Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:58])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:18][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][C:15]=2[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[CH:6][C:5]=1[OH:57].[OH-].[Na+].Cl>CCO.O>[OH:57][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=3)=[CH:16][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:58])=[O:2]
Reactant: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.980 g, 1.21 mmol, 1 eq) in EtOH (20 mL) was added 50% NaOH (10 mL) and the reaction was heated at reflux overnight. It was cooled to rt, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford the title compound (0.92 g, 96%) as a white foam. 1H NMR (DMSO-d6) δ 13.60 (bs, 1H); 11.40 (bs, 1H); 8.59 (bt, 1H); 8.00-7.92 (m, 6H); 7.74-7.65 (m, 4H); 7.56 (d, 1H); 7.25-7.10 (m, 5H); 6.08-6.00 (m, 2H); 3.66 (bd, 2H); 3.52 (bd, 2H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.27 (m, 8H); IR (KBr) 3350, 2950, 2850, 1670, 1620, 1550, 1500, 1460, 1320, 1230, 1220, 1160, 1120, 1095, cm−1; mass spectrum [(−)APCI], m/z 792 (M−H)−; Anal. Calcd. for C44H41F6NO6: C, 66.58; H, 5.21; N, 1.76, Found: C, 64.86; H, 5.22; N, 1.68.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][CH3:14])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:15](Cl)(Cl)=[O:16].[CH3:19][S:20][CH2:21][CH2:22][NH2:23]>ClCCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:14])[C:15]([NH:23][CH2:22][CH2:21][S:20][CH3:19])=[O:16])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CSCCN
Reactant: CNc1cnc(-c2cncc(F)c2)s1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CSCCNC(=O)N(C)c1cnc(-c2cncc(F)c2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a solution of [2-(5-fluoropyridin-3-yl)-thiazol-5-yl]-methyl-amine (0.4 g, 1.91 mmol) in DCE (5 mL) at 0° C. was added phosgene (1.3 mL, 2.5 mmol, 20 wt % solution in toluene). After 5 min, DMAP (0.5 g, 4.1 mmol) was added in one portion and the ice bath was removed. After another 5 min, the mixture was heated to reflux and stirred for 20 min. The reaction was cooled to ambient temperature and half of the solution was transferred to a vial and to this was added 2-(methylthio)ethanamine (0.183 g, 2.0 mmol) and DMAP (0.244 g, 2.0 mmol). The reaction was capped and heated at 80° C. overnight. The reaction was quenched upon addition of ethyl acetate and 0.1 N HCl. The layers were separated, and the organic layer was washed separately with saturated aqueous NaHCO3 and brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an off-white solid (0.253 g, 81%): mp 117-119° C.; 1H NMR (300 MHz, CDCl3) δ 8.94 (br s, 1H), 8.50 (d, J=2.7 Hz, 1H), 7.99-7.94 (m, 1H), 7.54 (s, 1H), 5.37 (m, 1H), 3.53 (q, J=11.8, 5.5 Hz, 2H), 3.43 (s, 3H), 2.72 (app t, J=6.6 Hz, 2H), 2.13 (s, 3H); ESIMS m/z 327.1 (M+H); m/z 325.0 (M−1).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: O=C(NCCCCc1ccccc1OCC(O)CO)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccccc1OCC(O)CO
Yield: 67.2 %

Procedure:
Cbz-protected amine 31 (2.1 g, 5.6 mmol) was dissolved in methanol (50 mL) and Pd/C (0.46 g, 5% wet.) was added in methanol (20 mL). The reaction mixture was stirred for 3 h at 1 atmosphere of hydrogen, then the solution was filtered through a pad of silica gel. The solvent was then evaporated to give free amine 32 (0.9 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (m, 2H), 1.50 (m, 2H), 2.92 (m, 1H), 3.22–4.05 (br s, 4H), 3.43 (m, 2H), 3.93 (m, 1H) 6.82 (d, 2H), 7.07 (d, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1(C2N=CNC=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrC1C=C(OC)C=CC=1>>[C:13]1([C:4]2[N:3]=[CH:2][N:1]([C:6]3[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=3)[CH:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(-n2ccnc2)c1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: COc1cccc(Br)c1
Product: Oc1cccc(-n2cnc(-c3ccccc3)c2)c1
Yield: 57 %

Procedure:
Following the procedure for preparation of 3-(1H-imidazol-1-yl) phenol (preparation 29), 4-phenylimidazole (20 g, 0.138 mole) and 3-bromoanisole (32 ml, 0.25 mole) were reacted to give the title compound in 57% yield; mp 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[CH2:19]([N:21]([CH2:24]C)[CH2:22]C)C.ClC(OC1C=CC=CC=1)=[O:28].CNC>O1CCCC1.CO>[CH3:19][N:21]([CH3:24])[C:22]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1)=[O:28]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (249 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, and then triethylamine (0.21 ml) and phenyl chloroformate (0.19 ml) were added dropwise thereto while cooling in an ice water bath, followed by stirring at room temperature for 15 min. To the reaction mixture was added 2 M solution of dimethylamine in methanol (4.0 ml), followed by stirring for 2 days. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3, then ethyl acetate) to provide the titled compound (219 mg, 68%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.C([Sn](CCCC)(CCCC)[C:23]1[C:27]([CH3:28])=[CH:26][S:25][C:24]=1[CH3:29])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][C:24]1[S:25][CH:26]=[C:27]([CH3:28])[C:23]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([CH3:17])[C:12]=1[C:15]#[N:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)csc1C
Reactant: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (40 mg, 0.12 mmol), tributyl(2,4-dimethylthiophen-3-yl)stannane (140.3 mg, 0.35 mmol) and PdCl2(PPh3)2 (24.55 mg, 0.03 mmol), were mixed with 0.5 mL degassed dioxane and 0.5 mL degassed DME under nitrogen in a microwave vial. The reaction was run at 145° C. in the microwave for 30 min. Water was added, the mixture was extracted with CH2Cl2 and the organic layer was concentrated. The crude product was purified on HPLC to give 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 34%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[I:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[I:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: O=C1COCC(=O)C1
Reactant: Cc1ccc(C=O)cc1I
Reactant: Cn1[nH]c(=O)cc1N
Product: Cc1ccc(C2C3=C(COCC3=O)Nc3c2c(=O)[nH]n3C)cc1I
Yield: 42.7 %

Procedure:
2H-Pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol), 3-iodo4-methyl-benzaldehyde (0.18 g, 0.75 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.084 g, 0.75 mmol) were processed as described in Example 26C to provide 0.14 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.49 (s, 3H), 4.0 (s, 2H), 4.52 (q, 2H), 4.88 (s, 1H), 7.05 (dd, 1H), 7.16(d, 1H), 7.56 (d, 1H), 9.58 (bs, 1H), 10.03 (s, 1H); MS (ESI−) m/z 436 (M−H)−; Anal. calcd for C17H16N3IO3.0.5 C2H5OH: C, 46.97;H, 4.16; N, 9.13. Found: C, 46.60;H, 4.42; N, 9.32.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1
Yield: 86.1 %

Procedure:
4.57 g 3-amino-2-chloropyridine (36 mmol) and 30 mL pyridine were mixed in an ice bath. 5.0 g benzoyl chloride (36 mol) was then added. After return to room temperature and reaction for 4 hr, the reaction was quenched by water. After extraction three times by ethyl acetate, an ethyl acetate layer was collected and washed by 1M HCl solution. After drying, filtration, concentration, and purification by silicon-gel column, 7.21 g solid was obtained, with a yield of 88%.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[OH:30])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: OC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-Iodoxybenzoic acid (1.42 g, 2.3 mmol; 45% purity) was added to an ice cold solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-methanol (520 mg, 1.5 mmol) in THF/DMSO 1/1 (28 ml). The reaction mixture was stirred for 1 h at ambient temperature, ice water/brine 1/1 was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/saturated aqueous ammonium chloride solution 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (404 mg, 1.2 μmol; 78%) as colorless solid. MS: m/e=339.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(SCCCCl)cc1
Product: O=S(CCCCl)c1ccc(F)cc1

Procedure:
Prepared by Procedure S and Scheme AA using 3-chloropropyl 4-fluorophenyl sulfide and 1 eq m-CPBA: 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.28-7.21 (m, 2H), 3.65 (m, 2H), 2.94 (m, 2H), 2.28 (m, 1H), 2.06 (m, 1H); ESMS m/e: 220.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:41][O:42][Si](C)(C)C)[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>ClCCl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:41][OH:42])[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CO[Si](C)(C)C)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.73 g (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-2-methoxy-3-trimethylsilanyloxymethyl-phenyl)-amide are dissolved in 15 ml dichloromethane, combined with 5.34 ml of a 5 M solution of hydrogen chloride in isopropanol and stirred for 30 minutes at ambient temperature. The mixture is divided between dichloromethane and saturated aqueous sodium hydrogen carbonate solution, the aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(-c3cccnc3)c2)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2ccnc(-c3cccnc3)c2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.09 mL, 0.79 mmol) was dropwise added to a solution of the methoxy compound (30.5 mg, 0.08 mmol) prepared in Example 24 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (35 mg, 79%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N+:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[CH3:19])[CH3:9].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Cl:31][C:32]([C:35]1[N:40]=[C:39](C(Cl)(Cl)Cl)[N:38]=[C:37]([C:45]([Cl:48])([Cl:47])[Cl:46])[N:36]=1)([Cl:34])[Cl:33]>C1(C)C=CC=CC=1>[CH2:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]1=[CH:19][C:39]1[N:40]=[C:35]([C:32]([Cl:31])([Cl:34])[Cl:33])[N:36]=[C:37]([C:45]([Cl:47])([Cl:48])[Cl:46])[N:38]=1)[CH3:9]
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1C(=Cc2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)Sc2ccccc21

Procedure:
Within a period of half an hour, 10 g (0.1 mol) of triethylamine was added dropwise to a suspension of 35 g (0.1 mol) of 3-ethyl-2-methyl-benzothiazolium-p-toluene-sulfonate and 43 g (0.1 mol) of tris-trichloromethyl-s-triazine in 300 ml of toluene. After completion of the addition the reaction mixture was stirred for half an hour, until the exothermic reaction ceased; the product which had precipitated was filtered off and dried. Compound 2 was obtained in nearly pure form in a quantity of 40 g. By evaporating the toluene in vacuo and treating the solid residue with ethanol, another 9 g of the product resulted. After recrystallization from 2-methoxy-ethanol 40 g (82%) of yellow needles of melting point 238° to 241° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]1=[O:25]>C(Cl)Cl>[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:19][C:18]1=[O:25]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)cc(=O)n1C
Solvent: ClCCl
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(=O)n1C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (0.85 ml, 5 mM) was added dropwise to a stirred solution of 1,6-dimethyl-4-hydroxypyridin-2-one [0.7 g, 5 mM] (obtainable as described by Castillo et al., Bull. Soc. Chim. France, 1982, 257) in dry methylene chloride (15 ml). The resulting solution was kept at room temperature for 18 hours, washed with aqueous sodium carbonate solution, dried (MgSO4) and the solvent evaporated. The residual solid was purified by flash chromatography (Merck 9385) using ether as eluant to give 1,6-dimethyl-4-(trifluoromethanesulphonyloxy)-2-pyridone as a solid (0.67 g), m.p. 65°-67° C.; NMR: 2.41(3H,s, CH3) 3.53(3H,s, NCH3), 6.05(1H,s, CH), 6.38(1H,s, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)=[O:8].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14]([Cl:24])=[O:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of (12(b)) (495 mg; 1.5 mmole) in dichloromethane (25 mL) was cooled in an ice bath and DMF (1 drop) and oxalyl chloride (0.175 mL; 2.0 mmole) added dropwise. The solution was stirred at ambient temperature under argon for 4 hours. The dichloromethane and excess oxalyl chloride were removed in vacuo. The residue was azeotroped uith toluene (2×15 mL) to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carbonyl-chloride (12(c)) which was used crude in the next step.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]1[C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[C:17]1([NH:16][C:11]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1C(=O)Sc2ccccc21
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1C(=O)Sc2ccccc21

Procedure:
470 mg (2.11 mmols) of ethyl 2-oxo-2,3-dihydro-3-benzo[b]thiophene-carboxylate and 206 mg (2.22 mmols) of aniline in 3 ml of xylene are boiled under reflux for 5 hours. After cooling, the product is precipitated by adding hexane (3 ml). After further dilution with 5 ml of ether and stirring, crystalline N-phenyl-2-oxo-2,3-dihydro-3-benzo[b]thiophene-carboxamide with a melting point of 140°-142° is obtained and filtered off.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CI.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[F:1][C:2]1([F:16])[CH2:3][C:4]([CH3:19])([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Temperature: -78 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To a solution of benzyl 3,3-difluorocyclobutanecarboxylate (2 g, 8.84 mmol) and MeI (2.202 mL, 35.4 mmol), in THF (15 mL) at −78° C. under a N2 atmosphere was added a solution of KHMDS (35.4 mL, 17.68 mmol, 0.5 M in toluene). The reaction mixture was then stirred at −78° C. for 6 h after which it was allowed to warm to RT and stir overnight. The reaction mass was then quenched with a saturated aq. solution of NH4Cl and extracted with diethyl ether (3×25 mL). The combined organic fractions were washed with water, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 20% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 296A as a pale yellow liquid (1.2 g, 56.5%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.23 (m, 5H), 5.17 (s, 2H), 3.22-2.97 (m, 2H), 2.60-2.28 (m, 2H), 1.51 (s, 3H).
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]([CH:18]=O)=O)[CH:13]=[CH:14][CH:15]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:18]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=2)[N:4]=1
Reactant: COc1cccc(C(=O)C=O)c1
Reactant: CSC(=N)NN
Solvent: O
Product: COc1cccc(-c2cnnc(SC)n2)c1
Yield: 78.7 %

Procedure:
3-(Methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.01 g, 79%) was prepared from methyl hydrazinecarbimidothioate (0.58 g, 5.50 mmol) and 3-methoxyphenylglyoxal monohydrate (1.00 g, 5.50 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[NH:14][C:13]=2[CH:12]=[C:11]([Br:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:19])[F:20])[N:14]([CH3:23])[C:13]=2[CH:12]=[C:11]([Br:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)nc2c(OCc3ccccc3)cc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution of 40 g (107.8 mmol) 4-benzyloxy-6-bromo-2-trifluoromethyl-1H-benzimidazole in acetone (600 ml) was treated with 44.7 g (323.4 mmol) potassium carbonate and the reaction was refluxed for 1 h. 13.4 ml Methyl iodide were added and the mixture was stirred for 2 h. After cooling to room temperature, the precipitate was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (petroleum ether/ethyl acetate=15:1) afforded 13.2 g (32%) of the title compound as a white solid. m.p. 141°-142° C.