Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc(-c2ncco2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3ncco3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-oxazol-2-yl)benzoic acid (105 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. Purification by flash column chromatography (silica, gradient 96:4 to 93:7 methylene chloride/methanol) provided the title compound. ESI MS m/z 506.2 [M+H]+.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:17][S:18][CH2:19][C@H:20]([NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([NH:23][C:24]1([CH2:27][OH:28])[CH2:26][CH2:25]1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C.C(Cl)Cl>[C:1]([O:14][CH2:15][C@@H:16]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:17][S:18][CH2:19][C@H:20]([NH2:29])[C:21]([NH:23][C:24]1([CH2:27][OH:28])[CH2:25][CH2:26]1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC

Procedure:
To a solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-(hydroxymethyl)-cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting gel was diluted with DCM and sonicated for 3 minutes. The mixture was added to toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give (R)-3-((R)-2-amino-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate as an off white solid. 1H NMR (CDCl3): δ 7.85 (br s, 1H), 5.11-5.18 (m, 1H), 4.36 (dd, 1H), 4.14 (dd, 1H), 4.05 (br s, 1H), 3.59 (q, 2H), 3.50 (dd, 1H), 3.06 (dd, 1H), 2.80 (dd, 1H), 2.68-2.76 (m, 2H), 2.32 (q, 4H), 1.51-1.68 (m, 4H), 1.19-1.35 (m, 32H), 0.90-0.94 (m, 2H), 0.88 (t, 6H), 0.79-0.83 (m, 2H). LRMS [M+H]=629.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc([N+](=O)[O-])c(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (0.5 g, 2.2 mmol) in 4.4 mL of acetic acid, at 0° C., is added nitric acid (0.28 mL, 4.4 mmol) dropwise. The mixture is stirred at ambient temperature for 18 h. The mixture is poured into water and extracted with EtOAc. The organic layer is washed with water, sat. NaCl and dried over sodium sulfate. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography using hexane/EtOAc (6:1) to afford 4-benzyloxy-2-hydroxy-5-nitrobenzaldehyde as a yellow solid: 1H NMR (acetone-d6) δ 11.84 (s, 1H), 10.08 (s, 1H), 8.59 (s, 1H), 7.64-7.45 (m, 5H), 6.99 (s, 1H), 5.54 (s, 2H); (M−H)−=272.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[CH:18][C:17]=1[CH3:35].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[CH:18][C:17]=1[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4OC)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4OC)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2-methoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:7][N:6]=1
Reactant: COc1cc(C)c(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc(OC)cc2C)cc1
Yield: 81 %

Procedure:
According to Scheme 30 Step 1: The title compound was prepared from 5-bromo-2-methoxy-4-methylpyridine (1 eq, 15.8 mmol, 3.20 g) and 4-methoxyphenylboronic acid (1.5 eq, 23.8 mmol, 3.61 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 21 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 130 g SiO2) using AcOEt/MeOH (95/5) as the eluent to afford 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (12.8 mmol, 2.94 g, 81%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][S:43]([C:39]3[S:38][CH:42]=[CH:41][CH:40]=3)(=[O:45])=[O:44])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (prepared essentially as described in Example 1, 200 mg in 10 mL pyridine) was added a catalytic amount of N,N-dimethylaminopyridine followed by 139 mg 2-thiophenesulfonyl chloride and the mixture stirred at room temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate and dried over sodium sulfate. Concentration in vacuo gave the crude title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OC)cc1O
Yield: 86.7 %

Procedure:
6.00 g of 2′,4′-dihydroxypropiophenone was dissolved in 70 ml of acetone. Thereafter, 7.09 g of potassium carbonate and 3.03 ml of methyl iodide were successively added to the reaction solution. The reaction solution was then heated to reflux. Approximately 3 hours later, the reaction solution was stood to cool and then filtered. The filtrate was concentrated under a reduced pressure. A saturated sodium chloride solution and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with 2 N hydrochloric acid and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was solidified from hexane-ethyl acetate, so as to obtain 5.64 g of the subject compound. 1H-NMR (CDCl3) δ (ppm): 1.23 (t, J=7.2 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 6.40-6.45 (m, 2H), 7.65 (dd, J=1.6 Hz, 8.0 Hz, 1H), 12.8 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:27])[CH2:25][CH3:26])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:41]([Si:38]([CH3:40])([CH3:39])[O:27][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:28]=[CH:29][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=3)=[N:10][C:11]=2[CH:17]=1)=[CH:25][CH3:26])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-propan-1-one (0.073 g, 0.172 mmol) in CH2Cl2 (4 mL)) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.109 g, 0.413 mmol) and triethylamine (0.07 mL, 0.516 mmol). After stirring for 2 hours, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a yellow oil (0.065 g, 86%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29]O)=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][Cl:35])=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CO)ccc54)ccc3o2)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CCl)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(hydroxymethyl)indole-3-carbonitrile (0.66 g) and thionyl chloride (0.5 ml) in chloroform (20 ml) was stirred at room temperature for 3 hours. After neutralization with aqueous sodium hydrogen carbonate, the resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.67 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].B1(B2C3CCCC2CCC3)C2CCCC1CCC2.C[O-].[K+].[F:33][C:34]([F:65])([F:64])[C:35]1[CH:36]=[C:37]([CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1)[CH2:38][N:39]([CH3:56])[C:40](=[O:55])[C:41]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])=[CH:45][C:44](I)=[N:43][CH:42]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC(C)(C)C>[F:62][C:60]([F:61])([F:63])[C:58]1[CH:57]=[C:37]([CH:36]=[C:35]([C:34]([F:65])([F:64])[F:33])[CH:59]=1)[CH2:38][N:39]([CH3:56])[C:40](=[O:55])[C:41]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])=[CH:45][C:44]([CH2:3][CH2:2][CH2:1][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[N:43][CH:42]=1
Reactant: C=CCc1ccc(OC)cc1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C1CC2CCCC(C1)B2B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1ccc(CCCc2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.9 %

Procedure:
Deoxygenation of a solution of 89 mg (0.58 mmol) 4-allylanisole in 3 ml tetrahydrofuran by three freeze-thaw cycles was followed by addition of 73 mg (0.29 mmol) 9-borabicyclo[3.3.1]nonane dimer at room temperature under an atmosphere of argon. After 1.5 h 43 mg (0.58 mmol) potassium methoxide were added, and stirring was continued for 20 min. In one portion 250 mg (0.432 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) were added, followed by a suspension of 10 mg (0.043 mmol) palladium(II) acetate and 37 mg (0.086 mmol) 1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride in 0.5 ml tetrahydrofuran. The reaction mixture was heated at reflux for 2 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether and washing with two portions of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were extracted with tert-butyl methyl ether. The combined organic extracts were dried with magnesium sulfate and concentrated. Column chromatography afforded 184 mg (71%) of the title compound as a light-yellow amorphous mass.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17](=[O:28])[NH:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[C:8](Br)=[N:9][C:10]=1[C:11](F)(F)F)=O)C.S1([CH2:35][CH2:34][CH2:33][CH2:32]1)(=O)=O>[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:34]1([CH2:35][N:7]([CH2:6][CH2:10][CH3:11])[C:4]([C:6]2[N:7]3[CH2:16][C:17](=[O:28])[N:18]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:8]3=[N:9][C:10]=2[CH3:11])=[O:3])[CH2:32][CH2:33]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(Br)n1CC(=O)Nc1c(C)cc(C)cc1C
Reactant: O=S1(=O)CCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n1CC(=O)N2c1c(C)cc(C)cc1C
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-5-trifluoromethyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylic acid ethyl ester (20.12 g, 0.044 mmol) and silver triflate (11.87 g, 0.046 mol) in sulfolane (200 mL) was heated at 150° C. for 6 h. The resulting reaction mixture was cooled to room temperature and filtered through a short pad of celite. The final purification was achieved by a reverse-phase preparative HPLC to give the desired product as yellowish solid. Yield−5.24 g (24%). LC/MS: tR=1.89 min., MS: [M+H]=382. 6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester, scheme 6: (AA)
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=2)[C:9]([F:12])([F:11])[F:10])[CH2:4]1.[CH:29]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[C:40]([CH:43]=O)[CH:39]=[CH:38]2)([CH3:31])[CH3:30]>>[F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:43]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[C:33]([O:32][CH:29]([CH3:31])[CH3:30])[CH:34]=[CH:35][CH:36]=5)[N:41]=4)=[N:20][N:19]=3)[CH:14]=2)[C:9]([F:12])([F:10])[F:11])[CH2:4]1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)NC1(CF)CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CCC(CF)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B using tert-butyl 3-(fluoromethyl)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidine-3-ylcarbamate and substituting 8-isopropoxyquinoline-2-carbaldehyde in Step F. LCMS APCI (+) m/z 603 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[NH:13][C:12](=[O:24])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:25]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[OH:25][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=2)[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)=[N:11][C:12]1=[O:24]
Reactant: C#CCOc1ccc2[nH]c(=O)nc(-c3ccc(C(C)C)cc3)c2c1
Reactant: C1=C(c2ccccc2)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(O)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 2.00 g (6.28 mmol) 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one, 0.72 ml (6.28 mmol) epoxy-styrene, 0.143 g (0.628 mmol) benzyl-triethylammonium chloride (TEBA), 0.086 g (0.628 mmol) potassium carbonate and 5 ml dioxane is heated at 90° C. for 18 h. Aqueous work up followed by chromatography on silica gives 1-(2-hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]=O)=[C:5]([NH2:12])[N:4]=1.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>C(OCCO)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]2[C:5](=[N:12][C:22]([NH2:23])=[C:21]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:25][CH:24]=3)[N:10]=2)[N:4]=1
Reactant: CC(=O)Oc1ccc(CC#N)cc1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: [Na]
Solvent: CCOCCO
Product: CC(=O)Oc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1
Reaction time: 2 h

Procedure:
410 mg metallic sodium were dissolved while stirring in 100 ml of 2-ethoxy ethanol. Thereafter, 1100 mg 2,4,6-Triaminonitrosopyrimidine are added while stirring together with 1140 mg p-acetoxybenzylcyanide and the mixture is heated while stirring up to the boiling point. The color of the mixture changed from violet to brown. After two hours boiling under reflux, the heat is turned off and the reaction mixture is allowed to cool. Thereafter, 70 to 80% of the 2-ethoxyethanol is distilled under the vacuum of the water system, and the residue is taken up in 500 mls of water. After four-fold extraction with ether the pH is adjusted to pH 5 with 2 N hydrochloric acid. The precipitate is filtered, it is washed with a small amount of ice-cold acetone and recrystallized from 10% acetic acid. Further purification can be carried out over a silica gel column. The title compound obtained melts at 319°-321° C. (carbonization).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17]([S:37][CH3:38])=[N:18][C:19](=O)[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1C=CC=CC=1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17]([S:37][CH3:38])=[N:18][C:19](=[S:48])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSc1nc(=O)n(Cc2cccc(C(=O)OC(C)(C)C)c2)cc1C1c2ccccc2C=Cc2ccccc21
Solvent: c1ccccc1
Product: CSc1nc(=S)n(Cc2cccc(C(=O)OC(C)(C)C)c2)cc1C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of the product from step (v) (0.46 g) and Lawesson's reagent (0.18 g) in benzene (5 ml) was heated at reflux for 2 hours. The mixture was evaporated and purified by chromatography eluting with 10% ethyl acetate in toluene. Yield 0.5 g.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])O.[Na+]>O>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of 30 g (0.277 mol) of o-phenylenediamine and 150 g of polyphosphoric acid ester (ppE) is heated to 120°. When the diamine has dissolved, 33 g (0.205 mol) of p-cyanophenylacetic acid are added thereto in one portion and the mixture is heated to 120° for a further 20 minuIes. After cooling to room temperature the viscous mass is treated with about 1 l of water and made weakly basic with solid sodium hydrogen carbonate. The mixture is extracted with methylene chloride and the extract is washed with water, dried over sodium sulphate and evaporated to dryness. Recrystallization of the residue from methylene chloride/ethyl acetate gives 29 g (60%) of 2-(p-cyanobenzyl)benzimidazole, m.p. 201°-203°, as a colourless crystalline powder.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:27][C:26]4[CH:38]=[CH:39][CH:40]=[N:41][C:25]3=4)[CH:21]=[CH:22][CH:23]=1)=[O:16])[CH:9]=[CH:8]2)(=O)C>Cl>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:27][C:26]4[CH:38]=[CH:39][CH:40]=[N:41][C:25]3=4)[CH:21]=[CH:22][CH:23]=1)=[O:16])[CH:9]=[CH:8]2
Reactant: CC(=O)Oc1ccc2cc(C(=O)Nc3cccc(-n4c(=O)c(Cc5cccnc5)nc5cccnc54)c3)ccc2c1
Agent: Cl
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A mixture of 4-[3-(6-acetoxy-2-naphthoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (840 mg) in 3N hydrochloric acid (25 ml) was stirred at room temperature for 2 hours. Then the mixture was concentrated and poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 4-[3-(6-hydroxy-2-naphthoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (127 mg).