Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:13]>>[NH2:13][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [OH-]
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 145 °C
Yield: 34 %

Procedure:
A solution of 2,6-dichloronicotinic acid (10 g, 46.9 mmol, Aldrich 90%) was dissolved in concentrated ammonium hydroxide (100 mL, 29.4%, Fisher) and heated at 130-160° C. in a pressure bottle for 1-2 days before solvent was removed in vacuo. The residue was treated with water and the pH was lowered to ˜8 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried, concentrated and the crude product was recrystallized from ethyl acetate to give 2-Amino-6-chloro-nicotinic acid as white crystalline (2.74g, 34 % yield). HRMS, observed: 172.0042, Calcd for M+: 172.0040
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)C.B(Br)(Br)Br>ClCCl>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1
Reactant: CCOc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3O)cc1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
To a suspension of 10-[(2′-ethoxy-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 33 (0.281 g, 0.518 mmol) in dry dichloromethane (2.6 mL) at 0° C. under nitrogen was added dropwise a 1.0 M solution of boron tribromide in dichloromethane (2.6 mL, 2.6 mmol) over ca. 5 minutes. The reaction mixture was allowed to warm to room temperature and then stirred for 5 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a tan solid (0.210 g). Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave the title compound (0.042 g, 16%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][CH2:21][C:10]2([CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH2:1]([N:8]1[CH2:23][CH2:22][CH2:21][C:10]2([CH2:13][NH:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCCN(Cc3ccccc3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCCC3(CNC3)C2)cc1
Temperature: 60 °C

Procedure:
tert-butyl 6-benzyl-2,6-diazaspiro[3.5]nonane-2-carboxylate (0.18 g) was mixed with CH2Cl2 (1 mL) and TFA (1 mL), then heated at 60° C. for 2 minutes and concentrated to dryness to provide the title compound as the trifluoroacetic acid salt.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C=O)C.[Br:11][C:12]1[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:11][C:12]1[CH:19]=[C:18]([CH2:20][Br:3])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1ccc(CO)cc1Br
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(CBr)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
To a stirring cold (0° C.) solution of POBr3 (0.6 mol, 171 g) in CH2Cl2 (1.6 L) was added dropwise DMF (0.75 L) over a period of 1 h. A solution of 2-bromo-4-hydroxymethyl-benzaldehyde (0.49 mol, 107 g) in CH2Cl2 (0.75 L) was then added dropwise over a period of 0.5 h. The resulting mixture was stirred at 0° C. for another 0.5 h and was then transferred via a cannula to a cold (0° C.) stirring aqueous solution of NaHCO3 (3 L, 1M) while maintaining the temperature of the aqueous solution below 10° C. After the transfer was completed, the mixture was extracted with CH2Cl2 (2 L). The organic extract was separated and washed with H2O (3 L) and brine (3 L), dried with MgSO4 (anhyd.) and concentrated to give an oil . The residue was extracted with 10% EtOAc/hexane (2 L). The organic extract was washed with H2O (2×1 L), dried with MgSO4 (anhyd.) and concentrated to a solid which was swished with hexane to give 154 g (˜100%) of the title compound as a beige solid.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH2:63]>CN(C)C=O.O>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:63][C:62]4[C:64]([CH3:68])=[CH:65][CH:66]=[CH:67][C:61]=4[CH3:60])=[O:23])=[CH:25][CH:26]=3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
To a stirred mixture of 4-(4-cyclohexylquinazolin-2-ylamino)benzoic acid (300 mg, 0.86 mmol), HATU (327 mg, 0.86 mmol) and Hunig's base (555 μL, 4.3 mmol) in dimethylformamide (1 mL) was added 2,6-dimethylaniline (620 mg, 5.12 mmol) and the reaction was heated to 50° C. overnight. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N sodium bicarbonate and a 5% aqueous solution of lithium chloride, then was extracted with 1 N hydrochloric acid. The combined acidic washes were neutralized with 1 N sodium hydroxide and extracted with dichloromethane. These combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue obtained was purified by recrystallization from methanol to give 4-[(4-cyclohexylquinazolin-2-yl)amino]-N-(2,6-dimethylphenyl)benzamide as a white solid (99.8 mg, 27%). 1H NMR (400 MHz, CDCl3): δ 8.06-7.94 (m, 5H), 7.82-7.71 (m, 2H), 7.58-7.49 (br s, 1H), 7.39-7.33 (m, 2H), 7.16-7.12 (m, 3H), 3.53-3.44 (m, 1H), 2.65-2.59 (s, 5H), 2.31 (s, 6H), 2.04-1.91 (m, 4H), 1.89-1.70 (m, 3H), 1.60-1.31 (m, 3H). MS (EI) for C29H30N4O: 451.0 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)cc1C(F)(F)F
Temperature: 145 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 4-methoxy-2-(trifluoromethyl)phenylacetic acid (500 mg) in acetic acid (5.00 mL) was added a 48% aqueous hydrobromic acid solution (5.00 mL), followed by stirring at 145° C. overnight. The reaction suspension was concentrated under reduced pressure, to the residue was then added water, and the resulting solid was collected by filtration to obtain 4-hydroxy-2-(trifluoromethyl)phenylacetic acid (300 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cn2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCc1cn(-c2ccc(Cl)cn2)cn1

Procedure:
Following the general method described in example 388, 1-(5-chloro-pyridin-2-yl)-1H-imidazole-4-carboxylic acid ethyl ester was reacted with diisobutylaluminum hydride. After hydrolytic workup and chromatography the title compound was obtained as a light brown crystalline solid. Mp. 82-87° C. (AcOEt/Et2O), MS: m/e=210 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:17][C:18]([NH2:20])=[O:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:2]([CH3:1])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=1)(=[O:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)NC(=O)CN(C)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 138 °C
Yield: 85.6 %

Procedure:
In this example, a catalytic amount (about 4 drops) of concentrated sulfuric acid was added to a suspension of 3.5 g of (N-methyl-3-trifluoromethylbenzylsulfonamido)-acetamide in 7 mls (7.6 g) of acetic anhydride at room temperature. The mixture was heated for 2 hours at about 138° C. and then poured into ice water and extracted into methylene chloride. The methylene chloride extract was washed with aqueous 5 wt.% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness affording 3.4 g of a white solid. The solid was triturated with ethyl ether affording 2.17 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:54][CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:51]=3)[C:46]2=[O:59])[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(OCC)(=O)C.C(O)CCC>[C:55]([C:50]1[CH:51]=[C:52]2[C:47](=[CH:48][CH:49]=1)[C:46](=[O:59])[N:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:54][CH2:53]2)([CH3:56])([CH3:57])[CH3:58]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(Br)cccc1N1CCc2cc(C(C)(C)C)ccc2C1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCc2cc(C(C)(C)C)ccc2C1=O
Temperature: 100 °C

Procedure:
1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (208 mg, 1 eq), Acetic acid 2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (203 mg, 0.472 mmol), XPHOS (14 mg, 0.06 eq), potassium phosphate tribasic (200 mg, 2 eq), n-butanol (2.8 mL) and water (0.93 mL) were charged to a 50 mL round bottom flask, and then nitrogen gas was bubbled through the mixture for 10 minutes, before adding Pd(dba)2 (8 mg, 0.03 eq). The resulting mixture was heated to 100° C. for 40 minutes, and by TLC analysis there was no starting material remaining. The reaction mixture was cooled to room temperature and then added ethyl acetate (150 mL) and water (40 mL). Partitioned and separated the layers and washed further with water (2×40 mL) and then brine (1×40 mL). Finally, the ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated and pumped to dryness to afford the title compound which was used in the next step without any further purification ((M+H)+=664).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]1([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](OC)=[O:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].C[Ti+3]>[C:5]1([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3([OH:25])[CH2:2][CH2:1]3)[CH2:22][CH2:23]2)(=[O:16])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Reactant: CC[Mg]Br
Agent: C[Ti+3]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)N1CCC(C2(O)CC2)CC1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Ethylmagnesium bromide (0.110 mL, 3.0 M in THF, 0.330 mmol) was added dropwise to a stirring solution of methyl 1-(naphthalen-1-ylsulfonyl)piperidine-4-carboxylate (0.100 g, 0.30 mmol) and methyltitanium triisopropoxide (0.300 mL, 1.0 M in THF, 0.300 mmol) in tetrahydrofuran (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 2 h then quenched with water (15 mL). The resulting flocculent solution was diluted with ethyl acetate (15 mL) and filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (1:1) to yield 0.035 g (35%) of the title compound as a white foam. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 0.36-0.41 (m, 2 H), 0.67-0.71 (m, 2H), 0.90-0.98 (m, 1 H), 1.72 (dd, J=13.89, 1.26 Hz, 2 H), 2.49 (td, J=12.51, 2.53 Hz, 2 H), 3.91-4.02 (m, 2 H), 7.54-7.60 (m, 3 H), 7.92 (d, J=8.34 Hz, 1 H), 8.06 (d, J=8.08 Hz, 1 H), 8.21 (d, J=7.33 Hz, 1 H), 8.76 (s, 1 H); ESI-MS: m/z 332.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:21]([CH3:27])[C:22]([O:24]CC)=[O:23]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:27][CH2:21][C:22]([OH:24])=[O:23])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxyindole (1.15 g, 5 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (200 mg, 5 mmol). After stirring for 30 minutes, ethyl bromopropionate (900 mg, 5.0 mmol) was added and the mixture was stirred at ambient temperature for 1 h, additional sodium hydride (100 mg, 2.5 mmol) was added. After stirring for 10 minutes, additional ethyl bromopropionate (180 mg, 1.0 mmol) was added. The mixture was stirred at ambient temperature overnight. The solvent was removed under high vacuum, the residue was dissolved in water (10 mL) and tetrahydrofuran (10 mL), NaOH (500 mg) was added and stirred for 2 h. After acidifying to pH 4-5, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with brine and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (1-5% ethyl acetate in methylene chloride) to give 3-(5-benzyloxyindolyl)propanic acid as white solid. The solid was dissolved in N,N-dimethylformamide (20 mL), K2CO3 (1.0 g) and iodomethane (840 mg) were added and the reaction was stirred at ambient temperature for 3 h. The mixture was concentrated under high vacuum and residue was purified by flash column chromatography (methylene chloride) to give the title compound as a colorless oil (1.10 g, 71%). 1H-NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.3 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (d, J=10.2 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 6.96 (dd, J=8.8, 2.5 Hz, 1H), 6.39 (d, J=3.1 Hz, 1H), 5.10 (s, 2H), 4.41 (t, J=6.9 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH2:34][CH3:35])[N:33]=[C:29]5[C:28](CC5C=CC(C6C=CC=CC=6C6N(C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)N=NN=6)=CC=5)=[C:27]4[CH2:73][CH3:74])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:87]([C:89]1[N:90](CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[C:91]2[N:92]([N:94]=[C:95]([CH2:97][CH3:98])[CH:96]=2)[N:93]=1)[CH3:88].C(C1NC2N(N=C(CC)C=2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)N=1)C.C(C1N=C2C=C(CC)N(CC3C=CC(C4C=CC=CC=4C4N(C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)N=NN=4)=CC=3)N2N=1)C>>[CH2:34]([C:32]1[N:33]=[C:29]2[CH:28]=[C:27]([CH2:73][CH3:74])[N:26]([CH2:25][C:22]3[CH:21]=[CH:20][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4[N:8]([C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)([C:81]5[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=5)[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=5)[N:9]=[N:10][N:11]=4)=[CH:24][CH:23]=3)[N:30]2[N:31]=1)[CH3:35].[CH2:87]([C:89]1[NH:90][C:91]2[N:92]([N:94]=[C:95]([CH2:97][CH3:98])[CH:96]=2)[N:93]=1)[CH3:88]
Reactant: CCc1nc2c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Reactant: CCc1cc2n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)nn2n1
Agent: CCc1nc2cc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCc1nn2nc(CC)c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c2[nH]1
Product: CCc1cc2[nH]c(CC)nn2n1

Procedure:
In the same manner as described in Example 38, 0.31 g of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-2,6-diethyl-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 48a), 2.60 g of 2,6-diethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 48b), 0.20 g of 2,6-diethyl-7-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 48c) and 2.04 g of 2,6-diethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 48d) were obtained from 2.00 g of 2,6-diethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.72-7.75 (m, 2H), 7.60-7.62 (m, 2H), 3.80-3.83 (m, 6H), 3.03-3.14 (m, 4H); MS (ESI−) M/Z 431 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.N1C(C)=CC=CC=1C.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:37][CH:36]([S:39]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1)(=[O:41])=[O:40])[CH3:38]
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (70 mg, 0.18 mmol) and 2,6-lutidine (123 μL, 0.882 mmol) in CH2Cl2 (2 mL) was treated with isopropylsulfonyl chloride (49.9 mg, 0.35 mmol). The reaction was stirred overnight and then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigourously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:10]1=[O:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[NH4+]>C(OCC)(=O)C.CCCCCC>[CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([CH2:14][CH2:15][OH:16])[C:10]1=[O:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](c1ccccc1)N1CCC(CCO[Si](C)(C)C(C)(C)C)(Cc2ccc(F)cc2)C1=O
Agent: [F-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1CCC(CCO)(Cc2ccc(F)cc2)C1=O

Procedure:
Prepare by the method of Example 17.4 using 1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4 mmol) to give, after chromatography on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound as diastereomers: Rf=0.49 and 0.27 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: C(COCC(CNC1C=C2C(=CC=1)N(CCCS([O-])(=O)=O)/C(=C\C=C\C=C1/S(=O)(=O)C3C=CC=CC=3C/1=O)/C2(C)C)=O)(O)=O.[Na+].[C:46]([CH2:49][O:50][CH2:51][C:52]([N:54]([CH3:87])[C:55]1[CH:86]=[CH:85][C:58]2[N:59]([CH2:78][CH2:79][CH2:80][S:81]([O-:84])(=[O:83])=[O:82])/[C:60](=[CH:62]/C=C/C=C3\S(=O)(=O)C4C=CC=CC=4C\3=O)/[S:61][C:57]=2[CH:56]=1)=[O:53])([OH:48])=[O:47].[Na+].CO/C=C/C=C1/S(=O)(=O)C2C=CC=CC=2C/1=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:46]([CH2:49][O:50][CH2:51][C:52]([N:54]([CH3:87])[C:55]1[CH:86]=[CH:85][C:58]2[N+:59]([CH2:78][CH2:79][CH2:80][S:81]([O-:84])(=[O:82])=[O:83])=[C:60]([CH3:62])[S:61][C:57]=2[CH:56]=1)=[O:53])([OH:48])=[O:47]
Reactant: CN(C(=O)COCC(=O)O)c1ccc2c(c1)S/C(=C\C=C\C=C1\C(=O)c3ccccc3S1(=O)=O)N2CCCS(=O)(=O)[O-]
Agent: CC(=O)[O-]
Agent: CC1(C)/C(=C/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)N(CCCS(=O)(=O)[O-])c2ccc(NCC(=O)COCC(=O)O)cc21
Agent: CO/C=C/C=C1\C(=O)c2ccccc2S1(=O)=O
Solvent: CC(=O)O
Product: Cc1sc2cc(N(C)C(=O)COCC(=O)O)ccc2[n+]1CCCS(=O)(=O)[O-]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Sodium 3-{(2Z)-5-{[(Carboxymethoxy)acetyl]methylamino}-2-[(2E,4Z)-4-(1,1-dioxido-3-oxo-1-benzothien-2(3H)-ylidene)but-2-enylidene]-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl}propane-1-sulfonate (24) and Sodium 3-{(2Z)-6-{[(Carboxymethoxy)acetyl]-methylamino}-2-[(2E,4Z)-4-(1,1-dioxido-3-oxo-1-benzothien-2(3H)-ylidene)but-2-enylidene]-1,3-benzothiazol-3(2H)-yl}propane-1-sulfonate (25). A mixture of the quaternary salt (22 or 23, 0.5 mmol) and enol ether 9 (0.625 g, 2.50 mmol) in 20 mL of a chloroformacetic acid mixture (1:1) was magnetically stirred at 60° C. under nitrogen. A solution of 0.200 g of sodium acetate in 5 mL of acetic acid was added by drops to the reaction mixture. The stirring was continued for an additional 24 h. After cooling the dye 25 crystallized from the reaction mixture and was separated by filtration and purified by recrystallization from acetic acid. The reaction mixture containing dye 24 was evaporated in a vacuum, and the pure dye was isolated by chromatography over silica gel, eluting with acetone-acetic acid (5:1), followed by recrystallization from acetic acid.