Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C@@H:9]([C@H:15]([OH:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([C:26]([F:27])([F:28])[F:29])[CH:3]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)c1ccccc1C
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C

Procedure:
4.7 g (0.0114 mol) of ethyl 2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-oxo-3-o-tolylpropionate were dissolved in methylene chloride, the solution was degassed in an ultrasonic bath and 200 mg of catalyst mix were added. The catalyst mix had been prepared beforehand by heating 78 mg of dichloro(p-cymene)ruthenium(II) dimer (RuCl2Cy) and 138 mg of BINAP in methylene chloride and ethanol at 50° C. for 1 h, followed by removal of the solvents.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9][C:10]3[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=3[N:19]([CH3:21])[CH3:20])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.CCOCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9]([C:10]3[CH:15]=[C:14]([N:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=3[N:19]([CH3:21])[CH3:20])=[O:32])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)c1ccc(N(C)C)c(Sc2nc3cc(Cl)ccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(N(C)C)c(S(=O)c2nc3cc(Cl)ccc3[nH]2)c1
Reaction time: 3 h

Procedure:
The product of step (a) above (550 mg) was dissolved in ethyl acetate (20 ml) and cooled to -10°. A solution of m-chloroperbenzoic acid (320 mg of 85%) in ethyl acetate (5 ml) was cooled to 0° and added to the above solution. After stirring at below 0° for 3 hours the solution was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine, and then dried and concentrated in vacuo. The residue was flash chromatographed to produce a yellow gum. Trituration with ether and petroleum ether produced the title compound as a pale yellow solid (125 mg), mp 161°-3°.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])=[O:9]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)c(Cl)n1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 2-chloro-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (0.116 g, 0.48 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.186 g, 0.48 mmol)[prepared according to Preparation 5] and N,N-diisopropylethylamine (0.42 ml, 2.42 mmol) in dichloromethane (2.49 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.25 g, 0.53 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (250 mg, 0.38 mmol, 78% yield) as a clear oil: LCMS (ES) m/e 570, 572 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Solvent: CC(C)O
Product: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2c(OC)c1OC
Yield: 20 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 20% yield from 6-chloro-indoline (1.1 eq.) and 4-chloro-6,7,8-trimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 139°-143° C.; GC/MS: 371 (M+); anal. RP18-HPLC RT: 4.70 min.).
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:33]([O:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:34]
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC(C#Cc1cccc(C)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the Compound of Example 39 (50 mg, 0.15 mmol), triethylamine (65 μL, 0.45 mmol) and 4-dimethylaminopyridine (10 mg, 0.07 mmol) in 3 mL of CH2Cl2 cooled at 0-5° C., methyl chloroformate (23 μL, 0.30 mmol) was added dropwise. The reaction mixture was stirred at r.t. overnight. Afterwards, it was evaporated to dryness and purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 8:2 affording the title product (0.28 g) as a brown oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[N:16]=1>>[CH3:21][C:17]1[N:16]=[C:15]([NH:14][C:4]([C:6]2[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[CH:20]=[CH:19][N:18]=1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Reactant: Cc1nccc(N)n1
Product: Cc1cc(Br)cc(C(=O)Nc2ccnc(C)n2)n1

Procedure:
The tide compound, white solid, MS (ISP): m/e=307.1, 309.2 (M+H)+, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 1. Step 5 was performed using 4-Amino-2-methylpyrimidine instead of 2-Amino-4-methylthiazole.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Na+].C(O)(=O)C.[S:19](=[O:21])=[O:20].[ClH:22]>O>[Cl:9][C:4]1[CH:3]=[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:7]=[N:6][C:5]=1[Cl:8]
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: Cl
Reactant: O=S=O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
5-Amino-2,3-dichloropyridine (20.0 g, 123 mmol) was dissolved in 600 ml conc. HCl, and the solution cooled to 5° C. Sodium nitrate (8.5 g, 123 mmol) in 75 ml water was added dropwise, below the surface of the reaction, at such a rate that the temperature was maintained below 10° C. The reaction was stirred 15 minutes after the addition was complete. This mixture was then added rapidly to a solution of 600 ml acetic acid saturated with sulfur dioxide and containing also cupric chloride dihydrate (1.5 g), the solution cooled to 5° C. The reaction PG,38 was stirred at 5° C. for 20 minutes, then room temperature for 30 minutes and finally poured into 12 liters ice/water. The resulting solids were filtered off, washed with water, and air-dried. Yield: 17.27 g, 57 percent, m.p. 48°-51° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10](O)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>C1C=CC=CC=1>[CH3:1][C:2]1[N:11]=[C:10]([Cl:25])[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc(O)c2cccc(Br)c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2cccc(Br)c2n1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
Part C: To a suspension of 14.2 g (59.5 mmol) of 2-methyl-4-hydroxy-8-bromo-quinazoline in 300 ml of benzene, 16 ml (120 mmol) of dimethylaniline and 6 ml (64 mmol) of phosphorus oxychloride were added under nitrogen. The light yellow solution resulting after heating to 80° C. while stirring was further heated at 80° C. for 3 hours. After cooling to room temperature 500 ml of benzene were added. The solution was extracted three times with 300 ml of 20% NaOH/water and 200 ml of water. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The product was purified by column chromatography over silicagel using ether/petroleum-ether 1:9 as the eluent. A total of 12.3 g of 2-methyl-4-chloro-8-bromo-quinazoline was obtained as a white solid (80% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([S:34]([N:37]5[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]5)(=[O:36])=[O:35])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 359 was prepared as a white solid (TFA salt) from compound 4 and compound 360 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.59 (1 H, s), 9.29 (1 H, s), 8.72-8.78 (2 H, m), 8.63-8.66 (1 H, m), 8.61 (1 H, d), 8.22 (1 H, dd, J=8.8, 2.4 Hz), 5.51 (1 H, quin, J=8.9 Hz), 3.37 (8 H, s), 2.46-2.60 (2 H, m), 2.13-2.34 (4 H, m), 1.87-2.01 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 478.9.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[OH:26])([O-:15])=[O:14].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CN(C)CCO
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DEAD (2.6 ml)was added to a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and Ph3P (4 g) in THF (50 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]ethyl}-dimethylamine. It was hydrogenated under H2 atmosphere to give {2-[4-(tert-butyl)-2-aminophenoxy]ethyl}-dimethylamine.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([CH2:10][S:11][C:12]3[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH2:21].[CH2:22]=O>CC#N>[OH:21][CH2:22][N:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=[C:12]1[S:11][CH2:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][S:1][C:5]=12
Reactant: C=O
Reactant: c1ccc2[nH]c(SCc3nccc4ccsc34)nc2c1
Reactant: O
Solvent: CC#N
Product: OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To 478.7 mg (1.60 mmol) of 2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole. 1/10 H2O (Ia-1) were added 8 ml of CH3CN and 324.6 mg (4.00 mmol) of 37% aqueous solution of HCHO, and the mixture was stirred for 15 minutes at 70° C. After evaporation the solvent under reduced pressure, the residual crystals were washed with ether, whereby 420.9 mg (Yield : 80.3%) of the objective compound (Ib-4), 1-hydroxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole was obtained as crystals.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]=[CH:24][NH:25][C:26]3[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=3)[CH:21]=2)[NH:16][CH:15]=1.C([O:39][CH2:40][CH3:41])C.[CH2:42]([OH:44])[CH3:43]>CN.C(=O)(O)[O-].[Na+]>[C:40]([OH:39])(=[O:44])/[CH:41]=[CH:29]\[C:30]([OH:32])=[O:31].[C:30]([OH:32])(=[O:31])/[CH:29]=[CH:43]\[C:42]([OH:39])=[O:44].[CH2:33]([O:32][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:24]=[N:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:13][CH2:12][NH2:3])=[CH:36][CH:35]=1)[CH3:34]
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(NC=Nc2ccc3[nH]cc(CCN4C(=O)c5ccccc5C4=O)c3c2)cc1
Reactant: CCO
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc(NC=Nc2ccc3[nH]cc(CCN)c3c2)cc1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of the product of Stage (i) in absolute ethanol (16 ml) and methylamine in ethanol (33% w/w 8 ml) was stirred at room temperature for 1.5 h. The solution was diluted with 8% sodium bicarbonate solution (ca 50 ml) and the mixture extracted with ethyl acetate (3×20 ml). The extracts were dried (Na2SO4), reduced to dryness under vacuo and the residue chromatographed on silica (A). The required fractions were collected and reduced to dryness. The residue (71 mg) was dissolved in a minimum quantity of absolute ethanol and a solution of maleic acid (47 mg) in ethanol (2 ml) added. The mixture was reduced to dryness and the foam obtained stirred with dry diethyl ether (ca 5 ml). The resulting solid was collected and dried to give the title compound as a powder (78 mg), m.p. 100°-105°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:30].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:30][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH:12]=1
Reactant: [Br-]
Reactant: Cc1ccc(-c2ccc3ccc4cc(C(C)(C)C)cc5ccc2c3c45)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(Br)c3ccc4cc(C(C)(C)C)cc5ccc2c3c45)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.6 %

Procedure:
Next, a mixed solution of 1.5 g of 7-t-butyl-1-(4-methylphenyl)pyrene, 25 ml of dichloromethane and 8 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 1.7 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2 hours and 20 ml of water was poured into the solution, followed by extraction with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 10 ml of methanol was added, followed by standing overnight. The precipitated solid was filtered and then vacuum-dried to obtain 1.9 g of 1-bromo-7-t-butyl-3-(4-methylphenyl)pyrene.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C@@H:6]([CH3:19])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:4].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:22][N:5]([C@@H:6]([CH3:19])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[C:3](=[O:4])[C:2]([F:20])([F:21])[F:1]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a stirred solution of methyl (S)-4-[2-(trifluoroacetamido)-1-propoxy]benzoate (695 mg, 2.28 mmol) and K2CO3 (630 mg, 4.56 mmol) in DMF (10 ml) was added MeI (210 ml, 3.37 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with H2O and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with EtOAc-CHCl3 (1:19, v/v) as eluent to give methyl (S)-4-[2-[(N-methyl)trifluoroacetamido]-1-propoxy]benzoate (720 mg, 99%) as a white solid. mp 73–75° C.; 1H-NMR (CDCl3) δ 1.36–1.39 (m, 3 H), 2.96 and 3.10 (each s, total 3 H), 3.89 (s, 3 H), 3.99–4.14 (m, 2 H), 4.84–4.92 (m, 1 H), 6.88–6.92 (m, 2 H), 7398–8.00 (m, 2 H); MS (FAB) m/z 320 (M++1); Anal. Calcd for C14H16F3NO4: C, 52.67; H, 5.05; F, 17.85; N, 4.39. Found: C, 52.76; H, 5.09; F, 17.53; N, 4.32.
Reaction SMILES: [OH:1][CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[N:17]1[CH:22]=CC=CC=1.[O:23]1CCCC1.C(Cl)(=O)OC1C=CC=CC=1>O>[O:23]=[C:22]1[N:17]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:1]1
Reactant: COC(=O)CCC(O)C(=O)c1ccccc1
Reactant: c1ccncc1
Reactant: C1CCOC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: O
Product: COC(=O)CCC1OC(=O)N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of methyl 4-hydroxy-5-oxo-5-phenylpentanoate (4.50 g), pyridine (1.80 ml) and tetrahydrofuran (30 ml) was slowly added phenyl chlorocarbonate (2.80 ml) at 0° C. and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dissolved in acetic acid (30 ml), ammonium acetate (7.79 g) was added and the mixture was refluxed for 3 hrs. The reaction mixture was concentrated and the obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography, and methyl 3-(2-oxo-4-phenyloxazolin-5-yl)propionate was obtained as colorless crystals (3.57 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 104–105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:45]([F:48])([F:47])[F:46])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][C:16]=3[F:40])[C:10]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:9]2)[CH:7]=1.[C:49](Br)(=[O:52])[CH2:50][CH3:51].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CO>[CH2:41]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:17][C:16]=2[F:40])[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49](=[O:52])[CH2:50][CH3:51])[CH:3]=[CH:4][C:5]=2[C:45]([F:46])([F:47])[F:48])[N:9]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Reactant: CCC(=O)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 60 %

Procedure:
The title compound was synthesized by reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G) with propionyl bromide (3 equivalents) and DBU (1.1 equiv) according to the method of Example 69. The material was obtained in 60% yield as a pale yellow solid, mp 181°-183° C.; homogeneous by TLC in 9:1 CH2Cl2 -MeOH; mass spectrum (FAB) m/e 796 (M+K)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]1[NH:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=3[C:16]=1[CH2:15]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Cc1cc(C)cc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1ccc(F)cc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH2:13]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:14][CH3:15]>>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N+:18]2[CH:19]=[CH:20][N:16]([CH2:13][CH2:14][CH3:15])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCCn1ccnc1
Reactant: ClCCCCc1ccc(Cl)cc1
Product: CCCn1cc[n+](CCCCc2ccc(Cl)cc2)c1
Product: [Cl-]
Temperature: 130 °C

Procedure:
Add 7.13 g (0.035 mole) of 1-chloro-4-(4-chlorobutyl)benzene to 3.52 g (0.032 mole) of 1-propyl-1H-imidazole and heat to 130° C. for 18 hours. Follow the progress of reaction by NMR (CDCl3). At the completion of the reaction, cool to room temperature to obtain the title compound.