Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:32])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)ncn2Cc1ccc2nc(SC)oc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)oc2c1
Yield: 63.5 %

Procedure:
A solution of 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl thio)benzo[d]oxazole (683 mg, 2.1 mmol) and m-CPBA (471 mg, 2.7 mmol) in DCM (10 mL) was stirred at 0° C. for 3.5 h. The reaction mixture was washed with aq Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (455 mg, 63.6%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.88 (m, 2H), 7.44 (m, 2H), 7.18 (s, 1H), 6.83 (s, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH:21]=[CH:22][CH3:23].C(Cl)Cl>O>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])/[CH:21]=[CH:22]/[CH3:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: CC(=O)OO
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(O)C12OC1(C)CCCC2(C)C

Procedure:
21 g. of 40 % peracetic acid and 0.6 g. of sodium acetate were added under nitrogen to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene (19.4 g.) and 12 g. of sodium acetate in 35 ml. of CH2Cl2 at 20°. The reaction mixture was left 2 more hours with stirring and it was then poured into 250 ml. of water.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccccc1)c(OCc1ccccc1)c2=O
Temperature: 90 °C
Yield: 90.8 %

Procedure:
Intermediate 174, N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.266 mmol) in a mixture of acetonitrile (10 ml) and water (10 ml) was treated with phenylboronic acid (0.042 g, 0.35 mmol), sodium carbonate (0.062 g, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.124 g (91% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.61 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.49 (2H, d, J=6.1 Hz, NCH2), 7.02 (2H, m, aromatics), 7.29–7.51 (12H, m, aromatics and NH). HRMS (ESI+) calculated for C30H29FN3O4 [M+H+]: 514.2142. Found: 514.2137.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)CCCC(C)(C)[NH+]1[O-]>ClCCl>[CH3:8][C:3]([CH3:9])([CH:2]=[O:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Agent: CC1(C)CCCC(C)(C)[NH+]1[O-]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
Methyl 3-hydroxy-2,2-dimethyl-propanoate (52.4 g, 396.49 mmol) is dissolved in dichloromethane (495 mL) and the mixture is cooled in an ice-water bath. Trichloroisocyanuric acid (101.36 g, 436.14 mmol) is added portionwise, followed by 2,2,6,6-tetramethylpiperidine-N-oxide (6.20 g, 39.65 mmol). The mixture is stirred at 0° C. for 15 min and then allowed to warm to RT and stirred for an additional 60 min. The solid is then filtered through CELITE® and rinsed with dichloromethane (300 mL). The filtrate is washed with a saturated solution of Na2CO3 in water. The organic phase is dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (41.24 g, 80%) as a greenish oil. The product is used without further purification in the next reaction step. 1H NMR (400 MHz, CDCl3); δ 1.34 (6H, s), 1.34 (6H, s), 3.74 (3H, s), 9.64 (1H, s).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:7][C:8]1[C:9]([C:5]#[N:6])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(Br)c1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ncccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trimethylsilylcyanide (10 g, 0.1 mol, 1.25 eq) were added to a solution of 3-brom-pyridine-N-oxide (80 mmol, 1 eq) in 80 mL of CH2Cl2. After that a solution of dimethylcarbamoylchloride (10.8 g, 0.1 mol, 1.25 eq). dissolved in 20 mL of dry CH2Cl2 was added drop-wise to the stirred solution. The mixture was stirred overnight at r.t. An aqueous solution of K2CO3 (80 mL, 10%) was added and the mixture was stirred for additional 10 min. The organic layer was separated and the aqueous layer was again extracted two times by means of 30 mL of CH2Cl2. The organic phases were combined and dried by means of Na2SO4. The product was used without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: N#Cc1cc2c(I)n[nH]c2cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Yield: 47.3 %

Procedure:
To a solution of 5.8 g of 3-iodo-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile in 70 mL of dichloromethane were added 13.1 mL of diisopropylethylamine, 2.4 g of tetra-n-butylammonium iodide and 12.0 g of trityl chloride at room temperature, and stirred at this temperature for a day. The solution was evaporated, diluted with ethyl acetate, washed successively with saturated ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10), to afford 5.2 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)=[O:4].C(O)(C)C.[Cl-].[NH4+]>[Fe].C(Cl)(Cl)Cl>[NH2:22][C:19]1[CH:20]=[CH:21][C:12]([S:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(Sc2ccc([N+](=O)[O-])cc2C(=O)OC)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2C(=O)OC)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1.09 g of methyl 2-(4-methoxycarbonylphenylthio)-5-nitrobenzoate obtained in the same procedures as described in Reaction Scheme (24) of Example 1 and 1.75 g of iron powder, were added 3 ml of isopropyl alcohol and an aqueous solution of ammonium chloride (0.05 g of ammonium chloride and 0.95 ml of water). The mixture was stirred for 10 minutes at 85° C. Chloroform was added to the reaction mixture. The mixture was filtered with celite, and was subsequently washed with chloroform. A mixture of the filtrate and the washing was washed with saturated brine, and was subsequently dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, 0.996 g of methyl 5-amino-2-(4-methoxycarbonylphenylthio)benzoate (yellow viscous substance) was obtained (Reaction Scheme (31) described below).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[NH2:5][C:6]1O[CH:8]=[C:9]([CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[C:10]=1[C:11]#[N:12]>C(O)C>[NH2:3][C:2]1[NH:4][C:6]2=[N:5][CH:8]=[C:9]([CH2:13][CH2:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[C:10]2=[C:11]([NH2:12])[N:1]=1
Reactant: CCOC(=O)c1ccc(CCc2coc(N)c2C#N)cc1
Reactant: N=C(N)N
Solvent: CCO
Product: CCOC(=O)c1ccc(CCc2cnc3[nH]c(N)nc(N)c2-3)cc1

Procedure:
To a solution of guanidine free base (prepared from 105 mg of guanidine hydrochloride and 60 mg of sodium ethoxide) in 10 mL of anhydrous ethanol are added 284 mg (1 mmol) of ethyl 4-[2-(2-amino-3-cyanofur-4-yl)ethyl]benzoate. The mixture is heated at reflux for 30 hrs and the solvent then evaporated in vacuo. The residue is chromatographed on silica gel, eluting with 5:95 methanol:methylene chloride, to yield ethyl 4-{2-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)ethyl}benzoate as a light brown solid; m.p. 202°-204° C. Mass spectrograph calculated for C17H19N5O2 : 325.1538, Found: 325.1543.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C[OH:18]>>[Cl:1][C:2]1[C:3]([S:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: [O-][n+]1cccc(Cl)c1SCc1ccccc1
Product: O=S(Cc1ccccc1)c1c(Cl)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4.7 g of the starting sulfide (Sec Example 24 above) dissolved in 25 ml of methanol were added a pinch of Na2WO4 followed by 1.5 g of 50% aqueous hydrogren peroxide. The mixture was stirred at room temperature for four hours, filtered, and the solid was washed with NaHSO3 solution, followed by water. The dried solid 2.2 g, melting point of 119-122° C., gave an NMR which indicated mostly the desired sulfoxide but some contamination by the sulfone and sulfide. A second crop of 1.1 g, melting point 118-123° C., was also obtained. Attempts to recrystallize from toluene and from ethyl acetate gave material still contaminated by sulfone, so the mixture was finally separated by preparative HPLC and then recrystallized from ethyl acetate, having a melting point of 124-126° C. The elemental analysis for C,N&N, the infrared spectrum, and the NMR spectrum were all consistent with the proposed structure.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[CH2:45][O:44]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.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([CH2:45][OH:44])[CH2:48][CH2:49][NH:50][C:38]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:41])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:17]1)=[O:39]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
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: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Yield: 46.3 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.35 g, 2.41 mmol), HATU (0.55 g, 1.45 mmol) and iPr2NEt (0.70 mL, 4.0 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.22 g, 46%).
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si](C)(C)C.O.C1(C)C=CC=CC=1>C(O)(=O)C.O1CCOCC1>[OH:1][C:2]([CH3:31])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7](=[O:8])[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CCCCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCO
Reaction time: 6 h
Yield: 32.2 %

Procedure:
7-(3-Hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane [0.5 g; prepared as hereinbefore described in Example 3(iii)], water (10 ml.) and glacial acetic acid (20 ml.) were left to stand together at room temperature for 6 hours. The solution was then evaporated in vacuo at a temperature below 50° C. Ethyl acetate (150 ml.) was added to the residue and the resulting solution was washed with water until the pH of the washings was 5, dried over sodium sulphate, and evaporated to give a crude product (0.37 g.). The crude product was subjected to preparative thin layer chromatography on silica gel, using a mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, eluting twice, to give 7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.12 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]Br.S(=O)(=O)(O)O>S([O-])([O-])(=O)=O.[Ag+2].O>[Br:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Reaction time: 16 h

Procedure:
28.2 g of p-fluoro-nitrobenzene were added to 20° C. to 10.4 ml of bromine and then 20 ml of water followed by 180 ml of concentrated sulfuric acid were added thereto at 0° C. 34 g of silver sulfate were added to the mixture and the temperature was allowed to rise to 20°-25° C. and the mixture was stirred for 16 hours and was poured into water. The mixture was filtered and the filter was washed with water and methylene chloride. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in isopropyl ether and crystallized therefrom. The mixture was filtered and the product was washed to obtain 8.2 g of 3-bromo-4-fluoro-nitrobenzene melting at 59° C. Using the procedure of Example 1, the latter was reacted to obtain 0-(4-nitro-2-bromo-phenyl)-hydroxylamine melting at 122° C.
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:20])=[O:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:14])=[CH:11][CH:10]=1)[S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:19])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2ccc(C(=O)O)cc2)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(N(Cc3ccccc3)S(=O)(=O)c3cn(C)cn3)cc2)CC1

Procedure:
To a stirred solution of 4-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid (37 mg, 0.1 mmol) in dry dimethylformamide (1 ml) was added N-methylpiperazine (20 mg, 0.2 mmol), triethylamine (28 μl, 0.2 mmol) then 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified using preparative HPLC to afford the title compound as a clear oil (30 mg, 66% HPLC retention time 4.5 min. Mass spectrum (ES+) m/z 454 (M+H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.95 eq of benzene was added and the reaction mixture stirred at ice bath temperature for 10 minutes. The cooling bath was removed, the reaction was allowed to warm to room temperature, and stirred. After 26 h at room temperature, an HPLC analysis indicated about 86% cyanuric chloride conversion to 2-chloro-2,6-bisphenyl-1,3,5-triazine. The stirring was continued for 24 h at room temperature. The HPLC analysis showed the cyanuric chloride conversion to 92% with >96% being 2-chloro-4,6-bisphenyl-1,3,5-triazine and less than 2% of 2,4,6-trisphenyl-1,3,5-triazine. The result was confirmed by LCMS
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH2:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH2:10][NH:11][C:15]1[C:16]([Cl:20])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cc(Br)cc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(CNc2nc(Cl)ncc2Cl)c1
Yield: 85.6 %

Procedure:
To a solution of 1-(3-bromo-5-methoxyphenyl)methanamine (2.57 g, 11.9 mmol) and 2,4,5-trichloropyrimidine (2.4 g, 13 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (3.3 g, 24 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (3.7 g, 87%). LCMS for C12H10BrCl2N3O (M+H)+: m/z=361.9, 363.9.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[PH4+].C(CCCC(OC)=O)=O.[CH:16]1[C:25]2[C:20](=[CH:21]C=CC=2)[CH:19]=[CH:18][C:17]=1/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CCCCCC.O1CCCC1>[CH3:4][C:3]1[CH:21]=[C:20]2[C:25](=[CH:1][CH:2]=1)[CH:16]=[C:17](/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19]2
Reactant: COC(=O)CCC/C=C/c1ccc2ccccc2c1
Reactant: [Li]CCCC
Agent: COC(=O)CCCC=O
Agent: [PH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C/c1ccc2cc(C)ccc2c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
1.6M Butyl lithium solution in hexane (6.7 ml) was added to a stirred suspension of the phosphonium salt (5.0 g) in dry tetrahydrofuran (50 ml) at 5° C. under nitrogen. The dark solution was cooled to -50° C. and methyl 4-formylbutyrate (1.5 g) was added dropwise. The pale solution was stirred for 30 minutes at about -60° C., allowed to warm to -10° C., poured on to ice-sodium chloride solution and extracted with ether. The extract was washed with dilute hydrochloric acid, dried and evaporated and the residue was extracted with petroleum spirit to give a mixture of (Z) and (E) esters as an oil (2.8 g). Isomerisation by the method described in (b) above gave the title compound (2.1 g), m.p. 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:17]([O-])=O.[Na+].[ClH:21]>O>[ClH:21].[NH:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:17]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(C(F)(F)F)c(NN)c1
Reaction time: 1 h

Procedure:
A mixture of 500 mg (2.15 mmol) of ethyl 3-amino-4-(trifluoromethyl)benzoate (from Step D) and 5 mL of concentrated hydrochloric acid was stirred at 0°-5° C. as a cold solution of 173 mg (2.50 mmol) of sodium nitrite in 0.8 mL of H2O was added. After being stirred at 0°-5° C. for 1 hour, the mixture was filtered while cold, and the filtrate was poured into a solution of 1.02 g (4.5 mmol) of stannous chloride dihydrate in 2 mL of concentrated hydrochloric acid stirred at 0° C. Precipitation occurred immediately. The mixture was kept in an ice bath for 1.5 hours, and then the solid was collected by filtration. The solid is dried to yield the title compound suitable for use in the pyrazole ring formation reaction. In this experiment, the material was characterized as the free base by partitioning the solid hydrochloride between 2N Na2CO3 (aqueous) and ethyl acetate. The ethyl acetate phase was washed with brine, dried, filtered, and concentrated to yield 375 mg (70%) of the free base of the title compound as a pale yellow oil; homogeneous by TLC in 4:1 hexane-EtOAc and 98:2 CH2Cl2 --MeOH. 200 MHz 1H NMR (CD3OD) for free base: δ1.38 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 7.34 (d, J=8 Hz, 1H), 7.48 (d, J= 8 Hz, 1H), 8.05 (s, 1H).