μL) is added to a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (155 mg) in methanol (4 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The organic solvents are evaporated in vacuo. The residue is diluted with water and neutralized with 1 M aqueous HCl solution (420 μL). The mixture is stirred for 1 hour. The precipitate formed is filtered off, washed with water and dried in vacuo to give the title compound. Yield: 110 mg; LC (method 4): tR=1.85 min; Mass spectrum (ESI+): m/z=535 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl.Cl.[NH2:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)[C:23]([Cl:39])=[CH:22][N:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)=[CH:25][C:20]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[N:21][CH:22]=1
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Reactant: Nc1cnn(CC(=O)O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCc2cccc(Nc3cc(Nc4cnn(CC(=O)O)c4)ncc3Cl)c2C1=O
Temperature: 150 °C
Yield: 63 %

Procedure:
Sodium tert-butoxide (805 mg, 8.38 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (498 mg, 2.33 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (300 mg, 0.93 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (86 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.075 mmol) was added and the mixture purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was evaporated and the residue partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 with 2N HCl solution. The aqueous solution was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL) and the resulting solid filtered and then washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to leave 2-[4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (250 mg, 63% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.96 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 4.71 (2H, s), 6.81 (1H, s), 6.89 (1H, d), 7.40 (1H, s), 7.43-7.50 (2H, m), 7.90 (1H, d), 8.01 (1H, s), 8.86 (1H, s), 11.23 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=427.33 and 429.29.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[ClH:32]>C1(C)C=CC=CC=1.CCOCC.CCO>[ClH:1].[ClH:32].[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(C(CCCN2CCN(c3ccccn3)CC2)c2ccc(F)cc2)cc1
Yield: 67 %

Procedure:
3.3 g (0.01 mole) of 1-chloro-4,4-bis(p-fluorophenyl)butane, 3.3 g (0.02 mole) of 1-(2-pyridyl)-piperazine and 0.05 g of KI were refluxed in 15 ml of toluene for 48 h. After cooling and addition of ether (30 ml) 1-(2-pyridyl)-piperazine hydrochloride precipitated and was filtered off. After subsequent washing several times with H2O the organic layer was dried with K2CO3. Evaporation of the solvent yielded the crude base. This was dissolved in ether and HCl in EtOH was added to precipitate the hydrochloride. Recrystallization from EtOAc/EtOH yielded 3.2 g (67%) of the title compound (2:1), m.p. 224°-27° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])([O-:17])=[O:16]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])=[O:26])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(NCC1CCN(c2ccncc2)CC1)Nc1ccccc1[N+](=O)[O-]
Yield: 63.8 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (1.34 g, 7.01 mmol) and 2-nitrophenyl isocyanate (1.21 g, 7.40 mmol) in methylene chloride was stirred at room temperature. Concentration in vacuo and purification by flash chromatography (silica gel, 5% methanol/1% triethylamine/94% chloroform) yielded 1.59 g (64%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>O1CCCC1.O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCC(O)CO
Reaction time: 40 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-1,3-dinitrobenzene (4.05 g, 20.0 mmol) and triethylamine (3.35 mL, 24.0 mmol) in tetrahydrofuran (70 mL) was added a solution of 3-amino-1,2-propandiol (3.64 g, 40.0 mmol) in tetrahydrofuran (10 mL) at room temperature. After 40 hr, the reaction mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound (5.02 g, 19.6 mmol, 98%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].S(=O)(=O)(O)O.P(=O)(O)(O)O.[CH3:17]C(=O)CC>>[CH:2](=[O:6])[CH:3]([CH3:17])[CH3:4].[CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4]
Reactant: CCC(C)=O
Agent: CC(O)C(C)O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(C)C=O

Procedure:
The dehydration of 2,3-butanediol has previously been carried out by means of heterogeneous and homogeneous catalysis. Aluminosilicates (A. N. Bourns, R. V. V. Nicholls, Can. J. Res. B 1946-1947, 24-25, 80 ff) and Nafion®-H (I. Bucsi, A. Molnár, M. Bartók, Tetrahedron 1994, 50, 27, 8195 ff) were used as heterogeneous catalysts. Sulfuric acid (A. C. Neish, V. C. Haskell, F. J. MacDonald, Can. J. Res. B 1945, 23, 281 ff) or phosphoric acid (E. R. Alexander, D. C. Dittmer, J. Am. Chem. Soc. 1951, 73, 1665 ff) were used for homogeneously catalysed dehydration. In all experiments, 2-butanone and isobutyraldehyde, and also its acetal with 2,3-butanediol, were obtained in varying proportions. Bourns was able to obtain 2-butanone in 85% yield in a gas phase reaction at 225° C. over aluminosilicate. The yield declined at higher temperatures, while above 450° C. only gaseous decomposition products were formed. Bucsi likewise achieved a selectivity for 2-butanone of 83% with almost complete conversion, by heterogeneous catalysis over Nafion®-H catalysts, while the formation of isobutyraldehyde could be almost completely eliminated (S=3%). Neish investigated the kinetics of dehydration to 2-butanone with addition of 3-20% (g g−1) sulfuric acid. For the rac-meso starting materials (isomeric mixture of (R,R)- and (S,S)- and meso-2,3-butanediol), distillation with 85% phosphoric acid results in a combined yield of 2-butanone and isobutyraldehyde of 59%. The use of high acid concentrations, however, is accompanied by increased corrosion of the reactor. Furthermore, an additional neutralization is required during workup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](I)=[N:6][C:7]=1[Cl:8].ClC1C=C(O)C=NC=1Cl.II.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]#[CH:42])=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.[Cu]I.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.CCOCC>[Cl:8][C:7]1[N:6]=[C:5]2[CH:42]=[C:41]([C@@H:37]3[CH2:38][CH2:39][CH2:40][N:36]3[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[O:10][C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1cc(Cl)c(Cl)nc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: II
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)c(Cl)cc2o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
5,6-Dichloro-2-iodo-3-pyridinol (750 mg, 2.6 mmol)(prepared by treatment of 5,6-dichloro-3-hydroxypyridine (Koch & Schnatterer, Synthesis 1990, 499) with I2 (ibid, p. 497), copper(I) iodide (89 mg, 0.47 mmol), bis(triphenylphosphine)palladium(II) chloride (91 mg, 0.13 mmol) and triethylamine (433 mL, 3.1 mmol) were combined in DMF (3.0 mL) and allowed to stir for 1 hour. 1-t-Butyloxycarbonyl-2-(S)-ethynylpyrrolidine (610 mg, 3.1 mmol) in DMF (1 mL) was added and the reaction mixture was heated to 60° C. for 16 hours. After cooling to ambient temperature, the reaction mixture was poured over Et2O/saturated K2CO3 solution and the phases separated. The organic phase was washed with brine:water (1:1) (4×), dried (MgSO4), concentrated and chromatographed (silica gel; EtOAc/hexane, 1:6) to afford an amber oil (408 mg, 44%): 1H NMR (CDCl3, 300 MHz) δ 1.32 and 1.45 (two br s, 9H), 1.95-2.40 (m, 4H), 3.45-3.74 (m, 2H), 5.02 (m, 1H), 6.62 (s, 1H), 7.81 (s, 1H); MS (CI/NH3) m/z: 357 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-bromo-3-chloro-5-nitrobenzene (4.5 g, 19.03 mmol), morpholine (1.7 mL, 19.03 mmol), sodium tert-butoxide (3.11 g, 32.4 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.87 g, 0.952 mmol), XPhos (0.91 g, 1.903 mmol), and toluene (40 mL) was stirred at 100° C. under nitrogen for 2 h, then filtered through Celite and concd. The resulting residue was partitioned between EtOAc and water, and the organic phase was washed with satd aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concd. Purification by column chromatography (silica; 0-25% EtOAc in hexanes) afforded 4-(3-chloro-5-nitrophenyl)morpholine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=243.0 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-Hydroxy-(R)-pyrrolidine (8.71 g, 0.1 mol) was dissolved in CH2Cl2 (260 mL) and cooled to 0° C. Triethylamine (33.5 mL, 0.24 mol) and benzyl chloroformate (14.9 mL, 0.11 mol) were added, and the resulting solution was stirred for 2 h at 0° C. The solution was gradually warmed to room temperature and allowed to stir overnight. The solution was washed with 1 M HCl, saturated NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate to afford 13.7 g (62% yield, 2 steps) of the desired product as a purple oil.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=O)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].[H][H]>C1COCC1.C(OCC)C>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OCC(=O)N(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCOc1ccc(CO)cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl 4-{[2-(dimethylamino)-2-oxoethyl]oxy}benzoate (for a preparation see Intermediate 19) (1.61 g, 6.79 mmol) in THF (40 mL) was cooled in ice and then treated with a 1M solution of LiAlH4 in diethyl ether (6.8 ml) and the mixture was stirred under nitrogen for 4 h. The reaction mixture was cautiously treated with saturated aq. sodium sulfate solution until the hydrogen evolution ceased. The mixture was then stirred under nitrogen for 1 h and filtered. The solid was washed with diethyl ether and the combined filtrate and washings evaporated under reduced pressure to give the title compound (1.32 g, 100%). LCMS (System B) RT=1.70 min, ES+ve m/z 196 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH2:16][CH2:17][CH:18]=[CH2:19])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:5][CH2:6]C=C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][O:2][C:3]([C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][CH2:6][CH:19]=[CH:18][CH2:17][CH2:16]1)=[O:20]
Reactant: C=CCCC(CCC=C)(C(=O)OC)c1cccc(F)c1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: COC(=O)C1(c2cccc(F)c2)CCC=CCC1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To 2-but-3-enyl-2-(3-fluoro-phenyl)-hex-5-enoic acid methyl ester (Example 12a) (5.0 g) in dichloromethane (100 mL) was added Grubbs Catalyst (2nd Generation, Sigma-Aldrich Company Ltd) (0.05 g). The mixture was warmed to reflux under nitrogen. After 20 hours the reaction was cooled to room temperature, evaporated to an oil and purified by column chromatography on silica eluting with ethyl acetate/isohexane (5/95) to yield an oil. Analysis of the product showed that significant amounts of starting material was present in the mixture so the mixture was subjected to a repetition of the reaction conditions and purification as above to afford the subtitled compound as a coloured oil (3.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1>CO.[Ni]>[NH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)CCNc1ccc(Cl)cc1N
Yield: 89.8 %

Procedure:
A solution of ethyl 3-[(4-chloro-2-nitrophenyl)amino]propanoate (1.0 g, 3.67 mmol) in methanol (50 mL) was stirred with Raney nickel (0.30 g) under hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo to afford the crude ethyl 3-[(2-amino-4-chlorophenyl)amino]propanoate (0.80 g, yield: 89.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2=[O:18].[CH2:19]1COCC1.C[Mg]Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2([CH3:19])[OH:18]
Reactant: COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Product: COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: -30 °C

Procedure:
To a slurry of 7-bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one (23 g, 75 mmol) in THF (751 mL, 75 mmol) at −40° C. was added methylmagnesium chloride, 3.0 M solution in THF (88 mL, 263 mmol) over 2 minutes such that the temperature did not rise above −35° C. The resulting red slurry was maintained at −30° C. After 1 hour the reaction, which was now homogeneous, was quenched with 50 mL of ethyl acetate. The solution was then carefully quenched with 800 mL of 50% ammonium chloride. The mixture was poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the organics were washed with brined, dried over sodium sulfate, filtered and concentrated. The aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered, and combined with the above derived oil. This organic solution was washed with brined, dried over sodium sulfate, filtered and concentrated to provide 7-bromo-3-methoxy-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)[OH:4].O=[C:21]([CH3:35])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:34][O:33][C:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)[OH:4])[CH3:35])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: CC(C)(C)c1cc(C(O)CN)cc(C(C)(C)C)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3 g of 2-amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol (prepared as described in Preparation 35), 2.2 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 100 ml of benzene, 60 ml of absolute methanol and 4 g of sodium cyanoborohydride were used, and that the product was purified by repeated column chromatography through silica gel, using as the eluent first ethyl acetate and then a 1:1 by volume mixture of benzene and ethyl acetate. 2.1 g of 2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4hydroxyphenyl)ethanol were obtained. This product was then mixed with 246 mg of fumaric acid, and the mixture was recrystallized from ethyl acetate, to give 1.5 g of the title compound as crystals, melting at 171°-174° C.
Reaction SMILES: C([CH:8]([NH2:33])[C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([Cl:28])[C:22]=4[C:21](=[O:30])[N:20]4[CH2:31][CH2:32][C@H:19]4[C:18]=23)[N:10]=1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH2:33][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([Cl:28])[C:22]=4[C:21](=[O:30])[N:20]4[CH2:31][CH2:32][C@H:19]4[C:18]=23)[N:10]=1
Reactant: CC(C)(C)OC(=O)C(N)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 81.9 %

Procedure:
36.8 g (77.5 mmol) of crude (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one and 90 ml of trifluoroacetic acid were stirred at room temperature for 2 hours. The solution was evaporated, the residue was dissolved in water and the aqueous solution was washed three times with methylene chloride. The aqueous phase was made alkaline with conc. ammonia and extracted eight times with methylene chloride (a total of about 1 l). By evaporating the organic phases, combined and dried over magnesium sulfate, there were obtained 23.8 g (82%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used without further purification as the starting material for the Example described hereinafter.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>C(OCC)(=O)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(CO)Nc1c(N)cnc2ccccc12

Procedure:
A mixture of 27.9 g (0.113 mole) of 2-[(3-nitro-4-quinolinyl)amino]-1-propanol in 1.2 l of ethyl acetate, 28 g of magnesium sulfate and 2.0 g of 5% platinum on charcoal was hydrogenated on a Paar apparatus until hydrogen uptake was completed. The catalyst and solid residue were removed by filtration and the filtrate was concentrated by evaporation to provide 2-[(3-amino-4-quinolinyl)amino]-1-propanol as a yellow oil.