Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.[CH3:35][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)([CH2:23][C:24]([OH:26])([CH3:35])[CH3:25])[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (0.0303 g, 0.0648 mmol) in THF (5 mL) was added MeMgBr (1.4 M in toluene/THF, 1 mL, 1.4 mmol) at 0° C. The mixture was warmed to it and stirred for 1 h before quenching with satd aq NH4Cl (1 mL). The mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by preparative HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.91 min, m/z 484 (MH+), 426; 1H NMR (400 MHz, CD3OD) δ 7.36-7.20 (m, 5H), 7.02-6.92 (m, 6H), 5.52 (q, J=7.0 Hz, 1H), 3.05-3.00 (m, 1H), 2.49-2.35 (m, 2H), 2.22-2.15 (m, 1H), 2.06 (s, 2H), 1.48 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.90 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −113.78 (m), −115.82 (m), −117.50 (m).
Reaction SMILES: O[C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3]N(CCOC1C=CC(I)=CC=1)C(=O)OC(C)(C)C.B(O)(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:22]1([C:2]2[CH:3]=[CH:23][CH:22]=[CH:2][CH:3]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(I)cc1)C[C@H](O)c1ccccc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: OB(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(-c2ccccc2)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 510.4 %

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-(4-iodophenoxy)ethyl]carbamate (350 mg) in toluene (6.0 ml) and ethanol (1.5 ml) was added boric acid (222 mg), [1,1′-bis(diphenylphosphino)ferrocene]-dichlorobispalladium(II), complex with dichloromethane (59 mg), 1,1′-bis(diphenylphosphino)ferrocene (20 mg) and aqueous solution of sodium carbonate (2M, 0.8 ml), and the mixture was stirred at 75° C. for 4 hours under nitrogen. The mixture was partitioned between with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give biphenyl product (285 mg). To a solution of the product in methanol (5.0 ml) was added 1N aqueous sodium hydroxide solution (1.5 ml), and the mixture was stirred at 40° C. for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in ethyl acetate (2.0 ml) was added 4N hydrogen chloride in ethyl acetate (2.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethoxy]-4-biphenylcarboxylic acid hydrochloride (210 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous diemthylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5 N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3) δ4.1(m,2), δ3.68(S,3), δ3.03(dd,1,J=4.3,2.7), δ2.8(ABq,2), δ1.17(d,3,J=6.6), δ0.98(s,9), δ0.89(s,9), δ0.23(s,6), δ0.1(s,6).
Reaction SMILES: C(OC([NH:8][C@@:9]([CH2:27][CH3:28])([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:22]C(C)(C)C(C)(C)[O:19]1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C.[ClH:29]>O>[ClH:29].[NH2:8][C@@:9]([CH2:27][CH3:28])([CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:22])[OH:19])[C:10]([OH:12])=[O:11]
Reactant: CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: O
Product: CC[C@](N)(CCCCB(O)O)C(=O)O
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxycarbonylamino)-2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.283 g, 0.709 mmol) in 6 N HCl (5 mL) was heated to a gentle reflux for 16 h. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×10 mL). The aqueous layer was concentrated to give an off-white solid that was dissolved in deionized water (3 mL) and passed through a C-18 Isolute SPE column (20 g) eluted with 10% methanol in deionized water (200 mL). The fractions containing product were concentrated under reduced pressure, redissolved in deionized water (5 mL), frozen in liquid nitrogen and lyophilized to give (S)-2-amino-6-borono-2-ethylhexanoic acid hydrochloride as an white foam (0.096 g, 67%). 1H NMR (D2O, 300 MHz) δ□ (m, 4H), 1.31-1.17 (m, 3H), 1.13-0.97 (m, 1H), 0.794 (t, J=7.6 Hz, 3H), 0.63 (t, J=7.8 Hz, 2H); ESI-LCMS m/z calcd for C8H18BNO4: 203.1. found 204.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]1([CH3:48])[CH2:47][O:46][CH2:45]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:43][C:44]5([CH3:48])[CH2:47][O:46][CH2:45]5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CCl)COC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CN2C(=O)COc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc32)COC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.11 mmol) in dry DMF (1 mL) was added potassium carbonate (44 mg, 0.32 mmol) and 3-(chloromethyl)-3-methyloxetane (38 mg, 0.32 mmol) under nitrogen. The resulting mixture was stirred for 2.5 hours at 80° C. A saturated solution of NaHCO3 was added and the mixture was extracted with AcOEt (3×). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (21 mg, 36%). 1H NMR (500 MHz, CDCl3): 7.23-7.17 (8H, m), 7.09-7.07 (2H, m), 4.94 (2H, s), 4.83 (2H, s), 4.64 (2H, d), 4.23 (2H, d), 4.05 (2H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.36 (3H, s), 1.40-1.10 (9H, br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:7]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: COc1cccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)c1
Yield: 84.3 %

Procedure:
In a manner similar to that described in Example 3, 3-methoxybenzoyl chloride (0.052 g, 0.00030 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.069 g of 4-[4-(3-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CN(c1nc(F)ccc1N)C1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-nitro-6-fluoro-2-pyridinyl)amino]piperidine (EXAMPLE 151, 5.81 g, 16.87 mmol) and platinum oxide (2.5 g) in ethanol (150 ml) is hydrogenated at 10 p.s.i. of hydrogen for one hr. Filtration and removal of the solvent gives 1-benzyl-4-[N-methyl-N-(3-amino-6-fluoro-2-pyridinyl)amino]piperidine. Without further purification, this material is dissolved in 85 ml acetonitrile and cooled to 0°. Acetone (3.76 ml, 51.2 mmol) and fused zinc chloride (465 mg, 3.4 mmol) are added and the mixture refluxed for 8 hrs. It is then poured into water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and concentrated. Chromatography of the concentrate (silica gel, 300 g; ethyl acetate/hexane (50/50)) gives the title compound, NMR (300 MHz, CD3OD) 7.64, 7.36-7.41, 6.73, 3.60, 3.35, 3.00, 2.74, 2.10-2.20, 1.81 and 1.77δ.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-b is(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 (s, 2 H), 7.61 (s, 1 H), 7.33 (dd, J=8.2, 1.4 Hz, 1 H), 5.79 (d, J=7.8 hz, 1 H), 4.91 (d, J=16 Hz, 1 H), 4.40 (d, J=16 Hz, 1 H), 4.16-4.06 (m, 1 H), 0.83 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24]([OH:26])=O)[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46]([NH2:50])([CH3:49])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClC(Cl)C>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46]([NH:50][C:24]([C:10]2[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])([CH3:49])[CH2:45][CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC1(N)CCN(Cc2ccccc2)CC1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCN(Cc4ccccc4)CC3)c12
Temperature: 40 °C
Yield: 432469.31 %

Procedure:
To a mixture of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (215 mg), DIPEA (313 μL) and 1-benzyl-4-methyl-piperidin-4-ylamine (175 mg) in dichloroethane (7 mL), which was being stirred at 40° C., was added BEP (200 mg). The mixture was stirred at 40° C. for 60 min, then at r.t. overnight. Water was added and the mixture was extracted with dichloromethane. To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added and stirred for 30 min. The mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica (dichloromethane/methanol gradient) to give 1420 g (43%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][Br:14]
Reactant: COC(=O)c1ccc(OC)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1CBr
Temperature: 5 °C
Yield: 57.7 %

Procedure:
A mixture of 4-methoxy-2-methyl-benzoic acid methyl ester (20 g, 111 mmol), N-bromosuccinimide (20.7 g, 117 mmol) and dibenzoylperoxide (0.54 g, 2 mmol) in CCl4 (150 mL) was irradiated with a 300 W lamp. The reaction maintains a steady reflux and after 4.5 h, the lamp was removed and the mixture cooled to 5° C. The mixture was then filtered, the filtrate evaporated and the residue purified twice by chromatography (SiO2, Heptane:Diethyl ether: 95:5 to 85:15) to afford the title product (16.6 g, 58%) as a white solid. MS m/e=258.1 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1.[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][NH:3]1
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C1)OCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C2=NNC(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Yield: 35.4 %

Procedure:
1.69 g (10.0 millimoles) of 8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are dissolved in a mixture of 75 ml of dichloro methane, 5 ml of methanol and 3 ml of glacial acetic acid. To the reaction mixture 0.38 g (10.0 millimoles) of sodium borohydride are added under cooling with ice-cold water in small portions. The reaction mixture is stirred at this temperature for an hour, then washed twice with 20 ml of water and 20 ml of saturated sodium chloride solution each, washed over magnesium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from 50 ml of acetonitrile each. Thus 1.20 g of the desired compound are obtained, yield 71%, mp.: 124–127° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])C.C[Si](I)(C)C>C(Cl)(Cl)Cl>[C:17]([C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2)c2ccccn2c1=O
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(C(=O)c2ccccc2)c2ccccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 3-ethoxycarbonyl-1-benzoyl-4H-quinolizin-4-one (2.14 g) in chloroform (65 ml) was added dropwise trimethylsilyliodide (1.04 ml) at 0° C. After stirring for 30 minutes at 0° C., trimethylsilyliodide (1.04 ml) was added. After stirring for hour at room temperature, trimethylsilyliodide (1.04 ml) was added. After stirring for 2 hours at room temperature, the reaction mixture was diluted with chloroform and washed with water. After drying over magnesium sulfate, the chloroform extract was filtered and concentrated. The precipitate was washed with a cold chloroform to give 1-benzoyl-4H-quinolizin-4-one-3-carboxylic acid (1.252 g) as yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:13]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (0.68 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 550 mg (yield: 98.4%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 72, 80.0 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (56%) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1.C(O)C.[Cl-].[NH4+].Cl>[Fe].O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CN(C)CCNc1ccc(N)cn1
Temperature: 80 °C

Procedure:
To a round bottom flask, charged with N1,N1-dimethyl-N2-(5-nitropyridin-2-yl)ethane-1,2-diamine (0.4 g, 1.90 mmol) from above, 5 mL of ethanol, 5 mL water followed by iron powder (0.416 g, 7.58 mmol) and ammonium chloride (0.402 g, 7.58 mmol). The resulting reaction mixture was heated at 80° C. for 3 hours. TLC analysis showed no acid remaining so the mixture was passed through a cellite cartridge to remove iron. The organic solution was concentrated under vacuo to give a brown oil residue. The resulting crude mixture was treated with hydrochloric acid (1 N) and washed with ethylacetate. The aqueous layer was basified to PH=10 using sodium carbonate and extracted with ethyl acetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The title product was obtained as a brown solid (0.23 g, 51% yield). MS m/z: 181.16 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17](=[O:22])[CH2:18][CH:19]4[CH2:21][CH2:20]4)[N:15]=3)[N:12]=2)=[CH:4][C:3]=1[NH2:25].[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[CH:19]1([CH2:18][C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:23]=[CH:24][C:2]([CH3:1])=[C:3]([NH:25][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:22])[CH2:20][CH2:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)cc1N
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CC5CC5)cn4n3)ccc2C)n(C)n1
Yield: 60.5 %

Procedure:
Using N-[6-(4-methyl-3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide (120 mg, 0.356 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (59 mg, 0.374 mmol) and N,N-dimethylacetamide (4.0 mL), and by a reaction in the same manner as in Example 148, the title compound (99 mg, 61%) was obtained as a pale-yellow powder.