Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:27]2[S:28][C:24]([CH3:23])=[N:25][N:26]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1nnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reaction time: 2 h
Yield: 45.2 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), 5-methyl-[1,3,4]thiadiazol-2-ylamine (37 mg, 0.32 mmol) and N,N-diisopropylethylamine (166 μL, 0.95 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-acetamide (58 mg, 45%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H19ClN4O4S [M+] 442.05, found 443 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.89 (m, 4 H, 2×CH2), 2.75 (s, 3 H, ArCH3), 3.32 (s, 3 H, SO2CH3), 4.97 (m, 1 H, OCH), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.68 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 10.33 (brs, 1 H, NH).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:23])=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1)[CH:2]=C.[O:24]1CCOCC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[Cl:23][C:5]1[C:4]([CH2:1][CH:2]=[O:24])=[CH:9][N:8]=[C:7]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=12
Reactant: C1COCCO1
Reactant: C=CCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CC=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3.90 g, 11.2 mmol) in 1,4-dioxane (75 mL) and water (15 mL) was treated with NaIO4 (9.62 g, 45.0 mmol) and OsO4 (2.5% in t-BuOH, 5.65 mL, 0.450 mmol). The mixture was stirred at rt for about 1 h then diluted with EtOAc (100 mL). The solids were collected by filtration and the cake was washed with EtOAc (2×100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (50 mL) then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel to give 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetaldehyde as a mixture of aldehyde and hydrate (1.45 g, 37%); LC/MS (Table 2, Method b) Rt=2.51 min; MS m/z 349 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>C(Cl)Cl>[C:18]([Si:15]([CH3:17])([CH3:16])[O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a mixture of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol (as prepared in the previous step, 1.50 g, 7.68 mmol) and t-butyl-dimethylsilyl chloride (1.51 g, 9.99 mmol) in 60 mL of DCM was slowly added imidazole (3.09 g, 45.4 mmol). After stirring at RT for 16 h, the mixture was treated with 40 mL of DCM and washed with H2O (30 mL), 15% aqueous citric acid (30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-5% EtOAc/hexane) to give 1.82 g (65%) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): δ 7.85 (d, 2H, J=8.8 Hz), 7.52 (d, 2H, J=8.8 Hz), 3.59 (s, 2H), 1.35 (s, 6H), 0.86 (s, 9H), −0.04 (s, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:42]1([CH2:52][NH2:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:42]1([CH2:52][NH:53][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccc2ccccc12)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of naphthalen-1-ylmethyl-amine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 582.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](O)=[O:17])[C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.ON1C2C=CC=CC=2N=N1.[Br:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[Br:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:16]([C:11]2[C:10]3[NH:9][C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2](=[O:1])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3[nH]c12
Reactant: Nc1ccc(OCCCBr)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCCCBr)cc1)c1cccc2c(=O)c3ccccc3[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 9,10-dihydro-9-oxo-4-acridinecarboxylic acid (1.5 g) and 1-hydroxybenzotriazole (1.1 g) in DMF (50 ml) was stirred at room temperature for 10 min. The product of part (ii) above (1.5 g) was then added followed by dicyclohexylcarbodiimide (1.3 g), and the mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with water and extracted with dichloromethane. The combined, dried organic extracts were concentrated to give the title compound (0.5 g) which was recrystallised from acetonitrile, MP 126°.
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)=[O:35])[CH:32]=3)[N:27]=[C:26]([O:42][CH3:43])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>C(OCC)C.C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)([C:13]4[S:12][CH:16]=[CH:15][N:14]=4)[OH:35])[CH:32]=3)[N:27]=[C:26]([O:42][CH3:43])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: c1cscn1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3cncn3C)ccc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3nccs3)c3cncn3C)ccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
BuLi 1.6 M in hexane (0.0111 mol) was added dropwise at −70° C. under N2 flow to a mixture of thiazole (0.0111 mol) in diethyl ether (30 ml). The mixture was stirred at −70° C. for 1 hour. A mixture of intermediate (9) (0.0074 mol) in THF (30 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, hydrolyzed and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.1 g (91.1%) of 4-(3-chlorophenyl)-2-methoxy-α-(1-methyl-1H-imidazol-5-yl)-α-(2-thiazolyl)-6-quinolinemethanol (intermediate 10).
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]=[CH:23][C:22]=4[O:31]CC4C=CC=CC=4)[C:16](=[O:39])[CH2:15]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:42])#[N:2].[BH4-].[Na+].CCOC(C)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]=[CH:23][C:22]=4[OH:31])[C:16](=[O:39])[CH2:15]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:42])#[N:2]
Reactant: C=CCOc1ccc(OCc2ccccc2)c(CN2CCN(Cc3cncn3Cc3ccc(C#N)c(F)c3)CC2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(O)c(CN2CCN(Cc3cncn3Cc3ccc(C#N)c(F)c3)CC2=O)c1

Procedure:
To a solution of the product of Step G (800 mg, 1.38 mmol) in 20 mL of THF at room temperature was added Pd(PPh3)4 (203 mg, 0.176 mmol), followed by sodium borohydride (86.2 mg, 2.28 mmol). The reaction was stirred for several hours, then poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was taken up in methanol, filtered, and the solids were dried in vacuo to afford the titled product as an off-white solid.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][O-:19].[Na+]>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18](=[O:19])[CH:2]([CH3:4])[CH3:3])=[C:12]([O:17][C:8](=[O:9])[CH:10]([CH3:15])[CH3:11])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: C[O-]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen there was added 17 g. of sodium methoxide. By distillation under reduced pressure, 50 ml. of liquid was removed and the mixture was then cooled and under an atmosphere of nitrogen 25 g. of isobutyryl chloride was added rapidly at 5-25° C. The reaction mixture was stirred at 25° C. for one hour and then was warmed to 70° C. and the solvent was removed by distillation. The resulting residue was slurried in 400 ml. of diethyl ether, and the slurry was filtered to remove about 10 g. of insoluble solid. The ethereal layer in the filtrate was separated, washed with dilute aqueous sodium hydroxide solution and then with water. There was thus obtained an ether solution of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone. To this solution there was added a solution obtained by adding 4 ml. of hydrochloric acid to 25 ml. of water, and the resulting mixture was shaken. The crystalline solid which formed was collected on a filter and dried at 70° C. There was thus obtained 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline powder which melted at 221- 223° C. (dec.)(uncorr.).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl-benzoate are dissolved in 60 ml of dry dimethylsulphoxide (DMSO) and combined with 5.55 g (31.5 mmol) of N-benzylpiperazine and 4.35 g (31.5 mmol) of potassium carbonate. The mixture is stirred for 12 hours at 90° C. After cooling, the reaction mixture is poured into 200 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and distilled off in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate and n-heptane.
Reaction SMILES: [CH2:1](O)C.[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C=O.C(=O)([O-])O.[Na+]>C(O)=O>[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][N:29]([CH3:1])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCO
Reactant: COc1cc(N2CCCNCC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(N2CCCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 84 %

Procedure:
To a 2 ml ethanol/2 ml water mixed solution of 60 mg (0.14 mmol) of the compound obtained in Example 133, 30 mg of paraformaldehyde and 1 ml of formic acid were added, and the mixture was heated under reflux for 24 hours. Then, the reaction mixture was brought to room temperature, an aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 53 mg (84%) of the captioned compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].[C:16](=[O:18])=[O:17].Cl>C(OCC)C>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:16]([OH:18])=[O:17])=[C:8]([F:15])[CH:9]=1
Reactant: O=C=O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Freshly titrated n-butyl lithium (27.0 ml, 1.39 M in hexanes) is added slowly (over about 30 minutes) to a −78° C. solution of diethyl ether (90 ml) containing 1,4-dibromo-2,5-difluorobenzene (1, 10.22 g, 0.038 mol). The resulting yellow solution is stirred at −78° C. for 2 hours to give a yellow suspension. Several pellets (˜10) of dry ice are added to the suspension, which is then allowed to warm slowly to room temperature as it degasses (approximately 40 minutes). The resulting suspension is acidified with a 1 M aqueous solution of hydrochloric acid (500 ml), and the product extracted with diethyl ether (5×200 ml). The combined organics are washed with water (4×100 ml) and filtered. The ether solution is concentrated to approximately 200 ml under reduced pressure, and the product extracted into a saturated aqueous solution of sodium bicarbonate (3×200 ml). The combined aqueous extracts are washed with methylene chloride (3×100 ml) and acidified with hydrochloric acid. The product is extracted with diethyl ether (3×200 ml), and the combined organic extracts washed with water (2×200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.74 (dd, JH-F=8.5 Hz, 6.5 Hz, 1H), 7.84 (dd, JH-F=10.0 Hz, 5.5 Hz, 1H), 13.7 (br, 1H, CO2H). 19F{1H} NMR (282 MHz, DMSO-d6): δ −114.0 (d, JF-F=17.0 Hz, 1F), −113.6 (d, JF-F=17.0 Hz, 1F). 13C{1H} NMR (75 MHz, DMSO-d6): δ 113.6 (dd, JC-F=23.5 Hz, 10.0 Hz), 118.4 (dd, JC-F=26.5 Hz, 2.5 Hz, CH), 120.0 (dd, JC-F=19.0 Hz, 12.0 Hz), 122.2 (d, JC-F=28.0 Hz, CH), 154.4 (dd, JC-F=245.0 Hz, 5.5 Hz, CF), 156.8 (dd, JC-F=251.5 Hz, 4.0 Hz, CF), 163.4 (m, CO2H).
Reaction SMILES: [Br:1][CH2:2][O:3][CH3:4].C1(C)C=CC=CC=1.[CH2:12]([P:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>CCCCCC>[Br-:1].[CH2:12]([P+:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:2][O:3][CH3:4])[CH3:13]
Reactant: CCP(CC)CC
Reactant: COCBr
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[P+](CC)(CC)COC
Product: [Br-]
Yield: 80 %

Procedure:
62 g (0.5 moles) of bromomethylmethyl ether (a reagent available from Tokyo Chemical Industry Co., Ltd.) was added dropwise in 236 g (0.5 moles) of a 25% toluene solution of triethylphosphine (HISHICOLIN (registered trademark) P-2, a trade name of Nippon Chemical Industrial Co., Ltd.), and the mixture was allowed to react at 70 to 80° C. for 6 hours. After completion of the reaction, hexane was added for crystallization, thereby obtaining 97 g (percent yield: 80%) of a crystal of triethyl(methoxymethyl)phosphonium bromide. 86 g (0.3 moles) of lithium bis(trifluoromethylsulfonyl)imide (a reagent available from Kanto Chemical Co., Inc.) was added to 73 g (0.3 moles) of this triethyl(methoxymethyl)phosphonium bromide, and the mixture was allowed to react in an aqueous system. Subsequently, the reaction mixture was stirred for aging at room temperature for 3 hours. After completion of stirring, a lower layer (product) was separated. The separated product was washed with pure water four times and then washed with hexane four times. After completion of washing, the product was dried in vacuo at 100° C. and at a degree of vacuum of 0.5 kPa for 5 hours. Confirmation of the obtained product was carried out by means of 1H-NMR, 13C-NMR, 31P-NMR and 19F-NMR. A yield of the product (colorless transparent liquid) was 104 g (percent yield: 78%), and it was confirmed by 3P-NMR that its purity was 98% or more.
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[NH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16]>CN(C=O)C>[C:19]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][C:14]=1[C:15]1[NH:16][N:5]=[N:4][N:3]=1)[O:10][C:9]1[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=1[NH2:7])#[N:20].[C:15]([C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[NH2:7])=[CH:12][C:13]=1[C:19]1[NH:20][N:5]=[N:4][N:3]=1)#[N:16]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccccc2N)ccc1-c1nnn[nH]1
Product: N#Cc1ccc(Oc2ccccc2N)cc1-c1nnn[nH]1
Temperature: 80 °C

Procedure:
Ammonium chloride (0.46 g, 8.5 mmol) and sodium azide (0.55 g, 8.5 mmol) were added to a solution of 4-(2-aminophenoxy)phthalonitrile (0.5 g, 2.1 mmol) in DMF (20 ml). The reaction mixture was heated at 80° C. for 48 hours, cooled to room temperature and evaporated to dryness in vacuo. The crude compound was purified on silica gel (eluent: methylene chloride:methanol (4:1)) to give 2-[3-cyano-4-(1H-tetrazol-5yl)phenoxy]aniline or 2-[4-cyano-3-(1H-tetrazol-5-yl)phenoxy]aniline as yellow crystals (yield: 0.64 g (95%)). 1H—NMR (CD3OD) in ppm: δ 5.2 (2H,s), 6.6 (1H, d,d), 6.85 (1H,d,d), 6.95 (1H,d,d.), 7.0 (1H,d,d.), 7.45 (1H,d), 7.65 (1H,d). 13C—NMR (CD3OD) in ppm: δ 105.3; 118.7; 119.4; 119.7; 120.7; 123.0; 128.3; 133.3; 138.3; 138.3; 140.7; 142.8; 158.9; 163.4.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC>C(Cl)(Cl)Cl>[C:2]([Cl:4])(=[O:3])[CH2:1][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of oxalyl chloride (53.5 g, 422 mmol) in 150 mL of chloroform was added drop wise to a solution of stearic acid (30.0 g, 105 mmol) in 250 mL of chloroform. After stirring overnight at ambient temperature the solution was concentrated and co-evaporated twice with chloroform. Drying under vacuum for 1 hour yielded a quantitative yield of a white solid. 1H-NMR (CDCl3): δ=2.85 (t, 2H), 1.70 (q, 2H), 1.30 (m, 28H), 0.85 (t, 3H) ppm. 13C-NMR (CDCl3): δ=173.6, 47.1, 31.9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 28.4, 25.1, 22.7, 14.1 ppm. FT-IR: ν=2292, 2853, 1799 (C═O stretch), 1466, 953, 720, 680 cm−1.