Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1.CN(C)C=O.N1C=CN=C1.Cl[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42]>>[O:28]=[C:9]1[C@@:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:12][N:8]1[C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:7][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H]1CC[C@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl (5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (2.0 g, 0.0052 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added 1H-imidazole (0.986 g, 0.0145 mol) and chlorotriethylsilane (1.13 mL, 0.00673 mol) at rt. After stirring for 2 h ice-water was added and the resulting mixture was stirred at room temperature for 30 minutes and extracted three times with AcOEt. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residual oil was purified by column chromatography using 30% by volume AcOEt in hexanes.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([Cl:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](C1N=C(Cl)C2NC(C)=C(I)C=2N=1)CCC>>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([Cl:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c2[nH]c(C)c(I)c2n1
Reactant: CCCCc1nc(Cl)c2c(n1)c(I)cn2COCc1ccccc1
Product: CCCCc1nc(Cl)c2c(n1)c(I)c(C)n2COCc1ccccc1

Procedure:
Prepared similarly to Intermediate 5 from 2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)#[N:4].Cl[C:27]1[CH:28]=[C:29]2[N:36]([CH3:37])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>C1COCC1>[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][O:25][C:27]2[CH:28]=[C:29]3[N:36]([CH3:37])[CH2:35][CH2:34][N:30]3[C:31](=[O:33])[N:32]=2)[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=1)#[N:4]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile (49.7 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH2:11]1[C:17](=O)[CH2:16][S:13](=O)(=O)[CH2:12]1.[NH3:19].Cl>C(O)C.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]2[C:12]3[S:13][CH2:16][CH2:17][C:11]=3[NH:19][C:17]3[CH2:11][CH2:12][S:13][C:16]2=3)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: N
Reactant: O=C1CCS(=O)(=O)C1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1cccc(C2C3=C(CCS3)NC3=C2SCC3)c1

Procedure:
3-Cyanobenzaldehyde (132 mg, 1.01 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (272 mg, 2.03 mmol) and 2.0 M NH3 in ethanol (0.75 mL, 1.5 mmol) were heated to 80° C. in ethanol (4 mL) in a sealed tube for 3 days, cooled, treated with 1.0 M HCl in ether (1 mL), heated to reflux for 1 hour, cooled and solvent evaporated. The crude was flash chromatographed over silica gel (15% methanol/chloroform), and the product triturated with ethyl acetate to provide 87 mg of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:12]=2[C:13]([O:15]CC2C=CC(F)=C(F)C=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].CO.O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)OCc2ccc(F)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,4-difluorophenyl)methyl 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoate (may be prepared by Description 100; 7 g, 16.73 mmol) in tetrahydrofuran (50 ml) was added lithium hydroxide (1.202 g, 50.2 mmol) followed by methanol (12.50 ml) and water (12.5 ml). The mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure to one third volume. The mixture was diluted with water (50 ml) and acidified to pH=1 using 2M aqueous HCl. The solid formed was filtered off, washed with water and air dried under vacuum to give a white solid. 4.85 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[O:10][CH2:9][C:8]1([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1.ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[C:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)([CH3:19])[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2(C)COc3cc(OC)ccc3C2CCCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(C)COc3cc(OC)ccc3C2CCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
(3RS,4RS)-4-(5-Hydroxypentyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylchroman (430 mg, 1.2 mmol) was dissolved in a solvent mixture of pyridine (12 ml) and dichloromethane (4 ml), which was then cooled down to 0° C. p-Toluenesulfonylchloride (460 mg, 2.3 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. Water was then added, and the organ layer was extracted with ethyl acetate. The organic extract was washed with 2N hydrochloric acid solution, dried over magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (315 mg, yield 53%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21](OC)=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH2:26][OH:27].C(O)(=O)C>CO>[CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21]([NH:26][OH:27])=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Reactant: NO
Agent: [K]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NO)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h
Yield: 36 %

Procedure:
To a vial containing methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH) and the resulting mixture was shaken at rt for 13 h. The solution was quenched with acetic acid (0.200 mL, 3.52 mmol) before being concentrated. To the resulting residue was added DMSO (1.2 mL) and it was purified via prep-HPLC to yield N6-benzyl-N2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicarboxamide (0.0113 g, 36.0%). LC-MS: (FA) ES+ 327; 1H NMR (Methanol-d4, 400 MHz) δ 7.86 (d, J=7.8 Hz, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.25-7.19 (m, 5 H), 4.68 (s, 2 H), 4.39 (s, 2 H), 3.79 (t, J=6.0 Hz, 2 H), 3.03 (t, J=6.0 Hz, 2 H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([Cl:16])[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=O)C.[OH-].[Na+].O.C(O)(=O)C>CO>[Cl:16][C:7]1[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1cc(Cl)c2c(c1)COC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C1Nc2c(Cl)cc(O)cc2CO1

Procedure:
An amount of 7.6 gm (31.4 mol) of 6-acetoxy-8-chloro-4H-3,1-benzoxazin-2-one is suspended in 50 ml of methanol, and 20 ml (40 mmol) of 2N sodium hydroxide solution are added, under stirring. The clear solution which is immediately produced is stirred for a further ten minutes at ambient temperature, water is added, and the mixture is made acidic with acetic acid. The precipitate is subjected to suction filtration and recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[CH2:13][S:14][CH3:15].[CH3:16][O-:17].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:17][CH3:16])[C:3]=1[CH2:13][S:14][CH3:15]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)c(CSC)c1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c(CSC)c1OC
Yield: 84.5 %

Procedure:
A solution of methyl 4-chloro-2-fluoro-3-methylsulphenylmethylbenzoate (11.4 g) in tetrahydrofuran was stirred, with addition of sodium methoxide (3.5 g). After 2 hours water was added and the mixture extracted with ether, dried (magnesium sulphate) and evaporated to give methyl 4-chloro-2-methoxy-3-methylsulphenylmethylbenzoate (10.1 g), NMR (CDCl3) 2.15 (s,3H), 3.9 (3s,8H), 7.15 (d,1H), 7.65 (d,1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][C:21]1[N:22]=[C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]2[CH:30]=1>C1COCC1>[CH3:29][C:28]1[C:23]2[N:24]([CH:30]=[C:21]([CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cc1cccn2cc(CCl)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccn2cc(CCC#C[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (259 mg, 2.31 mmol) in THF (7.5 mL) at −78° C. was added n-BuLi 2.5M in hexane (1.1 mL, 2.8 mmol). After 90 min at −78° C. 2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (500 mg, 2.8 mmol) in THF (5 mL) was added dropwise. The solution became blue-green at −78° C. The solution was stirred at −78° C. for an additional 1 h. The reaction was quenched with water and the solvent was removed under reduced pressure. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 590 mg of 8-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 100%) as an yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].Cl[CH2:16][CH2:17][CH:18](O[Si](CC(C)C)(C)C)[CH2:19][CH3:20].[Mg].Cl[CH:31]1[CH2:35][CH2:34][CH:33]=[CH:32]1>O1CCCC1>[CH:19]1([CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:18][CH2:17][CH:16]=[CH:20]1.[CH3:10][C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH:4]([CH2:13][CH3:14])[CH2:3][CH2:2][CH:35]1[CH2:34][CH2:33][CH:32]=[CH:31]1)([CH3:12])[CH3:11]
Reactant: CCC(CCCl)O[Si](C)(C)CC(C)C
Reactant: ClC1C=CCC1
Reactant: CCC(CCCl)O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure followed is the same as that described in Example 20 substituting (5-chloro-3-pentyloxy)(2,2-dimethylethyl)dimethylsilane {3-chloro-1-ethylpropoxy)(1,1-dimethylethyl) dimethylsilane,} (78 g, 0.33 moles) diluted in tetrahydrofuran (100 ml), granular magnesium (24 g, 1.00 moles) in tetrahydrofuran (100 ml), 0.1 M solution of Li2CuCl4 (1.0 mmole), 3-chlorocyclopentene (33 g, 0.33 moles) diluted in tetrahydrofuran (50 ml). The crude product is distilled under reduced pressure leaving a clear yellow oil (21 g, 0.078 moles), BP 69° C./ 0.1 mm.
Reaction SMILES: [NH2:1][C:2]1C=CC=[CH:4][C:3]=1O.[NH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:11]=1[OH:22].C[N:24]([CH3:26])C>C(O)C>[C:16]1([C:14]2[CH:13]=[CH:12][C:11]3[O:22][C:4](=[C:3]([C:26]#[N:24])[C:2]#[N:1])[NH:9][C:10]=3[CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: Nc1ccccc1O
Reactant: CN(C)C
Solvent: CCO
Product: N#CC(C#N)=C1Nc2cc(-c3ccccc3)ccc2O1

Procedure:
The procedure described in Example 1 is repeated using, instead of 2-aminophenol, an equivalent amount of 2-amino-4-phenylphenol in ethanol and holding the mixture under reflux in the presence of 1 ml. of trimethylamine for 60 hours. The crude product is crystallized from acetone to obtain (5-phenyl-2-benzoxazolinylidene)malononitrile of melting point ca. 236° C. (dec.).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1.[C:36]([O:47][CH3:48])(=[O:46])[C:37]1[CH:45]=[CH:44][CH:43]=[C:39]([C:40]([O-])=[O:41])[CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:20][CH2:21][N:22]([C:40]([C:39]5[CH:38]=[C:37]([CH:45]=[CH:44][CH:43]=5)[C:36]([O:47][CH3:48])=[O:46])=[O:41])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: Cc1ccccc1C1(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A mixture of 2-methyl-1-(8-{2-[4-(2-methyl phenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole dihydrochloride (0.40 g, 0.84 mmol), monomethyl isophthalate (0.15 g, 0.84 mmol) and triethylamine (0.4 mL, 2.9 mmol) in dimethylformamide (3 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.35 g, 0.92 mmol) and stirred at rt for 1 h. The mixture was diluted with water and the resultant precipitate was collected, washed with water, dried and purified by chromatography on silica gel eluting with 1:33 methanol:dichloromethane to give methyl 3-{[4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl) piperidin-1-yl]carbonyl}benzoate as a glass (0.240 g, 47%). 1H NMR (400 MHz, CDCl3) δ 8.08 (m, 2H), 7.67 (m, 2H), 7.59 (m, 1H), 7.49 (t, 1H), 7.13-7.29 (m, 6H), 4.62 (m, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 3.56 (m, 2H), 3.26 (m, 2H), 2.54 (m, 5H), 2.36 (m, 4H), 1.95 (m, 10H), 1.64 (m, 4H). HRMS C38H44N4O3 m/z 605.3492 (M+H)Cal. 605.3497 (M+H)Obs..
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.[OH-:18].[K+].Cl.[NH2:21]O.Cl>C(O)C.O>[OH:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](=[N:21][OH:18])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=NO)c2ccc(Cl)cc2)c1O
Reaction time: 8 h

Procedure:
The ketone of Example 4 (7.5 g, 0.03 mole) in ethanol (18 ml.) was added with stirring to a solution of (85%) potassium hydroxide (20.74 g, 0.3 mole) in water (85 ml) at 10° C., this colloidal solution was treated with solid hydroxylamine hydrochloride (8.54 g, 0.12 mole) and stirred overnight. The solution was acidified with 5N HCl to give a solid, which was filtered, washed with water and stirred for 45 minutes, then treated with 5% Na2CO3 solution (30.5 ml), to remove unwanted oxime stereoisomer, filtered, washed with 5% Na2CO3 solution (100 ml) and then with water until free of alkali. The dried solid had m.p. 175°-177° C. Recrystallisation from 54% benzene-light petroleum (b.p. 60°-80° C.) mixture gave the oxime, m.p. 178° C. ("bonded isomer") 5.45 g.
Reaction SMILES: [PH:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].Br[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CCO[PH](=O)OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl phosphonate (3.02 g, 21.88 mmol, 1.10 equiv) in toluene (10 mL), Pd(PPh3)4 (1.15 g, 1.00 mmol, 0.05 equiv), TEA (2.21 g, 21.88 mmol, 1.10 equiv), 1-bromo-4-nitrobenzene (4 g, 19.90 mmol, 1.00 equiv). The resulting solution was stirred for 15 h at 90° C. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 3.53 g (68%) of diethyl 4-nitrophenylphosphonate as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1ccc(-c2cccnc2)cc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3cccnc3)cc1)O2
Reaction time: 3 h

Procedure:
A mixture of 1.15 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 1.14 g (4 mmol) of 3-(4-iodophenyl)pyridine, 0.2 g of triphenylphosphine, 50 mg of cuprous iodide, 1.5 ml of triethylamine and 20 ml of acetonitrile was degassed with argon for 10 minutes. Palladium acetate, 75 mg, was then added and stirring was continued for 3 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was dried and evaporated. The residue was crystallized from ethyl acetate and recrystallized from methanol/ethyl acetate to give colorless crystals with m.p. 190°-192° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.C[C:25]1[C:30]([NH:31]S(C)(=O)=O)=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:2]5[CH:11]=[CH:29][C:28]([C:27]6[NH:31][CH:30]=[CH:25][N:26]=6)=[CH:4][CH:3]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-c5ncc[nH]5)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 77.1.1) to give the title compound as a white solid. (HPLC: tR 2.15 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 12.58 (s, br, 1H), 8.96 (s, 1H), 8.20-8.15 (m, 1H), 8.14-8.07 (m, 1H), 8.05-7.94 (m, 3H), 7.63-7.53 (m, 3H), 7.31-7.07 (m, br, 2H), 3.95 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[CH2:9])[CH3:2].[F:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=1[F:21]>C(OCC)C>[CH2:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4]=1[CH3:9])[CH3:2].[F:10][C:11]1[C:16]([O-:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=1[F:21]
Reactant: C=C1N(C)CCN1CC
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Product: CC[n+]1ccn(C)c1C
Product: [O-]c1c(F)c(F)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
1.48 ml (11.95 mmol) 1-ethyl-3-methyl-2-methylene imidazoline is added to a solution of 2.20 g (11.95 mmol) pentafluorophenol in diethylether cooled to −78° C. by means of a syringe. The reaction mixture is warmed to room temperature over a period of 5 h and stirred at room temperature for 8 h. The precipitated, colorless solid is filtered off, washed twice with 20 ml diethylether and, subsequently, dried in vacuum. The desired product is obtained as a colorless solid which melts at 144° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CS(C)=O>[CH3:13][C:11]1[N:12]=[C:5]2[C:4]([O:3][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)=[CH:9][CH:8]=[CH:7][N:6]2[CH:10]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn2cccc(OCc3ccc([N+](=O)[O-])cc3)c2n1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.3 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (1.0 g) in dimethyl sulfoxide (10 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 4-nitrobenzyl bromide (1.6 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-methyl-8-(4-nitrobenzyloxy)imidazo[1,2-a]pyridine (0.77 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:18]1[CH:19]=[C:20]([CH3:25])[N+:21]([O-:24])=[CH:22][CH:23]=1)([O-])=O>CN(C)C(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:19]=[C:20]([CH3:25])[N+:21]([O-:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(F)cc2)cc[n+]1[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6.2 g (55 mmol) of 4-fluorophenol are dissolved in 75 ml of N,N-dimethylacetamide and 20.7 g (150 mmol) of finely powdered potassium carbonate was added. 7.7 g (50 mmol) of 4-nitro-2-picoline-N-oxide are added to this suspension and the mixture is warmed at 80° C. for 3 hours. A further 7 g (50 mmol) of potassium carbonate are subsequently added and the mixture is stirred for one hour at 100° C. After cooling, it is freed from N,N-dimethylacetamide in vacuo, and the residue is taken up in water, extracted a number of times using dichloromethane, dried over MgSO4 and concentrated, and the residue is brought to crystallization using diisopropyl ether, m.p. 122°-124° C.