Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]([C:37]#[N:38])=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[CH2:24]1)#[N:21].O>C(O)(=O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]2[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]2=[C:22]([C:20]#[N:21])[C:37]#[N:38])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CC(C#N)=C1CC(=C(C#N)C#N)c2ccccc21
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Solvent: CC(=O)O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=C2C(=C(C#N)C#N)c3ccccc3C2=C(C#N)C#N)c(OC)c1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
In 10 ml of anhydrous acetic acid were dissolved 0.8 g (3.04 mmol) of 4-(dibutylamino)-2-methoxybenzaldehyde and 0.73 g (3.01 mmol) of 1,3-bis(dicyanomethylidene)indan. The mixture was stirred with heating at 80° C. for 2 hours. The reaction mixture was poured into 200 ml of water and the precipitate was separated by filtration, washed with water, and dried. The crystal was purified by silica gel column chromatography and washed with methanol to give 1.27 g of a black crystal having a mp of 195-198° C. (yield: 86.4%).
Reaction SMILES: [N:1]1([C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[N:1]1([CH:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C=C(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-yl-2-propenoate (318 mg, 861 μmol) in a mixture of ethanol and water (17:2, 4.2 mL) was added palladium on carbon (47 mg, 10% w/w Pd) and ammonium formate (218 mg, 3.46 mmol). The suspension was brought to reflux for 3 hours, cooled to room temperature, and was filtered through a pad of Celite® and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.51 min, MH+ 371.7].
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 1 g portion of Boc—(D)—Arg(Tos)—Gly—OBn (1.74 mmol) was dissolved in 10 mL of CH2Cl2, cooled to 0° C. and treated with 10 mL of TFA. The solution was stirred at 0° C. for 3 h. Solvent and excess TFA were evaporated thoroughly to give the title compound as an oil which was used directly in Example 10.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 150 °C
Yield: 41.1 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.377 g, 1.92 mmol) and 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (0.520 g, 2.11 mmol) in DMA (20 mL) was added NaHSO3 (0.240 g, 2.3 mmol) followed by p-TsOH (0.037 g, 0.192 mmol) and the reaction heated at 150° C. for 6 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 (150 mL), washed with brine (2×150 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.333 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1H), 7.88-7.91 (m, 2H), 6.78-6.82 (m, 3H), 6.42 (d, J=2.2 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.62-3.80 (m, 6H), 3.36-3.48 (m, 2H), 1.98-2.12 (m, 5H). ESI MS m/z 421 [M−H]−.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43](Cl)=O>C1(C)C=CC=CC=1>[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43]1[O:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH:12]=1
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(CCC(F)(F)F)cc2c1
Reaction time: 2 h

Procedure:
A suspension of 4.0 g (8.1 mmol) of (2-hydroxy-5-nitrophenyl) methyltriphenylphosphonium bromide in 50 ml of toluene is heated to reflux, then 5.1 ml (36 mmol) of triethylamine and 1.9 g (12 mmol) of 4,4,4-trifluorobutyryl chloride are added. The mixture is stirred for 2 hours, then it is filtered and the filtrate is concentrated under reduced pressure. By chromatography of the residue on a silica column using a 0-30% mixture of dichloromethane in cyclohexane, 1.1 g of product are obtained. Melting point: 70-71° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].CS(O[CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31])(=O)=O>CN(C=O)C>[CH:30]([O:29][CH2:28][CH2:27][N:4]1[C:5]2=[N:10][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][C:7](=[O:17])[N:6]2[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]1)([CH3:32])[CH3:31]
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC1(C)CNc2nc(N3CCOCC3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCN1CC(C)(C)Cn2c1nc(N1CCOCC1)cc2=O
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
0.17 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.03 g of 60% NaH are added and stirring is performed for 30 mins. 0.24 g of 2-isopropoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured in a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.08 g (yield=35%) of 9-(2-isopropoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([OH:38])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1.O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:38][CH2:4][CH2:3][O:2][CH3:1])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1
Reactant: COCCBr
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 40 °C
Yield: 64 %

Procedure:
2-Bromoethyl methyl ether (22 μl) and potassium carbonate (43 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent to give the title compound as a white solid (51 mg, 64%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (t, 2H), 3.50-3.37 (m, 2H), 3.35 (s, 3H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 505.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Phosphorus oxychloride (500 μL, 1.3 mmol) and N,N-dimethylformamide (704 μL, 9 mmol) were dissolved in 15 mL of anhydrous dichloromethane under stirring at room temperature, and the reaction solution was stirring for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5e (586 mg, 2 mmol) was dissolved in 8 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed. The reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution. The mixture was extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×5). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, yield 78.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1([N:28]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[N:30]=[CH:29]1)[C:24](=[S:27])[NH:25][CH3:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:27][C:24](=[N:25][CH3:26])[C:19]2([N:28]3[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[N:30]=[CH:29]3)[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[OH:17])=[CH:5][CH:4]=1
Reactant: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.5 %

Procedure:
21.7 ml (160 mmol) of 4-methoxybenzyl chloride and 32.94 g (238 mmol) of potassium carbonate were added to a solution of 45.23 g (159 mmol) of the 2-hydroxy-N-methyl-1-(4-nitroimidazol-1-yl)cyclohexanecarbothioamide (L form) prepared in the Example 17 in 300 ml of N,N-dimethylformamide. The obtained mixture was stirred at room temperature for 17 hours to give a yellowish-brown suspension. Water and common salt were added to this suspension and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue (65.5 g) was recrystallized from dichloromethane/ethyl acetate to give 42.78 g of the title compound as a light yellowish-brown crystal (yield: 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:13]([O:15]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:14]>C1(C)C=CC=CC=1.[Pd].CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:15])[CH3:14]
Reactant: O=Cc1cc(Br)cc2ccoc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C=O)c2occc2c1
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (2.00 g), 1-ethoxy-1-tributylstannanylethene (3.53 g)and bis(triphenylphosphine)palladium (II) chloride (63 mg) in dry toluene (4 ml) was heated at reflux under nitrogen for 18 h. A further portion of palladium catalyst (63 mg) was added and heating at reflux continued for a further 6 h. The reaction was allowed to cool, diluted with ether (40 ml) and filtered through a plug of Hyflo. The filtrate was washed successively with hydrochloric acid (50 ml; 2M) and brine (50 ml), then dried, and concentrated in vacuo to give an orange oil. Purification by FCC eluted with hexane to hexane:ethyl acetate (4:1) gave the title compound as a yellow powder (1.21 g), m.p. 91-93°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:24]1[C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc2c1nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c1nc([C@H](C)N)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of [(S)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (380 mg, 1.08 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at RT for 3 h. Additional TFA (0.5 mL) was added and stirring was continued for 30 min. Volatiles were then removed under reduced pressure and the residue was then dissolved in a small amount of DCM and loaded onto an SCX-2 cartridge which was initially washed with 10% MeOH in DCM. The product was eluted with 2M NH3/MeOH affording (S)-1-(4-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (222 mg, 82%). LCMS: RT 2.16 [M-NH2]+ 235.1
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([O:34][C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Using anhydrous conditions, 1.25 g of product from Example 45 in 27 ml of anhydrous tetrahydrofuran, is cooled to -78° C. under argon. 0.325 ml of isobutyl chloroformate is added, followed by 2.7 ml of lithium bis(trimethylsilyl)amide. The reaction mixture is stirred at -78° C. for 1 hour, followed by stirring at -55° C. for another hour and then concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 1.22 g of the desired product.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (600 mg, 2.24 mmol) and 1-bromohexadecane (1.37 mL, 4.49 mmol), alcohol 59 was obtained as a colorless oil (775 mg, 70% yield).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=1[CH:34]([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:21][CH2:22][N:23]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[CH:34]([CH3:36])[CH3:35])[CH2:24][CH2:25]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: CC(C)c1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Temperature: 120 °C
Reaction time: 56 h

Procedure:
The mixture of 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine (162.8 mg; 0.47 mmol; 1.0 eq.), 6-chloro-5-isopropyl-pyrimidin-4-ylamine (81.6 mg; 0.47 mmol; 1.0 eq.) and potassium carbonate (82.1 m g; 0.59 mmol; 1.25 eq.) in DMSO (3 ml) was stirred 120° C. for 56 hr. The crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=478, obsd=478). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.66-7.59 (m, 1H), 7.54 (ddd, J=7.7, 4.9, 2.1 Hz, 1H), 7.48 (s, 1H), 7.08 (t, J=9.1 Hz, 1H), 6.13 (s, 2H), 3.87 (t, J=6.2 Hz, 2H), 3.11 (t, J=6.9 Hz, 4H), 2.93-2.80 (m, 3H), 2.68 (t, J=6.2 Hz, 2H), 2.30-2.21 (m, 3H), 1.92 (dtd, J=24.6, 12.8, 12.1, 4.0 Hz, 5H), 1.30 (d, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:19][OH:20].C(O)C>N1C=CC=CC=1>[N:19](=[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)[CH3:2])[OH:20]
Reactant: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)Sc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
A mixture of 2-acetylphenoxathiin (J.A.C.S. 1936, 58, 717) (484 mg, 2 mmol), hydroxylamine hydrochloride (556 mg, 8 mmol), ethanol (8 mL) and pyridine (4 mL) was stirred at room temperature for 45 minutes. The ethanol was evaporated and the residue triturated with water until a solid was obtained. Filtration afforded the title oxime (465 mg) as a cream-colored solid, m.p.: 143°-148° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:20]1([C:19](=[O:26])[CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Lithium diisopropyl amide (16.9 mL, 1.5 M in cyclohexane, 25.4 mmol) was added to THF (40 mL) at −78° C. A solution of 4-picoline (2.50 mL, 25.4 mmol) in THF (30.0 mL) was added dropwise to the LDA solution. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled down to −78° C. A solution of N-methoxy-N-methylbenzamide (1) (5.00 g, 29.6 mmol) in THF (20.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered, and the solvent was removed under vacuum to give the crude product. The crude material was triturated with hot hexane, and filtered to give 1-phenyl-2-(pyridin-4-yl) ethanone (2) as a yellow solid (3.53 g, 17.9 mmol, 70% yield).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH:18]=O.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1/[CH:18]=[C:8]1\[CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[C:9]\1=[O:11]
Reactant: O=C1CCCc2cccnc21
Reactant: Cc1[nH]cnc1C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]cnc1/C=C1\CCc2cccnc2C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of (3) (0.990 g, 6.73 mmol) and 5-methyl-1H-imidazole-4-carbaldehyde (0.890 g, 8.05 mmol) in 40% sulfuric acid (10 mL) was heated at 110° C. for 16 h. The reaction was cooled to rt. Crushed ice was added and the mixture was stirred vigorously, while NaOH(s) was added carefully. At pH ˜6 the product precipitated from solution. The mixture was stirred for 30 m at room temperature, and filtered to isolate (E)-7-((5-Methyl-1H-imidazol-4-yl)methylene)-6,7-dihydroquinolin-8(5H)-one (4) as a yellow solid, 1.39 gram (5.81 mmol, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([OH:24])=[O:23])[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1cccc(-c2c(C(=O)O)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from ethyl 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 483.9.